CN106749539A - A kind of preparation method of oxytocin deamidation impurity - Google Patents
A kind of preparation method of oxytocin deamidation impurity Download PDFInfo
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- CN106749539A CN106749539A CN201710001527.XA CN201710001527A CN106749539A CN 106749539 A CN106749539 A CN 106749539A CN 201710001527 A CN201710001527 A CN 201710001527A CN 106749539 A CN106749539 A CN 106749539A
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- 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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Abstract
The invention discloses a kind of preparation method of oxytocin deamidation impurity.The preparation method comprises the steps：Oxytocin deamidation impurity precursor crude product solution is carried out by anti-phase cyclisation, anti-phase purifying, anti-phase desalination using efficient liquid phase RP chromatography successively, you can；The filler of efficient liquid phase RP chromatography is silica gel C18；Described oxytocin deamidation impurity precursor crude product is the oxytocin deamidation impurity precursor crude product containing two free sulfhydryl groups.Novelty of the present invention has used reverse phase absorption method to be cyclized, purify and desalination, disposable to solve the problems, such as cyclisation, purifying and desalination, optimizes production technology, is adapted to industrialize continuous production.
Description
Technical field
The present invention relates to field of biological pharmacy.More particularly it relates to a kind of preparation of oxytocin deamidation impurity
Method.
Background technology
Oxytocin, also known as oxytocins, English entitled Oxytocin, structural formula：
Molecular formula is：C43H66N12O12S2, molecular weight is 1007.2
Oxytocin be used for induced labor, hasten parturition, the uterine hemorrhage that postpartum and post-abortion cause because uterine atony or contracting abdomen are bad；
Understand placenta reserve function (oxytocins enrages experiment)；Collunarium can promote milk ejection.Oxytocin energy indirect stimulation uterine smooth muscle is received
Contracting, simulates the uterine contractile effect of normal labor, causes cervical dilatation, uterus to the reaction of oxytocin in During Pregnancy by
It is cumulative to add, peak is reached when mature.Oxytocin can also pierce mammotropic smooth muscle contraction, contribute to milk to be discharged from breast, but simultaneously
The galactosis amount of mammary gland is not increased.
For a medicine, a small amount of impurity contained therein is to trigger the most important reason of medicine side effect, therefore right
The inspection of its purity is one of important foundation of guarantee drug safety validity, and the content of purity test, according to each medicine
Property and feature it is somewhat different, but be substantially intended to be related to respective " relevant material " to check research.Synthesis polypeptide it is relevant
Process contaminants of the material in building-up process and unstable due to polypeptide and catabolite, polymer for producing etc. are miscellaneous
Matter, although the purifying process of synthesis polypeptide has had great progress at present, process contaminants are still the relevant material of synthesis polypeptide
Important sources, mainly due to some process contaminants of synthesis polypeptide, (such as disappearance peptide, fracture peptide, oxidation peptide, disulfide bond are handed over for this
Product for changing etc.) property with medicine in itself may be very approximate, so as to cause certain difficulty to purifying.Research shows to close
Most common catabolite is deamidation product, oxidation product, hydrolysate into polypeptide.In the various amino acid of composition polypeptide
In, asparagine, glutamine and peptide chain C sections of acid amides are prone to deamidation reaction and (are especially raised and high temperature bar in pH value
Under part).
Because the property of some impurity with target product closely, hence sets up suitable method abundant in synthesis polypeptide
It is the great difficulty faced during the relevant material of synthetic polypeptide medicaments is studied to detect these impurity.
Oxytocin deamidation impurity in the country's protected oxytocin resin using synthesis in solid state before this mostly at present, then by cracking
Dry the oxytocin deamidation impurity precursor crude product (trifluoroacetic acid of Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly
Salt), high dilution cyclisation, purifying turns the steps such as salt, finally gives oxytocin deamidation impurity.High dilution is cyclized due to sample
Product concentration is dilute, bulky, very unfavorable for later-period purification.A kind of effective propolypeptide of the preparation containing disulfide bond is also lacked now
The method for expecting medicine analog, therefore still in the urgent need to developing the new preparation method containing disulfide bond polypeptide.
