CN102584953B - Purification method for atosiban - Google Patents
Purification method for atosiban Download PDFInfo
- Publication number
- CN102584953B CN102584953B CN201210028890.8A CN201210028890A CN102584953B CN 102584953 B CN102584953 B CN 102584953B CN 201210028890 A CN201210028890 A CN 201210028890A CN 102584953 B CN102584953 B CN 102584953B
- Authority
- CN
- China
- Prior art keywords
- atosiban
- solution
- perchlorate
- thick peptide
- purification process
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
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
Abstract
The invention belongs to the technical field of pharmaceutical chemistry, and discloses a purification method for atosiban. The purification method comprises the following steps of: treating atosiban coarse peptide solution by taking trivalent iron ion salt as a reducing agent; removing impurities which are not fully oxidized in the atosiban coarse peptide solution; purifying the atosiban coarse peptide solution by using high performance liquid chromatography; and converting atosiban perchlorate prepared through purification to prepare an atosiban pure product by using the high performance liquid chromatography. The purification method provided by the invention is easy and feasible to operate; the prepared atosiban pure peptide product has high purity; meanwhile, the yield of the atosiban pure peptide product prepared by the method is high; and over 1,000 g of the atosiban pure peptide product can be obtained in one batch and is sufficient to meet the industrial requirements.
Description
Technical field
The invention belongs to the pharmaceutical chemistry technical field, relate in particular to a kind of purification process of Atosiban.
Background technology
Atosiban, English name Atosiban, chemical name is: 1-(3-mercaptan lactic acid)-2-(0-ethyl-D tyrosine)-4-L-Threonine-8-L-ornithine-pitocin.Atosiban is the ring type polypeptide of synthetic, comprises three alpha-non-natural amino acid D-Tyr (Et) in peptide chain, Mpa and Orn and a pair of between Mpa and Cys the disulfide linkage of Cheng Huan, molecular formula is C
43h
67n
11o
12s
2, molecular weight is 994.19, its structural formula is as follows:
Atosiban is a kind of breakthrough product in the Obstetric and Gynecologic Department medicine, it is a kind of Oxitocin analogues, it is the pitocin competitive antagonist of acceptor on intrauterine basal decidua, fetal membrane, can be directly and pitocin competition ocytocin receptor, suppress pitocin and ocytocin receptor combination, act on uterus thereby directly suppress pitocin, suppress uterine contraction; Hydrolytic action that also can inhibition of phosphatidylinositol3, blocking-up second messenger's generation and the activity of Ca2+, thus indirectly suppress the reaction of uterus to pitocin, uterine contraction is inhibited, reach the purpose of preventing miscarriage.In the past several years, its efficacy and saferry has been assessed in many clinical trials.Atosiban can suppress uterine contraction rapidly, extends gestation, postpone not term birth, and, to mother, fetus and baby does not have detrimentally affect.Therefore Atosiban has good application prospect clinically, has very high exploitation and is worth.
At present, the domestic and international report about the Atosiban synthetic process has a lot.As glycine (Gly) and the chloromethyl resin of protecting by Boc prepares amino-acid resin; then obtain peptide resin by remaining protected amino acid of circulation condensation coupling; peptide resin obtains the full guard peptide after the ammonia solution; go to side chain protected group by the de-solution of sodium hydrogen, carry out the iodine cyclisation and obtain the purpose peptide.The RinkAminde resin that obtains amido linkage with the TEA cracking for another example, as initial resin, is selected the Fmoc solid phase synthesis process.Yet aforesaid method gained Atosiban purpose peptide purity is all lower, does not reach industrialized requirement, using value is not high.
Summary of the invention
In view of this, the object of the present invention is to provide a kind of purification process of Atosiban.
