CN108640985B - Method for purifying somaglutide - Google Patents
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Abstract
The invention discloses a method for purifying Somaltulip, which comprises the following steps: pretreating a crude product of the Somaltul peptide to obtain a crude peptide water solution of the Somaltul peptide; step two, taking tetraalkylsilane bonded silica gel filler as a stationary phase, taking phosphoric acid as a mobile phase A and acetonitrile as a mobile phase B, and carrying out first HPLC purification to remove impurities of the soma peptide fragment; removing the solvent to obtain a first-step sample solution of the somaglutide; step four, taking the octaalkylsilane bonded silica filler as a stationary phase and taking an ammonium acetate solution as a mobile phase A; performing HPLC purification for the second time by taking acetonitrile as a mobile phase B to remove impurities with physical and chemical properties similar to those of the somaglutide; removing the solvent to obtain a second sample solution of the somaglutide, and obtaining a somaglutide sample solution; according to the invention, after two times of HPLC purification, the purity of the sample obtained for the first time is 92%, and the purity of the sample obtained for the second time is 99%, so that the purity and yield of the somaglutide are improved.
Description
Technical Field
The invention relates to the field of peptide purification, in particular to a method for purifying somaglutide.
Background
The name of Chinese: somaltulide
The name of English: sermaglutide
The peptide sequence is:
H-His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys(Octadecanedioic-γ-Glu-PEG2-PEG2)-Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly-OH；
the first long-acting GLP-1 analog, developed by Danish Novonide, shares 97% homology with human glucagon-like peptide-1 (GLP-1). Compared with the somaglutide, the modified somaglutide has the advantages of enhanced hydrophilicity, inhibition of hydrolysis of DPP-4 enzyme, prolonged biological half-life period, long-acting blood sugar reduction, promotion of islet cell regeneration, prolongation of gastric emptying and other functions, and has various functions of reducing blood sugar, promoting islet cell regeneration, slightly prolonging gastric emptying and the like, and the application prospect is wide.
The somaglutide is used as a new generation of hypoglycemic drugs based on incretins, has long action time, fully retains multiple physiological activities of natural GLP-1, can safely and effectively reduce blood sugar and can protect multiple cardiovascular hazard factors. The somaglutide injection is subcutaneously injected, the peak time of blood concentration is 20-14 hours, the half-life period is 11-13 hours, the injection is injected once a day, 24-hour blood sugar control is provided, and the pharmacokinetic characteristic of the somaglutide injection is not influenced by gender or age. The somaglutide is a revolutionary medicine in the field of treatment of type 2 diabetes mellitus.
The solid-phase synthesis of the Somaltulide can generate various impurities which influence the purity and yield of a sample, and the Somaltulide sample obtained by separation by the existing purification technology has low purity and low yield; the present invention solves such problems.
Disclosure of Invention
In order to solve the defects of the prior art, the invention aims to provide a method for purifying the somaglutide, and the method is used for purifying the somaglutide twice by HPLC (high performance liquid chromatography), wherein the purity of a sample obtained for the first time is 92 percent, and the purity of a sample obtained for the second time is 99 percent, so that the purity and the yield of the somaglutide are improved.
In order to achieve the above object, the present invention adopts the following technical solutions:
a method of purifying somaglutide, comprising the steps of:
pretreating a crude product of the Somaltul peptide to obtain a crude peptide water solution of the Somaltul peptide;
step two, taking tetraalkylsilane bonded silica gel filler as a stationary phase, taking phosphoric acid as a mobile phase A and acetonitrile as a mobile phase B, and carrying out first HPLC purification to remove impurities of the soma peptide fragment;
removing the solvent to obtain a first-step sample solution of the somaglutide;
step four, taking the octaalkylsilane bonded silica filler as a stationary phase and taking an ammonium acetate solution as a mobile phase A; performing HPLC purification for the second time by taking acetonitrile as a mobile phase B to remove impurities with physical and chemical properties similar to those of the somaglutide;
and fifthly, removing the solvent to obtain a second sample solution of the somaglutide, and obtaining the somaglutide sample solution.