The content of the invention
The technical problems to be solved by the invention are to overcome the preparation of oxytocin deamidation impurity in the prior art
Complex process, yield are low, sample concentration is dilute, bulky defect, and provide a kind of preparation of oxytocin deamidation impurity
Method.The preparation method of oxytocin deamidation impurity of the invention is with containing a pair of polypeptide crude products of free sulfhydryl groups (- SH) --- contracting
Palace element deamidation impurity precursor crude product is initiation material, by the cyclisation of high pressure liquid phase reverse-phase chromatography, purifying and desalting steps, is prepared
The method of the oxytocin deamidation impurity of high-purity.Polypeptide of the invention is 1 critical impurities in oxytocin preparation process, because
This can carry out qualitative and quantitative analysis, for carrying as the standard reference material of oxytocin detection process to oxytocin and impurity
The quality standard of oxytocin high, control product quality is significant.
The present invention is to solve above-mentioned technical problem by the following technical programs：
The invention provides a kind of preparation method of oxytocin deamidation impurity, it comprises the steps：Using efficient liquid
Oxytocin deamidation impurity precursor crude product solution is carried out anti-phase cyclisation, anti-phase purifying, anti-phase desalination by phase RP chromatography successively,
；The filler of efficient liquid phase RP chromatography is silica gel C18；
Described oxytocin deamidation impurity precursor crude product is that the oxytocin deamidation impurity precursor containing two free sulfhydryl groups is thick
Product；
Described oxytocin deamidation impurity is
Wherein, described oxytocin deamidation impurity precursor crude product is preferably using solid-phase synthesis by cracking drying
Obtained oxytocin deamidation impurity precursor crude product, HPLC purity is 60~90%；Described oxytocin deamidation impurity precursor
The structural formula of crude product is the trifluoroacetate of Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly.
Wherein, it is thick that described oxytocin deamidation impurity precursor crude product solution is preferably oxytocin deamidation impurity precursor
Product are dissolved in the 5g/L solution that the acetonitrile solution that concentration of volume percent is 5% is formed.
In the present invention, described anti-phase cyclisation, anti-phase purifying, anti-phase desalination are complete in the anti-phase elution process of a step
Into.
Wherein, described anti-phase cyclisation, anti-phase purifying, the condition of anti-phase desalination are preferably as follows：Mobile phase A 1 is pure water, A2
It is the H of percent by volume 0.01~0.05% (preferably 0.02~0.03%)2O2PH is 7.5~9.0 NaOH aqueous solution,
Mobile phase B is acetonitrile, and mobile phase C is described oxytocin deamidation impurity precursor crude product solution, and flow velocity is 80~110mL/min
(preferably 100mL/min), Detection wavelength is 220nm；
Condition according to following table carries out online loading, wash-out, and percentage is percent by volume；
| Elution step | Elution time | Eluent |
| 1 | 0~10min | 100%C |
| 2 | 10~25min | 95%A1+5%B |
| 3 | 25.1~30min | 95%A2+5%B |
| 4 | 30.1~35 | 95%A1+5%B |
| 5 | 35~50min | 95%A1+5%B → 80%A1+20%B |
| 6 | 50~65min | 80%A1+20%B → 73%A1+27%B |
| 7 | 65~75min | 50%A1+50%B |
| 8 | 75~80min | 95%A1+5%B |
Collect the eluent that retention time is 50~65min and obtain oxytocin deamidation dirt solution.
Wherein, the filling condition of described efficient liquid phase RP chromatography is preferably as follows：Filler is Kromasil silica gel
C18, aperture 10nm, 10 μm of particle diameter.
Oxytocin deamidation impurity is a kind of peptide material, unstable in the basic conditions, degradable, especially highly basic ring
Under border, the de- concentration of integrated survey of the present invention alkali cleaning and time, to ensure to reduce the destruction and loss of sample in desalination processes.
Innovative point of the present invention be will cyclisation, purifying and the step of desalination one is anti-phase obtains polypeptide sterling, oxytocin deamidation is miscellaneous
Containing two free sulfhydryl groups in matter precursor crude product, traditional handicraft cyclisation and purifying substep are carried out, and bulky, the increase being cyclized
The difficulty of purifying, for cyclisation rapidly and efficiently and preparation technology, designs the more recent application of silica gel C18 fillers.The present invention
Novelty has used reverse phase absorption method to be cyclized, purify and desalination, disposable to solve the problems, such as cyclisation, purifying and desalination.
On the basis of common sense in the field is met, above-mentioned each optimum condition can be combined, and obtain final product each preferable reality of the present invention
Example.
Agents useful for same of the present invention and raw material are commercially available.
Positive effect of the invention is：
(1) first be adsorbed onto reduced form polypeptide crude product in fixing phase, using polypeptide by the present invention using the method for online cyclisation
With the hydrophobic binding of reverse phase filler, the acid ion of neutral wash-out weak binding on a column, and using pH meta-alkalis containing H2O2's
Mobile phase is rinsed, and promotes two sulfydryls into disulfide bond, obtains target polypeptides crude product, and sample retains on a column.