For realizing purpose of the present invention, the present invention adopts following technical scheme:
A kind of purification process of Atosiban comprises the following steps:
Step 1, with the aqueous acetic acid of 50v/v%～100v/v%, dissolve the thick peptide of Atosiban, filter and collect filtrate, add ferric ion salt according to 2% the ratio that is not less than the thick peptide weight of Atosiban, then water by the acetic acid dilution proportion in thick peptide solution below 50v/v%;
Step 2, the thick peptide solution of high performance liquid chromatography separating step 1 gained, take octadecylsilane or eight alkyl silane bonded silica gels is stationary phase, after the thick peptide solution loading of step 1 gained, the mixing solutions of perchlorate aqueous solution and acetonitrile of take is moving phase, at acetonitrile volume ratio 20%～40% scope internal linear gradient elution, collect elutriant, obtain Atosiban perchlorate solution, the solution that the perchlorate volume ratio that wherein said perchlorate aqueous solution is pH2.5～pH3.2 is 0.1v/v%～0.8v/v%;
Step 3, the Atosiban perchlorate solution that adopts reversed-phased high performace liquid chromatographic that step 2 is obtained change into acetate solution, obtain.
The thick peptide of Atosiban of the present invention refers to and adopts liquid phase synthesizing method or solid-phase synthesis and other method is that make, Atosiban that do not pass through refinement treatment or purity can not fulfilling medicinals Atosiban.
Preferably, the aqueous acetic acid of the described 50v/v%～100v/v% of step 1 of the present invention dissolves the thick peptide of Atosiban to be not more than 100g/L concentration.In a specific embodiment, the concentration of the thick peptide of described Atosiban is 100g/L, and the thick peptide of every 100g Atosiban adds the aqueous acetic acid of 1L 50v/v%～100v/v%.
Purification process step 1 of the present invention is first dissolved the thick peptide of Atosiban, and the ferric ion salt of then usining is processed the thick peptide solution of Atosiban as reductive agent, removes not oxidation wherein impurity completely.Wherein said ferric ion salt is preferably iron(ic) chloride or ferric sulfate.
The add-on of ferric ion salt of the present invention is not less than 2% of the thick peptide weight of Atosiban, and the thick peptide of every 100g Atosiban adds 2g or the above ferric ion salt of 2g.Preferably, the add-on of described ferric ion salt is 4%～8% of the thick peptide weight of Atosiban, and the thick peptide of every 100g Atosiban adds 4～8g ferric ion salt.
Purification process of the present invention, ferric ion salt reductive agent to Atosiban thick peptide solution processed after water by the acetic acid dilution proportion in thick peptide solution below 50v/v%.Preferably, in the thick peptide solution after described dilution, the ratio of acetic acid is 30v/v%～40v/v%.
Purification process step 2 of the present invention is utilized the thick peptide solution of high performance liquid chromatography separating step 1 gained, take octadecylsilane chemically bonded silica as stationary phase, after the thick peptide solution loading of step 1 gained, the mixing solutions of perchlorate aqueous solution and acetonitrile of take is the moving phase wash-out, collect elutriant, obtain Atosiban perchlorate solution.
Those skilled in the art can, according to the amount of the thick peptide of purifying Atosiban, select the chromatographic column purifying of different size size (pillar diameter * length) as 5cm * 25cm specification chromatographic column, 15cm * 25cm specification chromatographic column, 30cm * 25cm specification chromatographic column or 45cm * 25cm specification chromatographic column.
Before loading, also need chromatographic column is rinsed, preferred, the acetonitrile solution above with 50v/v% rinses.After chromatographic column is rinsed, by the thick peptide solution loading of the Atosiban of step 1 gained.According to the diameter difference of purifying chromatographic column, select different applied sample amounts.
It is moving phase that purification process step 2 of the present invention be take the mixing solutions of perchlorate aqueous solution and acetonitrile, the volume of perchlorate aqueous solution and acetonitrile and be 100%.At acetonitrile volume ratio 20%～40% scope internal linear gradient elution, at perchlorate aqueous solution's volume ratio 80%～60% scope internal linear gradient elution.
As preferably, described perchlorate aqueous solution is the sodium perchlorate aqueous solution, the potassium perchlorate aqueous solution or the ammoniumper chlorate aqueous solution.
Preferably, the solution that the perchlorate volume ratio that described perchlorate aqueous solution is pH2.5～pH3.2 is 0.3v/v%～0.6v/v%.More preferably, the solution that the perchlorate volume ratio of pH3.0 is 0.5v/v%.
Preferably, purification process step 2 of the present invention also comprises that the Atosiban perchlorate solution to making carries out enrichment step.The described concentrated Atosiban perchlorate solution that will make of being preferably is concentrated into about 10-20mg/mL in being no more than vacuum rotary steam under the condition of 35 ℃.