In the method for purifying the somaglutide, step one, a crude somaglutide product is pretreated to obtain an aqueous solution of the crude somaglutide; the pretreatment step comprises the following steps:
1) dissolving the crude soxhlet peptide into an acetonitrile water solution to obtain a crude soxhlet peptide water solution;
2) filtering the soxhlet peptide aqueous solution with a filter membrane to remove insoluble particles, and collecting the filtrate for later use.
In the method for purifying the somaglutide, impurities of the somaglutide fragment comprise: H-His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-OH, H-Ala-Ala-Lys (octadecendioic-gamma-Glu-PEG 2-PEG2) -Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly-OH.
In the second step of the method for purifying the somaglutide, the tetraalkylsilane bonded silica gel filler is used as a stationary phase, 0.2% phosphoric acid is used as a mobile phase A, acetonitrile is used as a mobile phase B, the detection wavelength is 230nm, the first HPLC linear gradient elution is performed, and fractions containing the somaglutide sample are collected; the particle size of the stationary phase is 10 mu m, and the preparation method of 0.2 percent phosphoric acid comprises the following steps: 1000ml of water is taken, 2ml of phosphoric acid is added, the mixture is uniformly mixed, and the pH value is adjusted to 2.3 by ammonia water to obtain 0.2 percent phosphoric acid.
In the third step of the method for purifying the somaglutide, a rotary evaporator is used for removing part of acetonitrile at the water bath temperature of 30-35 ℃ and the vacuum degree of below-0.09 MPa to obtain a first-step sample solution of the somaglutide, wherein the sample solution is alkaline.
The method for purifying the somaglutide comprises a fourth step of performing second HPLC gradient elution by using an octaalkylsilane bonded silica filler as a stationary phase, a 20mmol/L ammonium acetate solution as a mobile phase A and acetonitrile as a mobile phase B, wherein the detection wavelength is 230nm, and collecting fractions containing the somaglutide sample; the preparation method of the 20mmol/L ammonium acetate solution comprises the following steps: 1000ml of water was taken, 1.54g of ammonium acetate was added thereto, and the pH was adjusted to 7.5 with aqueous ammonia to obtain a 20mmol/L ammonium acetate solution.
In the method for purifying the somaglutide, the impurities with similar physical and chemical properties to the somaglutide comprise: D-His1、D-Ser10、D-Ala19、D-Glu21、D-Arg30、Endo-Gly31、Endo-Gly29、Des-Gly16。
The method for purifying the somaglutide comprises a fifth step of removing part of acetonitrile by using a rotary evaporator at the water bath temperature of 30-35 ℃ and the vacuum degree of below-0.09 MPa to obtain a somaglutide sample solution, wherein the sample solution is acidic.
The invention has the advantages that:
the tetraalkylsilane bonded silica gel filler is combined with mobile phase 0.2% phosphoric acid, so that most of impurities and fragment impurities of the somaglutide can be removed; the purity of the collected sample reaches 92%.
The chromatographic condition gradient elution combining the octaalkylsilane bonded silica filler as a fixed phase and the ammonium acetate solution of 20mmol/L as a mobile phase can remove impurities with physical and chemical properties similar to those of the somaglutide in the sample, and the sample with the purity of more than 99 percent can be obtained at one time; the purity and yield of the finished product of the soxhlet peptide are improved.
Drawings
FIG. 1 is a 1/2 diagram of HPLC of crude somaglutide of the present invention;
FIG. 2 is a 2/2 diagram of HPLC of crude somaglutide of the present invention;
FIG. 3 is an HPLC plot of the somaglutide after the first HPLC purification of the invention;
figure 4 is an HPLC diagram of the somaglutide after a second HPLC purification of the invention.
Detailed Description
The invention is described in detail below with reference to the figures and the embodiments.
A method of purifying somaglutide, comprising the steps of:
pretreating a crude product of the Somaltul peptide to obtain a crude peptide water solution of the Somaltul peptide; the pretreatment step comprises the following steps:
1) dissolving the crude soxhlet peptide into an acetonitrile water solution to obtain a crude soxhlet peptide water solution;
2) filtering the Somaltulipide aqueous solution with a filter membrane to remove insoluble particles, and collecting the filtrate for later use, wherein the filter membrane is preferably a 0.22 μm filter membrane.
