CN105646669A - Carbetocin purification method - Google Patents
Carbetocin purification method Download PDFInfo
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- CN105646669A CN105646669A CN201610190022.8A CN201610190022A CN105646669A CN 105646669 A CN105646669 A CN 105646669A CN 201610190022 A CN201610190022 A CN 201610190022A CN 105646669 A CN105646669 A CN 105646669A
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- 108700021293 carbetocin Proteins 0.000 title claims abstract description 40
- NSTRIRCPWQHTIA-DTRKZRJBSA-N carbetocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSCCCC(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(OC)C=C1 NSTRIRCPWQHTIA-DTRKZRJBSA-N 0.000 title claims abstract description 40
- 229960001118 carbetocin Drugs 0.000 title claims abstract description 40
- 238000000034 method Methods 0.000 title claims abstract description 26
- 238000000746 purification Methods 0.000 title claims abstract description 23
- 239000000243 solution Substances 0.000 claims abstract description 26
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 22
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000000741 silica gel Substances 0.000 claims abstract description 18
- 229910002027 silica gel Inorganic materials 0.000 claims abstract description 18
- 239000007864 aqueous solution Substances 0.000 claims abstract description 17
- 238000010828 elution Methods 0.000 claims abstract description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims abstract description 9
- 239000008367 deionised water Substances 0.000 claims abstract description 9
- 229910021641 deionized water Inorganic materials 0.000 claims abstract description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 7
- PMZXXNPJQYDFJX-UHFFFAOYSA-N acetonitrile;2,2,2-trifluoroacetic acid Chemical compound CC#N.OC(=O)C(F)(F)F PMZXXNPJQYDFJX-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000004007 reversed phase HPLC Methods 0.000 claims abstract description 4
- 239000012071 phase Substances 0.000 claims description 33
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 16
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical group CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 238000001514 detection method Methods 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 238000010532 solid phase synthesis reaction Methods 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 238000000926 separation method Methods 0.000 abstract description 2
- 230000005526 G1 to G0 transition Effects 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 abstract 1
- 238000001035 drying Methods 0.000 abstract 1
- 230000008014 freezing Effects 0.000 abstract 1
- 238000007710 freezing Methods 0.000 abstract 1
- 239000000843 powder Substances 0.000 abstract 1
- 102000004196 processed proteins & peptides Human genes 0.000 abstract 1
- 238000002390 rotary evaporation Methods 0.000 abstract 1
- 239000007787 solid Substances 0.000 abstract 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 abstract 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 239000000523 sample Substances 0.000 description 12
- 210000004291 uterus Anatomy 0.000 description 11
- 101800000989 Oxytocin Proteins 0.000 description 7
- 102400000050 Oxytocin Human genes 0.000 description 7
- 238000011068 loading method Methods 0.000 description 6
- XNOPRXBHLZRZKH-UHFFFAOYSA-N Oxytocin Natural products N1C(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CC(C)C)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C(C(C)CC)NC(=O)C1CC1=CC=C(O)C=C1 XNOPRXBHLZRZKH-UHFFFAOYSA-N 0.000 description 5
- 208000018525 Postpartum Hemorrhage Diseases 0.000 description 5
- XNOPRXBHLZRZKH-DSZYJQQASA-N oxytocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 XNOPRXBHLZRZKH-DSZYJQQASA-N 0.000 description 5
- 229960001723 oxytocin Drugs 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 208000036029 Uterine contractions during pregnancy Diseases 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000010926 purge Methods 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000005374 membrane filtration Methods 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 239000012488 sample solution Substances 0.000 description 3
- 230000008719 thickening Effects 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 230000035935 pregnancy Effects 0.000 description 2
- 208000000091 Maternal Death Diseases 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000035606 childbirth Effects 0.000 description 1
- 230000001595 contractor effect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 230000008774 maternal effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/16—Oxytocins; Vasopressins; Related peptides
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Peptides Or Proteins (AREA)
Abstract
The invention discloses a carbetocin purification method adopting reversed-phase high-performance liquid chromatography. The technical problems of high cost, operation complexity and low yield of carbetocin obtained by separation in the prior art are mainly solved. The method includes steps: 1) dissolving crude peptides obtained by solid synthesis into deionized water, taking a reverse phase silica gel column of octadecyl bonded silica gel as a stationary phase, taking 0.1 TFA aqueous solution as a phase A of a mobile phase and 0.1% TFA acetonitrile solution as a phase B of the mobile phase, performing gradient elution purification to collect a peptide solution of a target peak value; 2) adopting an HPLC method for conversion to obtain acetate; 3) subjecting a final high-purity peptide solution to pressure reduction, rotary evaporation, concentration, freezing and drying to obtain finished peptide powder. The carbetocin purification method is suitable for industrial carbetocin purification and is simple in operation, safe and low in cost.
Description
Technical field
The invention belongs to reverse-phase HPLC technique field, a kind of method especially relating to mass industrialization purifying Carbetocin.
Background technology
Carbetocin is the long-acting oxytocin nonapeptide analog with agonist characteristics of a kind of synthesis. Can be administered by Single-dose intravenous immediately after cesarotomy under epidural or lumbar anesthesia, to prevent uterus tension force not enough and postpartum hemorrhage. The clinic of carbetocin is similar with naturally-produced oxytocin with pharmacological property. As oxytocin, carbetocin is combined with the ocytocin receptor of uterine smooth muscle, causes the Rythmic contractions characteristic in uterus, on original contraction basis, increases its frequency and increases uterus tension force. Under non pregnant state, the ocytocin receptor content in uterus is very low, increases, reach peak during childbirth during gestation. Therefore nogestational uterus is not acted on by carbetocin, but the uterus of gestation and the uterus of harsh product are had effective uterine contraction effect.
Relative to oxytocin, the long action time of carbetocin, the uterine contraction produced therefrom cannot stop simply by terminating administration. So before baby gives birth to, no matter any reason all can not give carbetocin, including selectivity or drug-induced production. Whether, after intravenous injection or intramuscular injection carbetocin, uterus is shunk rapidly, can reach a clear and definite intensity in 2 minutes. The active function in uterus be may last about 1 hour by Single-dose intravenous injection carbetocin, is therefore enough to prevent the postpartum hemorrhage in harsh puerperal. After giving carbetocin puerperal, all long than oxytocin is in the frequency shunk with amplitude.
Research shows, when after cesarotomy under epidural or lumbar anesthesia immediately Single-dose intravenous give carbetocin 100 microgram, not enough at prevention uterus tension force and in reducing postpartum hemorrhage, carbetocin is substantially better than placebo. The restoration of old ways that carbetocin can also promote uterus is given puerperal early stage.
Postpartum hemorrhage is one of common severe complication of clinical obstetrics, is the first cause of current China maternal death. In four big reasons of postpartum hemorrhage, strength of uterine contraction is hemorrhage accounts for first place. Therefore, actively preventing and treating uterine contractions fatigue is hemorrhage, is the key reducing maternal mortality rate. At present China only only 2 pharmaceutical factories produce the medicament of carbetocins, first have to before producing medicament to guarantee to have and industrialization can produce the crude drug of carbetocin.Based on carbetocin also concrete very big application prospect clinically, there is significantly high Development volue, therefore, it is possible to industrialization obtain that highly purified carbetocin fine work just becomes very important.
Applicant once submitted 1 purifying Carbetocin patent application last year to, number of patent application is 201510107759.4, although this application yield is higher, but in purge process, introduce many inorganic sodiums, owing to its storage time is short, have the deposition of a lot of inorganic salts without flushing chromatographic column in time after purification is complete, cause the damage of chromatograph pillar, need often to change, and then too increase the cost of purification. And often rinse chromatographic column, purification time significantly can be extended again. Therefore on the basis of certain yield, how the problem that production cost is exactly the present invention and needs research is reduced better.
Summary of the invention
It is an object of the invention to provide a method being suitable to industrialization purifying Carbetocin, mainly solve prior art separation and obtain carbetocin cost height, the technical problem of troublesome poeration.
For achieving the above object, technical scheme is as follows:
A kind of method of purifying Carbetocin, comprises the steps:
1) by thick for solid phase synthesis gained peptide deionized water dissolving, fixing is reverse phase silica gel post mutually, mobile phase is: the TFA(trifluoroacetic acid containing 0.1% mass percentage concentration) aqueous solution is A phase, TFA acetonitrile solution containing 0.1% mass percentage concentration is B phase, carry out gradient elution purification, collect the peptide solution of purpose peak value;
2) the high-purity peptide solution after purification adopts HPLC turn the exchange of salt method and change into acetate;
3) final high-purity peptide solution vacuum rotary steam concentrated frozen is dried, obtain Powdered finished product.
The scheme being more highly preferred to is: gradient B%:15-65%, and detection wavelength is 220nm.
The scheme being more highly preferred to is: the described reverse phase silica gel that reverse phase silica gel post is octadecyl silane.
The scheme being more highly preferred to is: described HPLC turns salt method, and pH is aqueous acetic acid and the two phase liquid of trifluoroacetic acid aqueous solution of 3.0 ~ 5.0, and chromatographic column is the reverse phase silica gel post of octadecyl silane.
The invention has the beneficial effects as follows: a process being suitable to industrialization purifying Carbetocin of the proposition of the present invention, use reversed phase high-performance liquid chromatography purifying Carbetocin, and with HPLC turn salt method exchange turn salt, the HPLC purity fine peptide more than 98.5% can not only be obtained, and can mass production, certain yield basis reaches purity height, the requirement that cost is low.