RPLC, English name reversed phase high performance liquid chromatography, be called for short RP-HPLC, the liquid chromatography system be comprised of non-polar stationary phase and polarity moving phase.It is just in time contrary with the liquid chromatography system (normal-phase chromatography) be comprised of polar stationary phase and low-pole moving phase.RP-HPLC is the topmost clastotype of current liquid chromatography, almost can be used for all organic separation that can be dissolved in polarity or weak polar solvent.The Atosiban perchlorate solution that purification process step 3 of the present invention adopts reversed-phased high performace liquid chromatographic that step 2 is obtained changes into acetate solution.
Preferably, described reversed-phased high performace liquid chromatographic is specially: take octadecylsilane or eight alkyl silane bonded silica gels is stationary phase, after step 2 gained Atosiban perchlorate solution loading, first with the ammonium acetate aqueous solution of the 0.1v/v%～0.8v/v% containing 3v/v%～10v/v% acetonitrile, rinse 15～30min, then use the aqueous acetic acid wash-out containing the 0.05v/v%～0.2v/v% of 30v/v%～60v/v% acetonitrile, collect elutriant, concentrate drying and get final product.
Before loading, also need chromatographic column is rinsed, preferred, the acetonitrile acetum above with 50v/v% rinses.After chromatographic column is rinsed, by step 2 gained Atosiban perchlorate solution loading.According to the diameter difference of purifying chromatographic column, select different applied sample amounts.
Preferably, the concentration for the ammonium acetate aqueous solution acetonitrile containing acetonitrile that rinses after described loading is 5v/v%～8v/v%, 6v/v% more preferably, and the concentration of ammonium acetate aqueous solution is 0.3v/v%～0.6v/v%, more preferably 0.4v/v%.
Preferably, the concentration of the described ammonium acetate aqueous solution acetonitrile containing acetonitrile for wash-out is 50v/v%, and the concentration of ammonium acetate aqueous solution is 0.1v/v%.
Preferably, also comprise before the described drying of purification process step 3 of the present invention that the elutriant to collecting carries out enrichment step.Described concentrated being preferably is concentrated into about 10-20mg/mL by the elutriant of collection in being no more than vacuum rotary steam under the condition of 35 ℃.
The water that purification process of the present invention is used is pure water, and meets the water for injection standard, is preferably ultrapure water; Acetic acid used in the present invention is analytically pure Glacial acetic acid; Acetonitrile used in the present invention is analytically pure acetonitrile acetic acid, is preferably chromatographically pure.
Purification process of the present invention is usingd ferric ion salt and as reductive agent, the thick peptide solution of Atosiban is processed, remove not oxidation wherein impurity completely, utilize afterwards the thick peptide solution of high performance liquid chromatography purifying Atosiban, then utilize Atosiban perchlorate that RPLC makes purifying to turn salt and make the Atosiban sterling.Operation is simple and feasible for purification process of the present invention, and the Atosiban sterling peptide purity made is high, can reach more than 99.5%, and maximum single mixing is less than 0.1%.The method of the invention Atosiban sterling peptide yield can reach more than 85% simultaneously, and total recovery can reach more than 50%, and one batch can obtain the above Atosiban sterling peptide of 1000g, be enough to meet industrialized requirement.
The accompanying drawing explanation
Fig. 1 shows the high performance liquid chromatography detection figure of the Atosiban sterling peptide that embodiment 1 makes.
Embodiment
The embodiment of the invention discloses a kind of purification process of Atosiban.Those skilled in the art can use for reference this paper content, suitably improve processing parameter and realize.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the artly, they all are deemed to be included in the present invention.Method of the present invention is described by preferred embodiment, and the related personnel obviously can be changed method as herein described or suitably change and combination within not breaking away from content of the present invention, spirit and scope, realizes and apply the technology of the present invention.
In order further to understand the present invention, below in conjunction with embodiment, the present invention is described in detail.
Embodiment 1:
Dissolve thick peptide with the aqueous acetic acid of volume ratio 50% according to the concentration of 100g/L, stir and make sample dissolve the rear membrane filtration of using fully, collect filtrate.5% the ratio according to thick peptide weight adds iron(ic) chloride reagent, and water is diluted to the volume ratio of the acetic acid in thick peptide solution 40% standby.