Step two, performing first HPLC purification to remove impurities of the soma peptide fragment;
impurities of the somarlu peptide fragments include:
H-His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-OH，
H-Ala-Ala-Lys (octadecedioic- γ -Glu-PEG2-PEG2) -Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Ar g-Gly-OH. Octadecaneedioic is the English name of stearic acid.
Taking tetraalkylsilane bonded silica gel filler as a stationary phase, 0.2% phosphoric acid as a mobile phase A and acetonitrile as a mobile phase B, carrying out first HPLC linear gradient elution with the detection wavelength of 230nm, and collecting fractions containing a soxhlet peptide sample; the particle size of the stationary phase is 10 mu m, and the preparation method of 0.2 percent phosphoric acid comprises the following steps: 1000ml of water is taken, 2ml of phosphoric acid is added, the mixture is uniformly mixed, and the pH value is adjusted to 2.3 by ammonia water to obtain 0.2 percent phosphoric acid.
And step three, removing part of acetonitrile by using a rotary evaporator at the water bath temperature of 30-35 ℃ and the vacuum degree of below-0.09 MPa to obtain the first-step sample solution of the Somalutide, wherein the sample solution is alkaline.
Step four, performing HPLC purification for the second time to remove impurities with physical and chemical properties similar to those of the somaglutide;
impurities with physical and chemical properties similar to those of somaglutide include: D-His1、D-Ser10、D-Ala19、D-Glu21、D-Arg30、Endo-Gly31、Endo-Gly29、Des-Gly16。
Taking octaalkylsilane bonded silica filler as a stationary phase, taking 20mmol/L ammonium acetate solution as a mobile phase A, taking acetonitrile as a mobile phase B, carrying out secondary HPLC gradient elution, and collecting fractions containing a soxhlet peptide sample; the preparation method of the 20mmol/L ammonium acetate solution comprises the following steps: 1000ml of water was taken, 1.54g of ammonium acetate was added thereto, and the pH was adjusted to 7.5 with aqueous ammonia to obtain a 20mmol/L ammonium acetate solution.
And fifthly, removing part of acetonitrile by using a rotary evaporator at the water bath temperature of 30-35 ℃ and the vacuum degree of below-0.09 Mpa to obtain a soxhlet peptide sample solution, wherein the sample solution is acidic.
In order to prove that the purification method can remove impurities and obtain the finished product of the somaglutide with high purity and high yield, crude peptide samples containing 3g, 8g, 32g and 72g of the somaglutide are used for purification experiments by the method, and the experimental processes are as follows:
example 1
Taking crude soxhlet peptide
Sample treatment: a sample containing 3g of crude soxhlet peptide (crude peptide: 4.6 g) was dissolved in acetonitrile aqueous solution, and after complete dissolution, it was filtered through a 0.22 μm filter. Collecting the filtered crude soxhlet peptide aqueous solution for later use.
First step HPLC purification
Chromatographic conditions are as follows: chromatographic column with tetraalkyl silane bonded silica gel stuffing as fixed phase (30mm × 250mm, 10 μm); taking 0.2% phosphoric acid (1000 ml water, adding 2ml phosphoric acid, mixing well, adjusting pH value to 2.3 with ammonia water) as mobile phase A; acetonitrile is used as a mobile phase B; the flow rate is 20mL per minute; the detection wavelength is 230 nm; the amount of the sample loaded on a single needle was 0.6 g. Elution is performed with the following table elution gradient.
Recovering a fraction of the sample of somaglutide having a purity greater than 95%. And removing part of acetonitrile by using a rotary evaporator at the water bath temperature of 30-35 ℃ and the vacuum degree of below-0.09 Mpa. Obtaining a first-step sample solution of the somaglutide.
Second step HPLC purification
Chromatographic conditions are as follows: a chromatographic column using octaalkylsilane bonded silica filler as a stationary phase (30mm multiplied by 250mm, 10 μm); taking a 20mmol/L ammonium acetate solution (1000 ml water is added with 1.54g of ammonium acetate, and ammonia water is used for adjusting the pH value to 7.5) as a mobile phase A; acetonitrile is used as a mobile phase B; the flow rate is 20mL per minute; the detection wavelength is 230 nm; the amount of the above sample was 0.43 g. Elution is performed with the following table elution gradient.