(2) using online cyclisation, the sample of cyclisation avoids wash-out to the present invention, and can directly convert carry out gradient after mobile phase and wash
De- purifying, obtains final sterling, is adapted to continuous production.
(3) present invention has innovatively used reverse phase absorption cyclisation, purifying, desalination one-step method that polypeptide sterling, optimization is obtained
Production technology, is adapted to the continuous production of industrialization.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to described reality
Apply among a scope.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or according to business
Product specification is selected.
In following embodiments, oxytocin deamidation impurity is
Embodiment 1 (HPLC methods detect oxytocin deamidation impurity precursor crude product and purifying midbody solution purity and quantify)
Instrument：The high performance liquid chromatographs of Agilent 1200
Splitter：Waters XBridge-C18,4.6 × 150mm, 5 μm
Mobile phase：A is the acetonitrile solution of percent by volume 50%, and B is 0.02M KH2PO4The aqueous solution of pH 3.0, flow velocity is
1.0mL/min, Detection wavelength is 220nm, room temperature detection, and gradient see the table below shown, and percentage is percent by volume.
| Elution step | Elution time | Eluent |
| 1 | 0~15min | 35%A+65%B |
| 2 | 15~25min | 35%A+65%B → 100%A |
| 3 | 25~28min | 100%A |
| 4 | 28.0~28.1min | 100%A → 35%A+65%B |
| 5 | 28.1~32min | 35%A+65%B |
Embodiment 2 (50mm internal diameters L＆L4002 prepares post filling)
With Load＆Lock dynamic axial compressions and static locking technology, filler is silica gel C18 (Kromasil C18),
Aperture 10nm, 10 μm of particle diameter fills column density 0.66g/mL, is filled to post bed pressure 133bar, and system is loaded using Varian chromatograms
System, 325g dry powder fillers after the stirring homogenate of 650mL isopropanols, pour into internal diameter 50mm L＆L4002 and prepare post, and compression ratio is 1.5:
1, carrier gas is N2, adjusting nebulizer gas pressure and cause oil pressure meter pressure for 200bar, dynamic axial compression to post bed height 25.5cm is made
Post is prepared used by anti-phase cyclisation, anti-phase purifying and anti-phase desalination scheme.
Anti-phase cyclisation, anti-phase purifying and the anti-phase desalination of the oxytocin deamidation impurity precursor crude material of embodiment 3
Instrument：Varian SD-1 high pressure liquid phase preparation systems
Chromatographic column：The self-chambering of embodiment 2 prepares 10 μm of 10nm of post Load＆Lock4002 50 × 255mm, C18
Oxytocin deamidation impurity precursor crude product is to dry obtained oxytocin deacylation by cracking using solid-phase synthesis
Amine impurity precursor crude product, structural formula is the trifluoroacetate of Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly.
Oxytocin deamidation impurity precursor crude product solution is dissolved in volume hundred for above-mentioned oxytocin deamidation impurity precursor crude product
The 5g/L solution for dividing the acetonitrile solution that specific concentration is 5% to be formed.
Mobile phase A 1 is purified water, and A2 is the H of percent by volume 0.022O2PH is the 7.5 NaOH aqueous solution, and Mobile phase B is
Acetonitrile, mobile phase C is described oxytocin deamidation impurity precursor crude product solution, its HPLC is determined as described in Example 1 pure
It is 82.25% to spend, and retention time is 9.20min.
The anti-phase cyclisation of the present embodiment, anti-phase purifying and anti-phase desalination condition are as follows：Flow velocity 100mL/min, 220nm inspection
Survey, purifying gradient see the table below shown, and percentage is percent by volume.
| Elution step | Elution time | Eluent |
| 1 | 0~10min | 100%C |
| 2 | 10~25min | 95%A1+5%B |
| 3 | 25.1~30min | 95%A2+5%B |
| 4 | 30.1~35 | 95%A1+5%B |
| 5 | 35~50min | 95%A1+5%B → 80%A1+20%B |
| 6 | 50~65min | 80%A1+20%B → 73%A1+27%B |
| 7 | 65~75min | 50%A1+50%B |
| 8 | 75~80min | 95%A1+5%B |
Collect the eluent that retention time is 50~65min and obtain oxytocin deamidation dirt solution, by the side of embodiment 1
It is 99.52% that method determines its HPLC purity, and retention time is 6.56min.