The chromatographic column that the octadecylsilane chemically bonded silica of take is stationary phase, chromatographic column is: 5cm * 25cm (diameter * length).Rinse chromatographic column well the back balance loading with the acetonitrile more than 50%, applied sample amount is 1.5-3g.The mixing solutions of perchlorate aqueous solution and acetonitrile of take is moving phase, and wherein mobile phase A is 0.4% high chloro acid solution (v/v) mutually, with the aqueous sodium hydroxide solution adjust pH 2.5 of 50mmol; Mobile phase B is acetonitrile mutually.The flow velocity of moving phase is 50-80mL/min, and the Mobile phase B of take is 20%～40% mutually, and linear gradient elution 60min collects elutriant, by the elutriant of collection vacuum rotary steam under the condition of 35 ℃, is concentrated into after about 10-20mg/mL standby.
The chromatographic column that the eight alkyl silane bonded silica gels of take are stationary phase, chromatographic column is: 5cm * 25cm (diameter * length).Rinse chromatographic column well rear loading with the acetonitrile acetum more than 50v/v%, applied sample amount 1.5-3g, rinse 15-30min with the ammonium acetate aqueous solution of the 0.4v/v% containing the 6v/v% acetonitrile, then use the aqueous acetic acid wash-out containing the 0.1v/v% of 50v/v% acetonitrile, collect elutriant, after vacuum rotary steam is concentrated into about 50-200mg/mL under 35 ℃ of conditions by the elutriant of collection, go to suitable big or small cillin bottle.Obtain Atosiban sterling peptide after lyophilize, HPLC detects the Atosiban sterling peptide made, and purity is 99.7%.
Embodiment 2:
Dissolve thick peptide with the aqueous acetic acid of volume ratio 80% according to the concentration of 100g/L, stir and make sample dissolve the rear membrane filtration of using fully, collect filtrate.4% the ratio according to thick peptide weight adds ferric sulfate reagent, and water is standby by the volume ratio dilution proportion to 30% of the acetic acid in thick peptide solution.
The chromatographic column that the eight alkyl silane bonded silica gels of take are stationary phase, chromatographic column is: 15cm * 25cm (diameter * length).Rinse chromatographic column well the back balance loading with the acetonitrile more than 50%, applied sample amount is 25-40g.The mixing solutions of perchlorate aqueous solution and acetonitrile of take is moving phase, and wherein mobile phase A is 0.3% high chloro acid solution (v/v) mutually, with the potassium hydroxide aqueous solution adjust pH 3.2 of 50mmol; Mobile phase B is acetonitrile mutually.The flow velocity of moving phase is 400-600mL/min, and the Mobile phase B of take is 20%～40% mutually, and linear gradient elution 60min collects elutriant, by the elutriant of collection vacuum rotary steam under the condition of 35 ℃, is concentrated into after about 10-20mg/mL standby.
The chromatographic column that the octadecylsilane chemically bonded silica of take is stationary phase, chromatographic column is: 15cm * 25cm (diameter * length).Rinse chromatographic column well rear loading with the acetonitrile acetum more than 50v/v%, applied sample amount 20-40g, rinse 15-30min with the ammonium acetate aqueous solution of the 0.1v/v% containing the 3v/v% acetonitrile, then use the aqueous acetic acid wash-out containing the 0.05v/v% of 30v/v% acetonitrile, collect elutriant, after vacuum rotary steam is concentrated into about 50-200mg/mL under 35 ℃ of conditions by the elutriant of collection, go to suitable big or small cillin bottle.Obtain Atosiban sterling peptide after lyophilize, HPLC detects the Atosiban sterling peptide made, and purity is 99.6%.
Embodiment 3:
Dissolve thick peptide with the aqueous acetic acid of volume ratio 90% according to the concentration of 100g/L, stir and make sample dissolve the rear membrane filtration of using fully, collect filtrate.8% the ratio according to thick peptide weight adds iron(ic) chloride reagent, and water is standby by the volume ratio dilution proportion to 40% of the acetic acid in thick peptide solution.