Recovering a fraction of the sample of somaglutide having a purity greater than 99.8%. And removing part of acetonitrile by using a rotary evaporator at the water bath temperature of 30-35 ℃ and the vacuum degree of below-0.09 Mpa. The solution contains 2.20g of the somaglutide quantitatively by a reference substance, and the yield reaches 73.3 percent.
Example 2
Taking crude soxhlet peptide
Sample treatment: a sample containing 8g of crude soxhlet peptide (crude peptide: 12.2 g) was dissolved in acetonitrile aqueous solution, and after complete dissolution, it was filtered through a 0.22 μm filter. The filtered crude peptide aqueous solution was collected for use.
First step HPLC purification
Chromatographic conditions are as follows: chromatographic column with tetraalkyl silane bonded silica gel stuffing as fixed phase (50mm × 250mm, 10 μm); taking 0.2% phosphoric acid (1000 ml water, adding 2ml phosphoric acid, mixing well, adjusting pH value to 2.3 with ammonia water) as mobile phase A; acetonitrile is used as a mobile phase B; the flow rate was 60mL per minute; the detection wavelength is 230 nm; the amount of the sample was 1.6 g. Elution is performed with the following table elution gradient.
Recovering a fraction of the sample of somaglutide having a purity greater than 95%. And removing part of acetonitrile by using a rotary evaporator at the water bath temperature of 30-35 ℃ and the vacuum degree of below-0.09 Mpa. Obtaining a first-step sample solution of the somaglutide.
Second step HPLC purification
Chromatographic conditions are as follows: column with octaalkylsilane bonded silica packing as stationary phase (50mm × 250mm, 10 μm): taking a 20mmol/L ammonium acetate solution (1000 ml water is added with 1.54g of ammonium acetate, and ammonia water is used for adjusting the pH value to 7.5) as a mobile phase A; acetonitrile is used as a mobile phase B; the flow rate was 60mL per minute; the detection wavelength is 230 nm; the amount of the sample was 1.2 g. Elution is performed with the following table elution gradient.
Recovering a fraction of the sample of somaglutide having a purity greater than 99.8%. And removing part of acetonitrile by using a rotary evaporator at the water bath temperature of 30-35 ℃ and the vacuum degree of below-0.09 Mpa. The solution contains 5.70g of the somaglutide quantitatively by a reference substance, and the yield reaches 71.2 percent.
Example 3
Taking crude soxhlet peptide
Sample treatment: a sample containing 32g of crude soxhlet peptide (crude peptide: 48.8 g) was dissolved in acetonitrile in water and, after complete dissolution, filtered through a 0.22 μm filter. The filtered crude peptide aqueous solution was collected for use.
First step HPLC purification
Chromatographic conditions are as follows: chromatographic column with tetraalkyl silane bonded silica gel stuffing as fixed phase (100mm × 250mm, 10 μm); taking 0.2% phosphoric acid (1000 ml water, adding 2ml phosphoric acid, mixing well, adjusting pH value to 2.3 with ammonia water) as mobile phase A; acetonitrile is used as a mobile phase B; the flow rate is 200mL per minute; the detection wavelength is 230 nm; the amount of the sample was 6.4 g. Elution is performed with the following table elution gradient.
Recovering the fractions containing the sample of somaglutide. And removing part of acetonitrile by using a rotary evaporator at the water bath temperature of 30-35 ℃ and the vacuum degree of below-0.09 Mpa. Obtaining a first-step sample solution of the somaglutide.
Second step HPLC purification
Chromatographic conditions are as follows: chromatographic column with octaalkylsilane bonded silica filler stationary phase (100mm × 250mm, 10 μm); taking a 20mmol/L ammonium acetate solution (1000 ml water is added with 1.54g of ammonium acetate, and ammonia water is used for adjusting the pH value to 7.5) as a mobile phase A; acetonitrile is used as a mobile phase B; the flow rate is 200mL per minute; the detection wavelength is 230 nm; the amount of the sample was 4.8 g. Elution is performed with the following table elution gradient.
Recovering a fraction of the sample of somaglutide having a purity greater than 99.8%. And removing part of acetonitrile by using a rotary evaporator at the water bath temperature of 30-35 ℃ and the vacuum degree of below-0.09 Mpa. The solution contains 23.60g of somaglutide quantitatively by comparison product, and the yield reaches 73.7%.
Example 4
Taking crude soxhlet peptide
Sample treatment: a sample containing 72g of crude soxhlet peptide (crude peptide: 109.4 g) was dissolved in aqueous acetonitrile and, after complete dissolution, filtered through a 0.22 μm filter. Collecting the filtered crude peptide water solution for later use, wherein the chromatogram of the crude somaltulin is shown in FIGS. 2 and 3.
First step HPLC purification
Chromatographic conditions are as follows: chromatographic column with tetraalkyl silane bonded silica gel stuffing as fixed phase (150mm × 250mm, 10 μm); taking 0.2% phosphoric acid (1000 ml water, adding 2ml phosphoric acid, mixing well, adjusting pH value to 2.3 with ammonia water) as mobile phase A; acetonitrile is used as a mobile phase B; the flow rate is 600mL per minute; the detection wavelength is 230 nm; the sample loading amount is 14.4 g; elution is performed with the following table elution gradient.
Recovering a fraction of the sample of somaglutide having a purity greater than 90%. And removing part of acetonitrile by using a rotary evaporator at the water bath temperature of 30-35 ℃ and the vacuum degree of below-0.09 Mpa. Obtaining a first-step sample solution of the somaglutide, and the chromatogram after the first-step HPLC purification is shown in FIG. 4.
Second step HPLC purification
Chromatographic conditions are as follows: a chromatographic column with an octaalkylsilane bonded silica filler stationary phase (150mm multiplied by 250mm, 10 mu m) is used as a chromatographic column; taking a 20mmol/L ammonium acetate solution (1000 ml water is added with 1.54g of ammonium acetate, and ammonia water is used for adjusting the pH value to 7.5) as a mobile phase A; acetonitrile is used as a mobile phase B; the flow rate is 600mL per minute; the detection wavelength is 230 nm; the amount of the above sample was 10.8 g. Elution is performed with the following table elution gradient.
Recovering a fraction of the sample of somaglutide having a purity greater than 99.8%. And removing part of acetonitrile by using a rotary evaporator at the water bath temperature of 30-35 ℃ and the vacuum degree of below-0.09 Mpa. The solution contains 52.30g of somaglutide quantitatively by comparison product, and the yield reaches 72.6%.
From 4 examples, it can be seen that the purity of the crude soxhlet peptide obtained by purifying the crude soxhlet peptide by the method is more than 99.8%, and the chromatogram after the second step of HPLC purification is shown in fig. 3.
The invention provides a method for purifying somaglutide, which comprises two times of HPLC purification, wherein the purity of a sample obtained for the first time is 92%, and the purity of a sample obtained for the second time is 99%, so that the purity and yield of the somaglutide are improved.
The foregoing illustrates and describes the principles, general features, and advantages of the present invention. It should be understood by those skilled in the art that the above embodiments do not limit the present invention in any way, and all technical solutions obtained by using equivalent alternatives or equivalent variations fall within the scope of the present invention.
Claims (4)
1. A method of purifying somaglutide, comprising the steps of:
pretreating a crude product of the Somaltul peptide to obtain a crude peptide water solution of the Somaltul peptide;
step two, taking tetraalkylsilane bonded silica gel filler as a stationary phase, taking 0.2% phosphoric acid as a mobile phase A and acetonitrile as a mobile phase B, carrying out first HPLC linear gradient elution, and collecting fractions containing a somagulide sample; the granularity of the stationary phase is 10 mu m, and the preparation method of the 0.2 percent phosphoric acid comprises the following steps: adding 2ml phosphoric acid into 1000ml of water, uniformly mixing, and adjusting the pH value to 2.3 by using ammonia water to obtain 0.2% phosphoric acid; performing first HPLC purification to remove impurities of the soma peptide fragment;
removing the solvent to obtain a first-step sample solution of the somaglutide;
step four, taking the octaalkylsilane bonded silica filler as a stationary phase, taking a 20mmol/L ammonium acetate solution as a mobile phase A, taking acetonitrile as a mobile phase B, carrying out secondary HPLC gradient elution, and collecting fractions containing the somaglutide sample; the preparation method of the 20mmol/L ammonium acetate solution comprises the following steps: adding 1.54g of ammonium acetate into 1000ml of water, and adjusting the pH value to 7.5 by ammonia water to obtain a 20mmol/L ammonium acetate solution; performing HPLC purification for the second time to remove impurities with physical and chemical properties similar to those of the somaglutide;
impurities of the somarlu peptide fragments include: H-His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-OH, H-Ala-Ala-Lys (octadecendioic-gamma-Glu-PEG 2-PEG2) -Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly-OH;
impurities with physical and chemical properties similar to those of somaglutide include: D-His1、D-Ser10、D-Ala19、D-Glu21、D-Arg30、Endo-Gly31、Endo-Gly29、Des-Gly16；
And fifthly, removing the solvent to obtain a second sample solution of the somaglutide, and obtaining the somaglutide sample solution.