Anti-phase cyclisation, anti-phase purifying and the anti-phase desalination of the oxytocin deamidation impurity precursor crude material of embodiment 4
Instrument：Varian SD-1 high pressure liquid phase preparation systems
Chromatographic column：The self-chambering of embodiment 2 prepares 10 μm of 10nm of post Load＆Lock4002 50 × 255mm, C18
Oxytocin deamidation impurity precursor crude product is to dry obtained oxytocin deacylation by cracking using solid-phase synthesis
Amine impurity precursor crude product, structural formula is the trifluoroacetate of Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly.
Oxytocin deamidation impurity precursor crude product solution is dissolved in volume hundred for above-mentioned oxytocin deamidation impurity precursor crude product
The 5g/L solution for dividing the acetonitrile solution that specific concentration is 5% to be formed.
Mobile phase A 1 is purified water, and A2 is the H of percent by volume 0.032O2PH is the 9.0 NaOH aqueous solution, Mobile phase B
It is acetonitrile, mobile phase C1 is described oxytocin deamidation impurity precursor crude product solution, and its HPLC is determined as described in Example 1
Purity is 82.25%, and retention time is 9.20min.
The anti-phase cyclisation of the present embodiment, anti-phase purifying and anti-phase desalination condition are as follows：Flow velocity 100mL/min, 220nm inspection
Survey, purifying gradient see the table below shown, and percentage is percent by volume.
| Elution step | Elution time | Eluent |
| 1 | 0~10min | 100%C |
| 2 | 10~25min | 95%A1+5%B |
| 3 | 25.1~30min | 95%A2+5%B |
| 4 | 30.1~35 | 95%A1+5%B |
| 5 | 35~50min | 95%A1+5%B → 80%A1+20%B |
| 6 | 50~65min | 80%A1+20%B → 73%A1+27%B |
| 7 | 65~75min | 50%A1+50%B |
| 8 | 75~80min | 95%A1+5%B |
Collect the eluent that retention time is 50~65min and obtain oxytocin deamidation dirt solution, by the side of embodiment 1
It is 99.50% that method determines its HPLC purity, and retention time is 6.55min.
Embodiment 5 (Mass Spectrometer Method of oxytocin deamidation impurity)
Embodiment 3,4 is determined using waters micromass ZQ substances level Four bar electrospray ionization mass spectrum (ESI-MS) to obtain
Oxytocin deamidation impurity molecular mass peak [M+1]+Measured value 1009.31, leading ion fragment peak [M+2]2+Measured value
505.17, all meet theoretical value 1008.2.
Claims (9)
1. a kind of preparation method of oxytocin deamidation impurity, it comprises the steps：Will using efficient liquid phase RP chromatography
Oxytocin deamidation impurity precursor crude product solution carries out anti-phase cyclisation, anti-phase purifying, anti-phase desalination successively, you can；Efficient liquid phase
The filler of RP chromatography is silica gel C18；
Described oxytocin deamidation impurity precursor crude product is the oxytocin deamidation impurity precursor crude product containing two free sulfhydryl groups；
Described oxytocin deamidation impurity is-Pro-Leu-GlY。
2. preparation method as claimed in claim 1, it is characterised in that described oxytocin deamidation impurity precursor crude product is to adopt
Obtained oxytocin deamidation impurity precursor crude product is dried by cracking with solid-phase synthesis, HPLC purity is 60~90%.
3. preparation method as claimed in claim 1, it is characterised in that the knot of described oxytocin deamidation impurity precursor crude product
Structure formula is the trifluoroacetate of Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly.
4. preparation method as claimed in claim 1, it is characterised in that described oxytocin deamidation impurity precursor crude product solution
For oxytocin deamidation impurity precursor crude product is dissolved in the 5g/L solution that the acetonitrile solution that concentration of volume percent is 5% is formed.
5. preparation method as claimed in claim 1, it is characterised in that described anti-phase cyclisation, anti-phase purifying, anti-phase desalination are equal
It is to be completed in the anti-phase elution process of a step.
6. preparation method as claimed in claim 1, it is characterised in that described anti-phase cyclisation, anti-phase purifying, anti-phase desalination
Condition is as follows：Mobile phase A 1 is pure water, and A2 is the H of percent by volume 0.01~0.05%2O2PH be 7.5~9.0 NaOH it is water-soluble
Liquid, Mobile phase B is acetonitrile, and mobile phase C is described oxytocin deamidation impurity precursor crude product solution, and flow velocity is 80~110mL/
Min, Detection wavelength is 220nm；
Condition according to following table carries out online loading, wash-out, and percentage is percent by volume；
Collect the eluent that retention time is 50~65min and obtain oxytocin deamidation dirt solution.