The chromatographic column that the octadecylsilane chemically bonded silica of take is stationary phase, chromatographic column is: 30cm * 25cm (diameter * length).Rinse chromatographic column well the back balance loading with the acetonitrile more than 50%, applied sample amount is 80-170g.The mixing solutions of perchlorate aqueous solution and acetonitrile of take is moving phase, and wherein mobile phase A is 0.8% high chloro acid solution (v/v) mutually, with the potassium hydroxide aqueous solution adjust pH 3.0 of 50mmol; Mobile phase B is acetonitrile mutually.The flow velocity of moving phase is 2000-3500mL/min, and the Mobile phase B of take is 20%～40% mutually, and linear gradient elution 60min collects elutriant, by the elutriant of collection vacuum rotary steam under the condition of 35 ℃, is concentrated into after about 10-20mg/mL standby.
The chromatographic column that the eight alkyl silane bonded silica gels of take are stationary phase, chromatographic column is: 30cm * 25cm (diameter * length).Rinse chromatographic column well rear loading with the acetonitrile acetum more than 50v/v%, applied sample amount 80-170g, rinse 15-30min with the ammonium acetate aqueous solution of the 0.8v/v% containing the 10v/v% acetonitrile, then use the aqueous acetic acid wash-out containing the 0.2v/v% of 60v/v% acetonitrile, collect elutriant, after vacuum rotary steam is concentrated into about 50-200mg/mL under 35 ℃ of conditions by the elutriant of collection, go to suitable big or small cillin bottle.Obtain Atosiban sterling peptide after lyophilize, HPLC detects the Atosiban sterling peptide made, and purity is 99.8%.
Embodiment 4:
Dissolve thick peptide with the aqueous acetic acid of volume ratio 60% according to the concentration of 100g/L, stir and make sample dissolve the rear membrane filtration of using fully, collect filtrate.5% the ratio according to thick peptide weight adds iron(ic) chloride reagent, and water is standby by the volume ratio dilution proportion to 30% of the acetic acid in thick peptide solution.
The chromatographic column that the octadecylsilane chemically bonded silica of take is stationary phase, chromatographic column is: 45cm * 25cm (diameter * length).Rinse chromatographic column well the back balance loading with the acetonitrile more than 50%, applied sample amount is 200-500g.The mixing solutions of perchlorate aqueous solution and acetonitrile of take is moving phase, and wherein mobile phase A is 0.6% high chloro acid solution (v/v) mutually, with the potassium hydroxide aqueous solution adjust pH 3.0 of 50mmol; Mobile phase B is acetonitrile mutually.The flow velocity of moving phase is 5000-8500mL/min, and the Mobile phase B of take is 20%～40% mutually, and linear gradient elution 60min collects elutriant, by the elutriant of collection vacuum rotary steam under the condition of 35 ℃, is concentrated into after about 10-20mg/mL standby.
The chromatographic column that the eight alkyl silane bonded silica gels of take are stationary phase, chromatographic column is: 45cm * 25cm3 (diameter * length).Rinse chromatographic column well rear loading with the acetonitrile acetum more than 50v/v%, applied sample amount 200-500g, rinse 15-30min with the ammonium acetate aqueous solution of the 0.6v/v% containing the 8v/v% acetonitrile, then use the aqueous acetic acid wash-out containing the 0.1v/v% of 50v/v% acetonitrile, collect elutriant, after vacuum rotary steam is concentrated into about 50-200mg/mL under 35 ℃ of conditions by the elutriant of collection, go to suitable big or small cillin bottle.Obtain Atosiban sterling peptide after lyophilize, HPLC detects the Atosiban sterling peptide made, and purity is 99.7%.
The explanation of above embodiment is just for helping to understand method of the present invention and core concept thereof.It should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention, can also carry out some improvement and modification to the present invention, these improvement and modification also fall in the protection domain of the claims in the present invention.