Accompanying drawing explanation
Fig. 1 is embodiment 1 product chromatogram.
Fig. 2 is embodiment 2 product chromatogram.
Fig. 3 is embodiment 3 product chromatogram.
Detailed description of the invention
Embodiment 1
1. sample treatment: will the carbetocin deionized water dissolving (concentration of ordinary dissolution is about 500mg/ml) of synthesis gained, be that to collect filtrate after 0.45um membrane filtration standby with aperture;
2. purification
Purification condition: chromatographic column: the chromatographic column with 18 alkyl silica gel bonded silica gel for fixing phase, pillar diameter and length is: 10cm �� 30cm. mobile phase: A phase: the TFA aqueous solution containing 0.05% mass percentage concentration; B phase: the TFA acetonitrile solution containing 0.05% mass percentage concentration. Flow velocity: 100-120ml/min. Detection wavelength: 220nm. Gradient: B%:20-60%, 80-100min. Sample size is 5.1-10.8g;
Purge process: rinse the acetonitrile of chromatographic column mass percentage concentration more than 80% well rear loading, applied sample amount is sample solution.Linear gradient elution, collects purpose peak, places in receiving flask standby by the peptide solution gathered;
3. turn salt: fixing mutually for the reverse phase silica gel post of octadecyl silane with the deionized water rinsing of mass percentage concentration more than 90%, (substantially neutral) is 3.0 ~ 4.5 acetate aqueous solutions with the pH configured and trifluoroacetic acid aqueous solution two phase liquid balances chromatographic column again after rinsing well, after chromatographic column balance is thorough, starts loading turns salt, applied sample amount is the purpose peptide solution gathered, linear gradient elution: first with the acetate aqueous solution of 15-30min mass percentage concentration 80-90%, acetonitrile solution then through 30-60min mass percentage concentration 20-65%, collect whole target peaks,
4. by turning all peptide solutions of gained after salt, carrying out being evaporated to 1g/200ml, thickening temperature is less than 37 DEG C, and then lyophilization obtains the purity carbetocin more than 98.5%, and purification yield can obtain more than 60%. Referring to Fig. 1.
Embodiment 2
1. sample treatment: will the carbetocin deionized water dissolving (concentration of ordinary dissolution is about 500mg/ml) of synthesis gained, be that to collect filtrate after 0.45um membrane filtration standby with aperture;
2. purification
Purification condition: chromatographic column: the chromatographic column with 18 alkyl silica gel bonded silica gel for fixing phase, pillar diameter and length is: 10cm �� 30cm. mobile phase: A phase: the TFA aqueous solution containing 0.1% mass percentage concentration; B phase: the TFA acetonitrile solution containing 0.1% mass percentage concentration. Flow velocity: 100-120ml/min. Detection wavelength: 220nm. Gradient: B%:15-55%, 80-100min. Sample size is 9.0-11.7g;
Purge process: rinse the acetonitrile of chromatographic column mass percentage concentration more than 80% well rear loading, applied sample amount is sample solution. Linear gradient elution, collects purpose peak, places in receiving flask standby by the peptide solution gathered;
3. turn salt: fixing mutually for the reverse phase silica gel post of octadecyl silane with the deionized water rinsing of mass percentage concentration more than 90%, (substantially neutral) is 3.5 ~ 5.0 acetate aqueous solutions with the pH configured and trifluoroacetic acid aqueous solution two phase liquid balances chromatographic column again after rinsing well, after chromatographic column balance is thorough, starts loading turns salt, applied sample amount is the purpose peptide solution gathered, linear gradient elution: first with the acetate aqueous solution of 15-30min mass percentage concentration 80-90%, acetonitrile solution then through 30-70min mass percentage concentration 15-60%, collect whole target peaks,
4. by turning all peptide solutions of gained after salt, carrying out being evaporated to 1g/200ml, thickening temperature is less than 37 DEG C, and then lyophilization obtains the purity carbetocin more than 98.5%, and purification yield can obtain more than 70%. Referring to Fig. 2.
Embodiment 3
1. sample treatment: will the carbetocin deionized water dissolving (concentration of ordinary dissolution is about 1000mg/ml) of synthesis gained, be that to collect filtrate after 0.45um membrane filtration standby with aperture;
2. purification
Purification condition: chromatographic column: the chromatographic column with 18 alkyl silica gel bonded silica gel for fixing phase, pillar diameter and length is: 15cm �� 50cm. mobile phase: A phase: the TFA aqueous solution containing 0.15% mass percentage concentration; B phase: the TFA acetonitrile solution containing 0.15% mass percentage concentration. Flow velocity: 150-180ml/min. Detection wavelength: 220nm. Gradient: B%:15-65%, 100-120min. Sample size is 18.0-20.0g;
Purge process: rinse the acetonitrile of chromatographic column mass percentage concentration more than 80% well rear loading, applied sample amount is sample solution.Linear gradient elution, collects purpose peak, places in receiving flask standby by the peptide solution gathered;
3. turn salt: fixing mutually for the reverse phase silica gel post of octadecyl silane with the deionized water rinsing of mass percentage concentration more than 90%, (substantially neutral) is 3.5 ~ 5.5 acetate aqueous solutions with the pH configured and trifluoroacetic acid aqueous solution two phase liquid balances chromatographic column again after rinsing well, after chromatographic column balance is thorough, starts loading turns salt, applied sample amount is the purpose peptide solution gathered, linear gradient elution: first with the acetate aqueous solution of 10-30min mass percentage concentration 60-80%, acetonitrile solution then through 50-100min mass percentage concentration 15-65%, collect whole target peaks,
4. by turning all peptide solutions of gained after salt, carrying out being evaporated to 1g/200ml, thickening temperature is less than 37 DEG C, and then lyophilization obtains the purity carbetocin more than 98.5%, and purification yield can obtain more than 75%. Referring to Fig. 3.
In sum; low with the method purifying Carbetocin cost; operation is simple; for industrialized purification carbetocin; safety coefficient is high; highly purified fine work can be obtained again while method is simple and easy to get, be strictly a good purification process, additionally be suitably modified on the basis of this patent and will need to be protected.
Claims (4)
1. a method for purifying Carbetocin, adopts reversed phase high-performance liquid chromatography, it is characterized in that comprising the steps:
1) by thick for solid phase synthesis gained peptide deionized water dissolving, fixing is reverse phase silica gel post mutually, mobile phase has biphase, trifluoroacetic acid aqueous solution containing 0.1% mass percentage concentration is A phase, trifluoroacetic acid acetonitrile solution containing 0.1% mass percentage concentration is B phase, carry out gradient elution purification, collect the peptide solution of purpose peak value;
2) the high-purity peptide solution after purification adopts HPLC turn the exchange of salt method and change into acetate;
3) final high-purity peptide solution vacuum rotary steam concentrated frozen is dried, obtain Powdered finished product.
2. the method for purifying Carbetocin according to claim 1, is characterized in that: described gradient elution, the value range B%=15-65% of mass percentage concentration, and detection wavelength is 220nm.
3. the method for purifying Carbetocin according to claim 1, is characterized in that: described reverse phase silica gel post is octadecylsilane chemically bonded silica.
4. the method for purifying Carbetocin according to claim 1, is characterized in that: described HPLC turns salt method, and pH is aqueous acetic acid and the two phase liquid of trifluoroacetic acid aqueous solution of 3.0 ~ 5.0, and chromatographic column is the reverse phase silica gel post of octadecylsilane chemically bonded silica.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610190022.8A CN105646669A (en) | 2016-03-30 | 2016-03-30 | Carbetocin purification method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610190022.8A CN105646669A (en) | 2016-03-30 | 2016-03-30 | Carbetocin purification method |
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| CN105646669A true CN105646669A (en) | 2016-06-08 |
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| CN201610190022.8A Pending CN105646669A (en) | 2016-03-30 | 2016-03-30 | Carbetocin purification method |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112851746A (en) * | 2019-11-26 | 2021-05-28 | 深圳翰宇药业股份有限公司 | Desalination method utilizing freeze-drying principle |
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|---|---|---|---|---|
| CN101531705A (en) * | 2009-04-21 | 2009-09-16 | 深圳市翰宇药业有限公司 | Method for purifying Carbetocin |
| CN102146122A (en) * | 2010-11-12 | 2011-08-10 | 深圳市健元医药科技有限公司 | Process for producing medicament with uterine contraction effect |
| CN103435687A (en) * | 2013-09-05 | 2013-12-11 | 杭州诺泰制药技术有限公司 | Method for purifying carbetocin |
| CN105037488A (en) * | 2015-08-25 | 2015-11-11 | 南京肽业生物科技有限公司 | Purification method of melanotan II |
| CN105223296A (en) * | 2015-10-16 | 2016-01-06 | 江苏开元医药化工有限公司 | The purification process of one class polypeptide |
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2016
- 2016-03-30 CN CN201610190022.8A patent/CN105646669A/en active Pending
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| CN101531705A (en) * | 2009-04-21 | 2009-09-16 | 深圳市翰宇药业有限公司 | Method for purifying Carbetocin |
| CN102146122A (en) * | 2010-11-12 | 2011-08-10 | 深圳市健元医药科技有限公司 | Process for producing medicament with uterine contraction effect |
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Application publication date: 20160608 |