CN101372504A - Method for purifying desmopressin - Google Patents
Method for purifying desmopressin Download PDFInfo
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- CN101372504A CN101372504A CNA2007100765431A CN200710076543A CN101372504A CN 101372504 A CN101372504 A CN 101372504A CN A2007100765431 A CNA2007100765431 A CN A2007100765431A CN 200710076543 A CN200710076543 A CN 200710076543A CN 101372504 A CN101372504 A CN 101372504A
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- 238000000034 method Methods 0.000 title claims abstract description 20
- 108010000437 Deamino Arginine Vasopressin Proteins 0.000 title claims abstract description 15
- 229960004281 desmopressin Drugs 0.000 title claims description 11
- NFLWUMRGJYTJIN-NXBWRCJVSA-N desmopressin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSCCC(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(N)=O)=O)CCC(=O)N)C1=CC=CC=C1 NFLWUMRGJYTJIN-NXBWRCJVSA-N 0.000 title claims description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 29
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 20
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 17
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000010828 elution Methods 0.000 claims abstract description 12
- 229960000583 acetic acid Drugs 0.000 claims abstract description 10
- 239000012362 glacial acetic acid Substances 0.000 claims abstract description 10
- 239000000243 solution Substances 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims abstract description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims abstract description 4
- 238000005349 anion exchange Methods 0.000 claims abstract description 4
- 239000007864 aqueous solution Substances 0.000 claims description 22
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 20
- 230000005526 G1 to G0 transition Effects 0.000 claims description 12
- 239000000377 silicon dioxide Substances 0.000 claims description 12
- 239000008363 phosphate buffer Substances 0.000 claims description 3
- 150000003016 phosphoric acids Chemical class 0.000 claims description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 abstract description 30
- 238000000746 purification Methods 0.000 abstract description 14
- 208000032843 Hemorrhage Diseases 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 208000031220 Hemophilia Diseases 0.000 abstract description 2
- 208000009292 Hemophilia A Diseases 0.000 abstract description 2
- 102100026383 Vasopressin-neurophysin 2-copeptin Human genes 0.000 abstract description 2
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 201000010064 diabetes insipidus Diseases 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 229920001184 polypeptide Polymers 0.000 abstract description 2
- 230000002265 prevention Effects 0.000 abstract description 2
- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 2
- 230000001225 therapeutic effect Effects 0.000 abstract description 2
- 229910019142 PO4 Inorganic materials 0.000 abstract 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 abstract 2
- 239000010452 phosphate Substances 0.000 abstract 2
- 239000000741 silica gel Substances 0.000 abstract 2
- 229910002027 silica gel Inorganic materials 0.000 abstract 2
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 239000008366 buffered solution Substances 0.000 abstract 1
- YNKFCNRZZPFMEX-XHPDKPNGSA-N desmopressin acetate trihydrate Chemical compound O.O.O.CC(O)=O.C([C@H]1C(=O)N[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSCCC(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](CCCNC(N)=N)C(=O)NCC(N)=O)=O)CCC(=O)N)C1=CC=CC=C1 YNKFCNRZZPFMEX-XHPDKPNGSA-N 0.000 abstract 1
- 229940028441 minirin Drugs 0.000 abstract 1
- 238000001356 surgical procedure Methods 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 230000009466 transformation Effects 0.000 abstract 1
- 239000000523 sample Substances 0.000 description 30
- 239000000706 filtrate Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000010926 purge Methods 0.000 description 6
- 239000012488 sample solution Substances 0.000 description 6
- FIEYHAAMDAPVCH-UHFFFAOYSA-N 2-methyl-1h-quinazolin-4-one Chemical compound C1=CC=C2NC(C)=NC(=O)C2=C1 FIEYHAAMDAPVCH-UHFFFAOYSA-N 0.000 description 3
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 229960002845 desmopressin acetate Drugs 0.000 description 3
- 238000011010 flushing procedure Methods 0.000 description 3
- 238000005374 membrane filtration Methods 0.000 description 3
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 3
- 235000019796 monopotassium phosphate Nutrition 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 229910021642 ultra pure water Inorganic materials 0.000 description 3
- 239000012498 ultrapure water Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 2
- 101800001144 Arg-vasopressin Proteins 0.000 description 1
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229960003726 vasopressin Drugs 0.000 description 1
Landscapes
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention relates to a method for purifying minirin which is mainly used for treating hemophilia, diabetes insipidus, therapeutic haemorrhage control and haemorrhage prevention before surgery, has better effect and little side effect, and is a polypeptide drug with good market prospect. The method adopts the technical proposal that purification in step one: crude peptide which is obtained by synthesis is dissolved and then is treated by gradient elution and purification in a way of taking octadecyl silane linking silica gel as immobile phase, phosphate buffered solution as A phase, and chromatographic grade acetonitrile (ACN) as B phase; purification in step two: the peptide solution obtained by the purification in step one is concentrated and then is treated by gradient elution and purification in a way of taking octadecyl silane linking silica gel as immobile phase, glacial acetic acid solution as A phase, and chromatographic grade acetonitrile (ACN) as B phase. Salt transformation: phosphate and trifluoroacetate are transformed into acetate by adopting the method of anion exchange. The method has the advantages of simple and convenient operation, high product purity, good yield and low cost, achieves industrialization standard, and is beneficial to generalization.
Description
Technical field
The present invention relates to field of medicine and chemical technology, be specifically related to a kind of method of purifying desmopressin.
Background technology
Desmopressin (Desmopressin) is the analog of natural argipressin, is the chemical structure of natural hormone to be carried out two places change and get.It is mainly used to treat hemophilia, diabetes insipidus and therapeutic control over bleeding and the preceding prevention of operation is hemorrhage, and its effect is better and side effect is little, is a kind of polypeptide drugs that market outlook are arranged very much.
Summary of the invention
The object of the present invention is to provide a processing method that is suitable for the industrialization purifying desmopressin, used the reversed-phased high performace liquid chromatographic purifying desmopressin, purity height and yield are good, reach industrialized requirement.
For achieving the above object, the present invention takes following technical scheme:
The first step purifying: will synthesize the thick peptide dissolving of gained back is stationary phase in order to octadecylsilane chemically bonded silica, is that A phase, trifluoroacetic acid aqueous solution (ACN) are the B phase with the phosphate buffer soln, carries out the gradient elution purifying.
The second step purifying: it is stationary phase in order to octadecylsilane chemically bonded silica that the first step purifying gained purpose peptide solution is concentrated the back, is that A phase, trifluoroacetic acid aqueous solution (ACN) are the B phase with the glacial acetic acid aqueous solution, carries out the gradient elution purifying.
Change salt: adopt anion exchange method that phosphoric acid salt, trifluoroacetate are changed into acetate.
The purifying scale comprises following specification chromatographic column: 5cm * 25cm (pillar diameter * length), 15cm * 25cm, 30cm * 25cm.
The invention has the advantages that simple to operationly, product purity height, yield are good, reach industrialized requirement, and be with low cost, is beneficial to popularization.
Embodiment
With embodiment the present invention is described in further details below:
Embodiment one:
1, sample preparation: the thick peptide of every gram makes sample dissolve the back membrane filtration fully with the dissolving of 10%-30% glacial acetic acid aqueous solution, collects filtrate for later use.
2, purifying for the first time: purification condition: chromatographic column: with the octadecylsilane chemically bonded silica is the chromatographic column of stationary phase, and pillar diameter and length are: 5cm * 25cm.Moving phase: A phase: potassium dihydrogen phosphate aqueous solution is transferred pH to 5.0-7.0 with potassium hydroxide solution; B phase: trifluoroacetic acid aqueous solution.Flow velocity: 50-60ml/min.Detect wavelength: 230nm.Gradient: B%:10%～40%40-60min.Sample size is 1-2g.
Purge process: rinse chromatographic column well back with the acetonitrile more than 50% and go up sample, applied sample amount is the 15-20ml sample solution.Linear gradient elution 40-50min collects the purpose peak, and the purpose peptide solution of collecting is standby after water temperature is no more than 37 ℃ of following vacuum rotary steams to be concentrated into about 25-30ml/g.
3, purifying for the second time: purification condition: chromatographic column: with the octadecylsilane chemically bonded silica is the chromatographic column of stationary phase, and pillar diameter and length are: 5cm * 25cm.Moving phase: A phase: the 0.1%-10% glacial acetic acid aqueous solution is the A phase; B phase: trifluoroacetic acid aqueous solution.Flow velocity: 50-60ml/min.Detect wavelength: 230nm.Gradient: B%:10%～40%50-70min.Sample size is 1-2g.
Purge process: rinse chromatographic column well back with the acetonitrile more than 50% and go up sample, applied sample amount is the 15-20ml sample solution.Linear gradient elution 50-70min collects the purpose peak, and the purpose peptide solution of collecting is standby after water temperature is no more than 37 ℃ of following vacuum rotary steams to be concentrated into about 70-80ml/g.
4, change salt: get the sand core funnel that 50-60g anionite-exchange resin places suitable size, go up sample with ultrapure water flushing to neutral back, can go up sample 10-20g, decompress filter is also collected filtrate, and filtrate is no more than in water temperature and goes to suitable big or small cillin bottle after 37 ℃ of following vacuum rotary steams are concentrated into about 5-8ml/g.Can obtain purity after the lyophilize greater than 99% desmopressin acetate, purification yield can reach more than 87%.
Embodiment two:
1, sample preparation: the thick peptide of every gram makes sample dissolve the back membrane filtration fully with the dissolving of 10%-30% glacial acetic acid aqueous solution, collects filtrate for later use.
2, purifying for the first time: purification condition: chromatographic column: with the octadecylsilane chemically bonded silica is the chromatographic column of stationary phase, and pillar diameter and length are: 15cm * 25cm.Moving phase: A phase: potassium dihydrogen phosphate aqueous solution is transferred pH to 5.0-7.0 with potassium hydroxide solution; B phase: trifluoroacetic acid aqueous solution.Flow velocity: 450-550ml/min.Detect wavelength: 230nm.Gradient: B%:10%～40%80-100min.Sample size is 10-20g.
Purge process: rinse chromatographic column well back with the acetonitrile more than 50% and go up sample, applied sample amount is the 180ml-220ml sample solution.Linear gradient elution 80-100min collects the purpose peak, and the purpose peptide solution of collecting is standby after water temperature is no more than 37 ℃ of following vacuum rotary steams to be concentrated into about 30-40ml/g.
3, purifying for the second time: purification condition: chromatographic column: with the octadecylsilane chemically bonded silica is the chromatographic column of stationary phase, and pillar diameter and length are: 15cm * 25cm.Moving phase: A phase: the 0.1%-10% glacial acetic acid aqueous solution is the A phase; B phase: trifluoroacetic acid aqueous solution.Flow velocity: 450-550ml/min.Detect wavelength: 230nm.Gradient: B%:10%～40%130-150min.Sample size is 10-20g.
Purge process: rinse chromatographic column well back with the acetonitrile more than 50% and go up sample, applied sample amount is the 180ml-220ml sample solution.Linear gradient elution 90-110min collects the purpose peak, and the purpose peptide solution of collecting is standby after water temperature is no more than 37 ℃ of following vacuum rotary steams to be concentrated into about 70-80ml/g.
4, change salt: get the sand core funnel that 200-250g anionite-exchange resin places suitable size, go up sample with ultrapure water flushing to neutral back, can go up sample 25-35g, decompress filter is also collected filtrate, and filtrate is no more than in water temperature and goes to suitable big or small cillin bottle after 37 ℃ of following vacuum rotary steams are concentrated into about 5-8ml/g.Can obtain purity after the lyophilize greater than 99% desmopressin acetate, purification yield can reach more than 89%.
Embodiment three:
1, sample preparation: the thick peptide of every gram makes sample dissolve the back membrane filtration fully with the dissolving of 10%-30% glacial acetic acid aqueous solution, collects filtrate for later use.
2, purifying for the first time: purification condition: chromatographic column: with the octadecylsilane chemically bonded silica is the chromatographic column of stationary phase, and pillar diameter and length are: 30cm * 25cm.Moving phase: A phase: potassium dihydrogen phosphate aqueous solution is transferred pH to 5.0-7.0 with potassium hydroxide solution; B phase: trifluoroacetic acid aqueous solution.Flow velocity: 1900-2200ml/min.Detect wavelength: 230nm.Gradient: B%:10%～40%150-180min.Sample size is 55-75g.
Purge process: rinse chromatographic column well back with the acetonitrile more than 50% and go up sample, applied sample amount is the 700ml-900ml sample solution.Linear gradient elution 180-220min collects the purpose peak, and the purpose peptide solution of collecting is standby after water temperature is no more than 37 ℃ of following vacuum rotary steams to be concentrated into about 25-30ml/g.
3, purifying for the second time: purification condition: chromatographic column: with the octadecylsilane chemically bonded silica is the chromatographic column of stationary phase, and pillar diameter and length are: 30cm * 25cm.Moving phase: A phase: the 0.1%-10% glacial acetic acid aqueous solution is the A phase; B phase: trifluoroacetic acid aqueous solution.Flow velocity: 1900-2200ml/min.Detect wavelength: 230nm.Gradient: B%:10%～40%200-240min.Sample size is 55-75g.
Purge process: rinse chromatographic column well back with the acetonitrile more than 50% and go up sample, applied sample amount is the 700ml-900ml sample solution.Linear gradient elution 200-240min collects the purpose peak, and the purpose peptide solution of collecting is standby after water temperature is no more than 37 ℃ of following vacuum rotary steams to be concentrated into about 60-70ml/g.
4, change salt: get the sand core funnel that 1000-1200g anionite-exchange resin places suitable size, go up sample with ultrapure water flushing to neutral back, can go up sample 90-120g, decompress filter is also collected filtrate, and filtrate is no more than in water temperature and goes to suitable big or small cillin bottle after 37 ℃ of following vacuum rotary steams are concentrated into about 5-8ml/g.Can obtain purity after the lyophilize greater than 99% desmopressin acetate, purification yield can reach more than 88%.
Claims (4)
1. the method for a purifying desmopressin is characterized in that it may further comprise the steps:
The first step purifying: will synthesize the thick peptide dissolving of gained back is stationary phase with octadecylsilane chemically bonded silica, is that A phase, trifluoroacetic acid aqueous solution (ACN) are the B phase with the phosphate buffer soln, carries out the gradient elution purifying.
The second step purifying: it is stationary phase in order to octadecylsilane chemically bonded silica that the first step purifying gained purpose peptide solution is concentrated the back, is that A phase, trifluoroacetic acid aqueous solution (ACN) are the B phase with the glacial acetic acid aqueous solution, carries out the gradient elution purifying.
Change salt: adopt anion exchange method that phosphoric acid salt, trifluoroacetate are changed into acetate.
2. the method for a kind of purifying desmopressin according to claim 1, it is characterized in that adopting with the octadecylsilane chemically bonded silica is stationary phase, should be as the phosphate buffer soln pH of A phase less than 7, but be not less than 5.
3. the method for a kind of purifying desmopressin according to claim 1, it is characterized in that adopting octadecylsilane chemically bonded silica is stationary phase, should be as the glacial acetic acid aqueous solution concentration of A phase less than 10%, but be not less than 0.1%.
4. the method for a kind of purifying desmopressin according to claim 1 is characterized in that adopting anion exchange method that phosphoric acid salt, trifluoroacetate are changed into acetate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100765431A CN101372504B (en) | 2007-08-22 | 2007-08-22 | Method for purifying desmopressin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100765431A CN101372504B (en) | 2007-08-22 | 2007-08-22 | Method for purifying desmopressin |
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| Publication Number | Publication Date |
|---|---|
| CN101372504A true CN101372504A (en) | 2009-02-25 |
| CN101372504B CN101372504B (en) | 2011-05-18 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN2007100765431A Expired - Fee Related CN101372504B (en) | 2007-08-22 | 2007-08-22 | Method for purifying desmopressin |
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Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102382188A (en) * | 2011-11-07 | 2012-03-21 | 深圳翰宇药业股份有限公司 | Method for preparing carperitide acetate |
| CN103304639A (en) * | 2013-06-08 | 2013-09-18 | 深圳翰宇药业股份有限公司 | Method for purifying desmopressin intermediates |
| CN103467574A (en) * | 2013-09-05 | 2013-12-25 | 杭州诺泰制药技术有限公司 | Purification method of desmopressin acetate |
| CN103848893A (en) * | 2012-12-07 | 2014-06-11 | 深圳翰宇药业股份有限公司 | Purifying method of linaclotide |
| CN105131079A (en) * | 2015-07-25 | 2015-12-09 | 济南康和医药科技有限公司 | Purifying method of desmopressin acetate |
| RU2581019C1 (en) * | 2015-03-26 | 2016-04-10 | Индивидуальный предприниматель Михайлов Олег Ростиславович | Method of purifying desmopressin (versions) |
| CN110256533A (en) * | 2018-03-12 | 2019-09-20 | 博瑞生物医药（苏州）股份有限公司 | A kind of multi-arm anticancer conjugate of high-purity |
| CN111690037A (en) * | 2020-07-31 | 2020-09-22 | 广州赛莱拉干细胞科技股份有限公司 | Method for synthesizing GHK acetate |
| CN113683663A (en) * | 2021-09-16 | 2021-11-23 | 杭州信海医药科技有限公司 | Purification method of organism-protected polypeptide crude product |
| CN113698456A (en) * | 2021-05-31 | 2021-11-26 | 海南双成药业股份有限公司 | Method for purifying argirelin |
| CN114369142A (en) * | 2021-12-31 | 2022-04-19 | 江苏诺泰澳赛诺生物制药股份有限公司 | Method for purifying desmopressin acetate |
| CN114907449A (en) * | 2022-06-21 | 2022-08-16 | 辰欣药业股份有限公司 | Purification and refining method of desmopressin acetate |
| CN116023441A (en) * | 2022-12-29 | 2023-04-28 | 江苏诺泰澳赛诺生物制药股份有限公司 | Method for preparing purified desmopressin sulfoxide impurity |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2135204C1 (en) * | 1993-06-29 | 1999-08-27 | Ферринг Б.В. | Compositions for nasal administration of desmopressin |
| DK0710243T3 (en) * | 1993-06-29 | 2000-10-16 | Ferring Bv | Synthesis of cyclic peptides |
| US5985835A (en) * | 1993-12-23 | 1999-11-16 | Ferring B.V. | Desmopressin for nocturia, incontinence and enuresis |
| GB0210397D0 (en) * | 2002-05-07 | 2002-06-12 | Ferring Bv | Pharmaceutical formulations |
-
2007
- 2007-08-22 CN CN2007100765431A patent/CN101372504B/en not_active Expired - Fee Related
Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102382188A (en) * | 2011-11-07 | 2012-03-21 | 深圳翰宇药业股份有限公司 | Method for preparing carperitide acetate |
| CN103848893B (en) * | 2012-12-07 | 2016-08-10 | 深圳翰宇药业股份有限公司 | A kind of purification process of Linaclotide |
| CN103848893A (en) * | 2012-12-07 | 2014-06-11 | 深圳翰宇药业股份有限公司 | Purifying method of linaclotide |
| CN103304639A (en) * | 2013-06-08 | 2013-09-18 | 深圳翰宇药业股份有限公司 | Method for purifying desmopressin intermediates |
| CN103467574A (en) * | 2013-09-05 | 2013-12-25 | 杭州诺泰制药技术有限公司 | Purification method of desmopressin acetate |
| CN103467574B (en) * | 2013-09-05 | 2015-05-13 | 杭州阿德莱诺泰制药技术有限公司 | Purification method of desmopressin acetate |
| RU2581019C1 (en) * | 2015-03-26 | 2016-04-10 | Индивидуальный предприниматель Михайлов Олег Ростиславович | Method of purifying desmopressin (versions) |
| CN105131079B (en) * | 2015-07-25 | 2018-09-14 | 济南康和医药科技有限公司 | A kind of purification process of desmopressin acetate |
| CN105131079A (en) * | 2015-07-25 | 2015-12-09 | 济南康和医药科技有限公司 | Purifying method of desmopressin acetate |
| CN110256533A (en) * | 2018-03-12 | 2019-09-20 | 博瑞生物医药（苏州）股份有限公司 | A kind of multi-arm anticancer conjugate of high-purity |
| CN110256533B (en) * | 2018-03-12 | 2022-05-10 | 博瑞生物医药（苏州）股份有限公司 | Extraction method of high-purity multi-arm anticancer conjugate |
| CN111690037A (en) * | 2020-07-31 | 2020-09-22 | 广州赛莱拉干细胞科技股份有限公司 | Method for synthesizing GHK acetate |
| CN113698456A (en) * | 2021-05-31 | 2021-11-26 | 海南双成药业股份有限公司 | Method for purifying argirelin |
| CN113698456B (en) * | 2021-05-31 | 2024-05-28 | 海南双成药业股份有限公司 | Purification method of arginin vasopressin |
| CN113683663A (en) * | 2021-09-16 | 2021-11-23 | 杭州信海医药科技有限公司 | Purification method of organism-protected polypeptide crude product |
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