Claims (9)
1. the purification process of an Atosiban, is characterized in that, comprises the following steps:
Step 1, with the aqueous acetic acid of 50v/v%～100v/v%, dissolve the thick peptide of Atosiban, filter and collect filtrate, add ferric ion salt according to 2% the ratio that is not less than the thick peptide weight of Atosiban, then water by the acetic acid dilution proportion in thick peptide solution below 50v/v%;
Step 2, the thick peptide solution of high performance liquid chromatography separating step 1 gained, take octadecylsilane or eight alkyl silane bonded silica gels is stationary phase, after the thick peptide solution loading of step 1 gained, the mixing solutions of perchlorate aqueous solution and acetonitrile of take is moving phase, at acetonitrile volume ratio 20%～40% scope internal linear gradient elution, collect elutriant, obtain Atosiban perchlorate solution, the solution that the perchlorate volume ratio that wherein said perchlorate aqueous solution is pH2.5～pH3.2 is 0.1v/v%～0.8v/v%;
Step 3, the Atosiban perchlorate solution that adopts reversed-phased high performace liquid chromatographic that step 2 is obtained change into acetate solution, obtain.
2. purification process according to claim 1, is characterized in that, the aqueous acetic acid of the described 50v/v% of take of step 1～100v/v% dissolves the thick peptide of Atosiban and adds the aqueous acetic acid of 1L50v/v%～100v/v% as the thick peptide of every 100g Atosiban.
3. purification process according to claim 1, is characterized in that, the described ferric ion salt of step 1 is iron(ic) chloride or ferric sulfate.
4. purification process according to claim 1, is characterized in that, the described ferric ion salt of step 1 is 4%～8% of the thick peptide weight of Atosiban.
5. purification process according to claim 1, is characterized in that, in the thick peptide solution after the described dilution of step 1, the ratio of acetic acid is 30v/v%～40v/v%.
6. purification process according to claim 1, is characterized in that, the described perchlorate aqueous solution of step 2 is the sodium perchlorate aqueous solution, the potassium perchlorate aqueous solution or the ammoniumper chlorate aqueous solution.
7. purification process according to claim 1, is characterized in that, step 2 also comprises that the Atosiban perchlorate solution to making carries out enrichment step.
8. purification process according to claim 7, is characterized in that, described simmer down to is concentrated into about 10-20mg/mL by the Atosiban perchlorate solution that makes in being no more than vacuum rotary steam under the condition of 35 ℃.
9. purification process according to claim 1, it is characterized in that, the described reversed-phased high performace liquid chromatographic of step 3 is specially: take octadecylsilane or eight alkyl silane bonded silica gels is stationary phase, after step 2 gained Atosiban perchlorate solution loading, first with the ammonium acetate aqueous solution of the 0.1v/v%～0.8v/v% containing 3v/v%～10v/v% acetonitrile, rinse 15～30min, then use the aqueous acetic acid wash-out containing the 0.05v/v%--0.2v/v% of 30v/v%-60v/v% acetonitrile, collect elutriant, concentrate drying and get final product.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210028890.8A CN102584953B (en) | 2012-02-09 | 2012-02-09 | Purification method for atosiban |
| PCT/CN2013/070505 WO2013117122A1 (en) | 2012-02-09 | 2013-01-16 | Method for purifying atosiban |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210028890.8A CN102584953B (en) | 2012-02-09 | 2012-02-09 | Purification method for atosiban |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102584953A CN102584953A (en) | 2012-07-18 |
| CN102584953B true CN102584953B (en) | 2014-01-01 |
Family
ID=46474265
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210028890.8A Active CN102584953B (en) | 2012-02-09 | 2012-02-09 | Purification method for atosiban |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN102584953B (en) |
| WO (1) | WO2013117122A1 (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584953B (en) * | 2012-02-09 | 2014-01-01 | 深圳翰宇药业股份有限公司 | Purification method for atosiban |