7. preparation method as claimed in claim 6, it is characterised in that described A2 is percent by volume 0.02~0.03%
H2O2PH is 7.5~9.0 NaOH aqueous solution.
8. preparation method as claimed in claim 6, it is characterised in that described flow velocity is 100mL/min.
9. preparation method as claimed in claim 1, it is characterised in that the filling condition of described efficient liquid phase RP chromatography
It is as follows：Filler is Kromasil silica gel C18, aperture 10nm, 10 μm of particle diameter.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110016072A (en) * | 2019-05-07 | 2019-07-16 | 上海上药第一生化药业有限公司 | A kind of refining methd of oxytocin |
| CN110028556A (en) * | 2019-05-07 | 2019-07-19 | 上海上药第一生化药业有限公司 | A kind of refining methd of oxytocin [- NH2] impurity |
| CN110041406A (en) * | 2019-05-07 | 2019-07-23 | 上海上药第一生化药业有限公司 | A kind of refining methd of oxytocin [+Gly] impurity |
| CN111812240A (en) * | 2020-07-15 | 2020-10-23 | 上海上药第一生化药业有限公司 | Separation method and application of oxytocin and three impurities |
| CN111830154A (en) * | 2020-07-15 | 2020-10-27 | 上海上药第一生化药业有限公司 | Separation method and application of oxytocin and 8 epimers thereof |
| CN111896642A (en) * | 2020-07-15 | 2020-11-06 | 上海上药第一生化药业有限公司 | Separation method and application of oxytocin and three kinds of deamidation impurities |
| CN111912917A (en) * | 2020-07-15 | 2020-11-10 | 上海上药第一生化药业有限公司 | Separation method and application of oxytocin and at least ten impurities |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103374054A (en) * | 2012-04-28 | 2013-10-30 | 上海第一生化药业有限公司 | One-step method based solid-phase polypeptide synthesis method |
| CN103980351A (en) * | 2014-05-27 | 2014-08-13 | 上海第一生化药业有限公司 | Method for preparing vasopressin and vasopressin tannate |
| CN104672308A (en) * | 2014-12-23 | 2015-06-03 | 青岛康原药业有限公司 | Method for preparing vasopressin tannate |
-
2017
- 2017-01-03 CN CN201710001527.XA patent/CN106749539B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103374054A (en) * | 2012-04-28 | 2013-10-30 | 上海第一生化药业有限公司 | One-step method based solid-phase polypeptide synthesis method |
| CN103980351A (en) * | 2014-05-27 | 2014-08-13 | 上海第一生化药业有限公司 | Method for preparing vasopressin and vasopressin tannate |
| CN104672308A (en) * | 2014-12-23 | 2015-06-03 | 青岛康原药业有限公司 | Method for preparing vasopressin tannate |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110016072A (en) * | 2019-05-07 | 2019-07-16 | 上海上药第一生化药业有限公司 | A kind of refining methd of oxytocin |
| CN110028556A (en) * | 2019-05-07 | 2019-07-19 | 上海上药第一生化药业有限公司 | A kind of refining methd of oxytocin [- NH2] impurity |
| CN110041406A (en) * | 2019-05-07 | 2019-07-23 | 上海上药第一生化药业有限公司 | A kind of refining methd of oxytocin [+Gly] impurity |
| CN110028556B (en) * | 2019-05-07 | 2021-04-13 | 上海上药第一生化药业有限公司 | Method for refining oxytocin impurity [ -NH2] |
| CN110016072B (en) * | 2019-05-07 | 2022-03-15 | 上海上药第一生化药业有限公司 | Method for refining oxytocin |
| CN111812240A (en) * | 2020-07-15 | 2020-10-23 | 上海上药第一生化药业有限公司 | Separation method and application of oxytocin and three impurities |
| CN111830154A (en) * | 2020-07-15 | 2020-10-27 | 上海上药第一生化药业有限公司 | Separation method and application of oxytocin and 8 epimers thereof |
| CN111896642A (en) * | 2020-07-15 | 2020-11-06 | 上海上药第一生化药业有限公司 | Separation method and application of oxytocin and three kinds of deamidation impurities |
| CN111912917A (en) * | 2020-07-15 | 2020-11-10 | 上海上药第一生化药业有限公司 | Separation method and application of oxytocin and at least ten impurities |
| CN111812240B (en) * | 2020-07-15 | 2022-05-24 | 上海上药第一生化药业有限公司 | Separation method and application of oxytocin and three impurities |
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