2. The method for purifying the somaglutide according to claim 1, wherein in the first step, crude somaglutide is pre-treated to obtain crude somaglutide aqueous solution; the step of pre-treating comprises:
dissolving the crude soxhlet peptide into an acetonitrile water solution to obtain a crude soxhlet peptide water solution;
filtering the soxhlet peptide aqueous solution with a filter membrane to remove insoluble particles, and collecting the filtrate for later use.
3. The method for purifying the somaglutide according to claim 1, wherein in step three, the water bath temperature of the rotary evaporator is 30-35 ℃, the vacuum degree is below-0.09 MPa, and part of acetonitrile is removed, so that a first-step sample solution of the somaglutide is obtained, wherein the sample solution is alkaline.
4. The method for purifying the somaglutide according to claim 1, wherein in the fifth step, the water bath temperature of the rotary evaporator is 30-35 ℃, the vacuum degree is below-0.09 MPa, and part of acetonitrile is removed to obtain a somaglutide sample solution, wherein the sample solution is acidic.
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| CN109354622A (en) * | 2018-12-05 | 2019-02-19 | 苏州汇通色谱分离纯化有限公司 | A kind of Suo Malu peptide purification filler special and its purification process |
| WO2020190757A1 (en) | 2019-03-15 | 2020-09-24 | Novetide Ltd. | Improved processes for the preparation of semaglutide |
| CN112285217B (en) * | 2019-07-27 | 2022-11-01 | 深圳市健元医药科技有限公司 | Ultra-high performance liquid chromatography analysis method of Somalutide |
| CN112279895B (en) * | 2019-07-27 | 2023-03-14 | 深圳市健元医药科技有限公司 | Preparation method of chemically synthesized acidic polypeptide |
| CN110540587B (en) * | 2019-08-30 | 2021-03-02 | 江苏诺泰澳赛诺生物制药股份有限公司 | Chromatographic method for effectively improving purification yield of synthetic peptide |
| CN110590934B (en) * | 2019-09-25 | 2020-12-08 | 北京乐普医药科技有限公司 | GLP-1 compound |
| CN110845602A (en) * | 2019-11-29 | 2020-02-28 | 苏州天马医药集团天吉生物制药有限公司 | Method for separating and purifying somaglutide |
| CN113024658B (en) * | 2019-12-25 | 2022-10-21 | 翰宇药业（武汉）有限公司 | Method for purifying liraglutide |
| CN113045640B (en) * | 2019-12-27 | 2023-03-24 | 翰宇药业（武汉）有限公司 | Purification method of GLP-1 analogue |
| CN113049690B (en) * | 2019-12-27 | 2022-07-22 | 翰宇药业（武汉）有限公司 | Polypeptide desalting method |
| CN112175068B (en) * | 2020-09-28 | 2021-06-25 | 深圳深创生物药业有限公司 | Method for purifying semaglutide |
| CN114146163B (en) * | 2021-12-07 | 2023-09-26 | 苏州天马医药集团天吉生物制药有限公司 | Preparation method of semaglutin preparation |
| CN114478686B (en) * | 2021-12-30 | 2023-07-21 | 江苏诺泰澳赛诺生物制药股份有限公司 | Method for purifying enfuwei peptide |
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