| CN102875664B (en) * | 2012-09-21 | 2014-06-18 | 深圳翰宇药业股份有限公司 | Purifying method of carperitide |
| EP2919903B1 (en) | 2012-11-14 | 2020-07-22 | W.R. Grace & CO. - CONN. | Compositions containing a biologically active material and a non-ordered inorganic oxide |
| CN103421092B (en) * | 2013-09-05 | 2015-05-13 | 杭州阿德莱诺泰制药技术有限公司 | Atosiban purification method |
| CN106279367B (en) * | 2016-08-15 | 2019-06-04 | 海南合瑞制药股份有限公司 | A kind of atosiban acetate crystal and preparation method thereof |
| CN108659104B (en) * | 2018-07-03 | 2020-06-09 | 北京市新里程医药科技有限公司 | Preparation method of terlipressin and pharmaceutical composition thereof |
| CN111057141B (en) * | 2018-10-17 | 2023-11-14 | 深圳市健元医药科技有限公司 | Tripeptide refining process |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4504469A (en) * | 1982-12-21 | 1985-03-12 | Ferring Ab | Vasotocin derivatives |
| CN101696236A (en) * | 2009-02-11 | 2010-04-21 | 海南中和药业有限公司 | Method for synthesizing atosiban by solid phase |
| CN101981048A (en) * | 2008-02-06 | 2011-02-23 | 拜康有限公司 | A method of purifying a peptide |
| CN102127146A (en) * | 2010-12-24 | 2011-07-20 | 深圳翰宇药业股份有限公司 | Method for preparing atosiban acetate |
| CN102146121A (en) * | 2010-11-19 | 2011-08-10 | 深圳市健元医药科技有限公司 | Process for producing antagonist medicament containing OXT (oxytocin) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2464655B1 (en) * | 2009-08-11 | 2017-02-15 | Biocon Limited | Chromatographic processes |
| CN102584953B (en) * | 2012-02-09 | 2014-01-01 | 深圳翰宇药业股份有限公司 | Purification method for atosiban |
-
2012
- 2012-02-09 CN CN201210028890.8A patent/CN102584953B/en active Active
-
2013
- 2013-01-16 WO PCT/CN2013/070505 patent/WO2013117122A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4504469A (en) * | 1982-12-21 | 1985-03-12 | Ferring Ab | Vasotocin derivatives |
| CN101981048A (en) * | 2008-02-06 | 2011-02-23 | 拜康有限公司 | A method of purifying a peptide |
| CN101696236A (en) * | 2009-02-11 | 2010-04-21 | 海南中和药业有限公司 | Method for synthesizing atosiban by solid phase |
| CN102146121A (en) * | 2010-11-19 | 2011-08-10 | 深圳市健元医药科技有限公司 | Process for producing antagonist medicament containing OXT (oxytocin) |
| CN102127146A (en) * | 2010-12-24 | 2011-07-20 | 深圳翰宇药业股份有限公司 | Method for preparing atosiban acetate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102584953A (en) | 2012-07-18 |
| WO2013117122A1 (en) | 2013-08-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102584953B (en) | Purification method for atosiban | |
| CN103102395B (en) | Preparation method of desmopressin acetate | |
| CN102993293B (en) | Method for purifying teriparatide acetate | |
| CN103694320B (en) | A kind of preparation method of that peptide of pulika | |
| CN103694316B (en) | A kind of preparation method of A Ji Rayleigh | |
| CN104231051A (en) | Preparation method for linaclotide | |
| CN109503705B (en) | Method for separating and purifying liraglutide | |
| CN102977192A (en) | Purification method of carbetocin | |
| CN103497245A (en) | Method for synthesizing thymalfasin | |
| CN111057142B (en) | Purification method of teriparatide | |
| CN105622726A (en) | Leuprolide acetate preparing method | |
| CN102875669B (en) | Method for separating and extracting ovotransferrin | |
| CN104231055A (en) | Ganirelix precursor and method for preparing ganirelix acetate by using ganirelix precursor | |
| CN101440127A (en) | Preparation of high-purity vancomycin hydrochloride | |
| CN104628826A (en) | Preparation method for linaclotide | |
| CN102863517B (en) | Goserelin purification method | |
| CN103665115B (en) | The chemical preparation process of cyclic decapeptide compound GG-110824 | |
| CN101798334B (en) | Purification method of human parathyroid hormone (1-34) | |
| CN103467574A (en) | Purification method of desmopressin acetate | |
| CN109053863A (en) | A kind of method of low cost preparation high-purity Linaclotide | |
| CN102875654B (en) | Method for preparing conotoxin polypeptide Eb1.6 | |
| CN102268073A (en) | Method for preparing somatostatin | |
| CN101525382B (en) | Method of purifying pramlintide | |
| CN109467591A (en) | A kind of purification process of Cetrorelix | |
| CN111269309A (en) | Purification method of GLP-1 analog polypeptide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |