CN109942678A - A kind of refining methd of Octreotide - Google Patents
A kind of refining methd of Octreotide Download PDFInfo
- Publication number
- CN109942678A CN109942678A CN201910375961.3A CN201910375961A CN109942678A CN 109942678 A CN109942678 A CN 109942678A CN 201910375961 A CN201910375961 A CN 201910375961A CN 109942678 A CN109942678 A CN 109942678A
- Authority
- CN
- China
- Prior art keywords
- octreotide
- crude product
- reverse phase
- phase
- mobile phase
- 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.)
- Granted
Links
Landscapes
- Treatment Of Liquids With Adsorbents In General (AREA)
- Saccharide Compounds (AREA)
Abstract
The invention discloses a kind of refining methd of Octreotide, which includes the following steps: Octreotide crude product solution successively carried out reverse phase enrichment using efficient liquid phase RP chromatography, reverse phase turns salt, reverse phase purifying；Octreotide crude product solution is that the reduced form Octreotide crude product solution of synthesis in solid state obtains after aoxidizing；The filler of efficient liquid phase RP chromatography is super resistance to water packing.The present invention is enriched with online reverse phase, reverse phase turns salt, polypeptide sterling is made in reverse phase purifying one-step method, the removal rate of impurity is higher in Octreotide crude product, the purity for obtaining Octreotide sterling is higher, optimize production technology, it is aqueous solution that wherein column equilibration, loading, which are enriched with and turn the mobile phase of salt phase, environment friendly and pollution-free, the waste liquid of outflow can directly carry out sewage treatment and recycle.
Description
Technical field
The present invention relates to a kind of refining methds of Octreotide.
Background technique
Octreotide acetate (Octreotide acetate), the conjunction being made of seven amino acid residue and Soviet Union's ammonia alcohol
At polypeptide, chemical structure isThe theoretical molecular weight of Octreotide is
1019.26, acetic acid content is 5%~12% in bulk pharmaceutical chemicals freeze-dried powder.Octreotide acetate can inhibit growth hormone, inhibit stomach and intestine
Pancreas secrete polypeptide etc., preparation are clinically used for needing the activity acromegalia of long-term RUPTURED ESOPHAGEAL VARICES TREATED WITH OCTREOTIDE, such as postoperative growth
Hormone residues cause serum growth hormone level to increase, and the Serum Growth of abundant curative effect has not yet been reached after hypophysis external -bean radiation therapy
Hormonal readiness increases, and part is not suitable for the preoperative therapy of operative treatment and new diagnosis growth hormone secreting adenoma patient.
Having listed the common purification process of polypeptide drugs mostly uses preparative high performance liquid chromatography at present, which is
Obtain the most efficient method of high-purity polypeptide target molecule.General polypeptide drugs purifying preparation process design is first mesolow color
Spectrum enriching target polypeptides, then high pressure chromatographic refining, it is contemplated that target polypeptides Octreotide molecular weight about 1kDa, without suitable
Molecular sieve gel column (its applied sample amount is small, and flow velocity is low, and treating capacity is small, relatively be suitble to molecular weight be greater than 10kDa albumen desalination) or
Ultrafiltration membrane selection.And common separation method has molecular sieve chromatography, ion-exchange chromatography and hydrophobic in mesolow chromatography
Interaction chromatography method, the partial size for the filler used in these chromatographic processes are empty usually from tens microns to several hundred microns etc.
Gap size is mostly several hundred nanometers etc., is unable to get the target polypeptides of high-purity.The Austria being cyclized using synthesis in solid state+dilution
Bent peptide crude product solution concentration is diluter, when being purified using general reverse-phase chromatographic column, only just generates during loading
The processing cost of a large amount of organic liquid waste, dangerous waste is very high.A kind of method for effectively preparing polypeptide salt bulk drug is also lacked now,
Therefore still there is an urgent need to develop the cost-effective techniques of new suitable purifying low concentration polypeptide and salt.
Chinese patent literature CN106749528A discloses a kind of preparation method of Octreotide.The preparation method includes following
Step: Octreotide precursor crude product solution is successively carried out by reverse phase cyclisation, reverse phase purifying, reverse phase using efficient liquid phase RP chromatography
Desalination；The filler of efficient liquid phase RP chromatography is styrene diethylene benzene copoly mer；The Octreotide precursor
Crude product is the Octreotide precursor crude product containing two free sulfhydryl groups.It is thick using the Octreotide precursor of reduced form in the preparation process of the patent
Product are starting material, and the lower purity for obtaining sterling of the removal rate of impurity is not high in crude product, and used in mobile phase NaOH as
Alkaline matter, it is unfavorable to the control of pH, the stability of product may be impacted.It is needed when being not only cyclized on a column
Largely the mobile phase containing organic solvent and a large amount of organic dangerous waste liquid is being purified and is turning also to produce in salt step, it is subsequent useless
The processing cost of liquid is larger.
Summary of the invention
When technical problem to be solved by the present invention lies in overcoming purification Octreotide in the prior art, Octreotide crude product solution
The removal rate of middle impurity is lower, and generate organic dangerous waste liquid measure it is big, caused by treatment cost of waste liquor it is big, uneconomic defect,
And provide a kind of refining methd of Octreotide.The refining methd of Octreotide of the present invention generates during purification of target product
Waste liquid be largely waste water can through sewage treatment can direct reuse, it is economic and environment-friendly, in Octreotide crude product the removal rate of impurity compared with
Height, the purity for obtaining Octreotide sterling are higher.
The present invention is to solve above-mentioned technical problem by the following technical programs:
The present invention provides a kind of refining methds of Octreotide comprising following step:
Octreotide crude product solution is successively carried out by reverse phase enrichment using efficient liquid phase RP chromatography, reverse phase turns salt, reverse phase
Purifying；The filler of the efficient liquid phase RP chromatography is super resistance to water packing；
The reverse phase is enriched with, reverse phase turns salt, reverse phase purifying is completed in a step reverse phase elution process, and described is anti-
Mutually enrichment, the condition that reverse phase turns salt, reverse phase purifies are as follows:
Wherein, mobile phase A is the acetic acid/water that percent by volume is 0.005~0.1%, and Mobile phase B is that percent by volume is
0.005~0.1% acetic acid/acetonitrile, sample C1 are the Octreotide crude product solution, and mobile phase C2 is 5~50mM NH4Ac-
NH4OH aqueous solution, the pH of the mobile phase C2 are 7.0~9.0, and flow velocity is 80~100ml/min；Collecting retention time is
The eluent of 108~114min is up to Octreotide solution.
The Octreotide crude product solution be synthesis in solid state reduced form Octreotide crude product through dissolution, dilution, oxidation and obtain.
Specific preparation process is as follows for the Octreotide crude product solution: being that starting is former with Rink Amide MBHA resin
Material, using fmoc-protected amino acid as monomer, using HOBt/DIC as condensing agent, successively connects amino acid one by one；Peptide examination is cut in addition
Agent carries out cutting peptide, and methyl tertiary butyl ether(MTBE) is added and is precipitated, reduced form Octreotide crude product is obtained；Reduced form Octreotide crude product is used
50% acetic acid/water dissolves, then is diluted with water, as reduced form Octreotide crude product solution；With alkaline matter by the reduced form
The pH of Octreotide crude product solution is adjusted to 7.0-9.0, and the hydrogen peroxide that concentration is 30% is added and is aoxidized, wherein every gram of reduced form
Octreotide crude product adds the hydrogen peroxide of 0.5ml 30%, obtains oxidized form Octreotide crude product solution, as Octreotide crude product solution.
Wherein, 50% acetic acid/water can adequately dissolve the reduced form Octreotide crude product.
Wherein, the concentration of the reduced form Octreotide crude product solution is 0.1~4mg/ml, preferably 0.5~2mg/
ml。
Wherein, the described peptide reagent of cutting is that this field is conventional, preferably the volume ratio TFA/TIS/ that is 90:7.5:2.5
H2O。
Wherein, the alkaline matter is that this field is conventional, preferably NaOH.
In the present invention, the structural formula of the Octreotide in the Octreotide crude product solution isSolvent in the Octreotide crude product solution be containing trifluoroacetic acid and
The aqueous solution of acetic acid.
In the present invention, the super resistance to water packing isThe super resistance to water packing of ODS-AQ.
In the present invention, the aperture of the super resistance to water packing is 7~10nm, and partial size is 10 μm.
In a certain better embodiment, with Load&Lock dynamic axial compression and static locking technology, filler isThe super resistance to water packing of ODS-AQ, aperture 10nm, 10 μm of partial size, being filled to column bed pressure is 1000psi, is used
Varian chromatography loading system, 300g dry powder-shapedThe super resistance to water packing of ODS-AQ, the stirring homogenate of 600mL isopropanol
Afterwards, the Load&Lock4002 for pouring into internal diameter 50mm prepares column, compression ratio 1.5:1, carrier gas N2, adjust the nebulizer gas pressure
So that oil pressure meter pressure is 1500psi, dynamic axial compression to column bed height 25cm is enriched with as reverse phase, reverse phase turns salt and anti-
Column is prepared used in phase purification schemes.
In the present invention, the Detection wavelength of the efficient liquid phase RP chromatography is 220nm.
In the present invention, the mobile phase A is the acetic acid/water solution that percent by volume is 0.02~0.05%；
And/or the Mobile phase B is acetic acid/acetonitrile that percent by volume is 0.02~0.05%；
And/or the mobile phase C2 is 10~20mM NH4Ac-NH4OH aqueous solution；
And/or the pH of the mobile phase C2 is 7.5~8.5；
And/or the HPLC purity of the Octreotide crude product solution is 60~85%, preferably 70%~85%, more
Add is 70~80% goodly.
In the present invention, during 45~46min, the eluent is changed to mobile phase C2 by sample C1 completely；?
During 65~66min, the eluent is changed to mobile phase A by mobile phase C2 completely.According to this field routine, when above-mentioned
Between section should not be construed as the restriction to elution requirement, length of time can be carried out according to the difference of high performance liquid chromatograph producer model
Corresponding adjustment.
In the present invention, in 125~126min after step (5), at the uniform velocity from 80% mobile phase A by the eluent
Be reduced to 50% mobile phase A, accordingly at the uniform velocity increase Mobile phase B to 50%, kept in 126~135min 50% mobile phase A+
50% Mobile phase B elution, to achieve the purpose that clean chromatographic column.
In the present invention, the reverse phase enrichment is elution step (1), and it is step (2)~(3), tool that the reverse phase, which turns salt,
Body, step (2) is with weak base NH4Ac-NH4OH removes the process of trifluoroacetic acid root in Octreotide crude product, and step (3) is removal
The process of ammonium ion in step (2), the reverse phase purifying is step (4) and (5), wherein step (4) removes weaker
The process of adsorbing contaminant.
In the present invention, the conversion rate of eluent described in the elution step (4) and (5) is one and at the uniform velocity changes
Process, the rate at the uniform velocity changed described in the elution step (4) be 2%B/min, i.e., per minute in former eluent
On the basis of increase by 2% described in Mobile phase B, while it is corresponding reduce 2% described in mobile phase A；Institute in the elution step (5)
Stating the rate that at the uniform velocity changes is 0.286%B/min, i.e., increase by 0.286% on the basis of former eluent per minute described in stream
Dynamic phase B, while mobile phase A described in corresponding reduction 0.286%.
Octreotide is a kind of peptide material, unstable under high ph conditions, degradable, especially under alkali environment, the present invention
Integrated survey turns pH and the time of eluting salt, with guarantee to reduce turn salt during sample destruction and loss.
On the basis of common knowledge of the art, above-mentioned each optimum condition, can any combination to get each preferable reality of the present invention
Example.
The reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is that:
(1) method that the present invention uses on-line preconcentration, using the super water resistance and absorption property of filler, by polypeptide crude product
It is adsorbed onto stationary phase and is enriched with, polypeptide and reverse phase filler hydrophobic binding.It is laggard that mobile phase can be directly converted after on-line preconcentration
The purifying of row gradient elution, obtains final sterling, is suitble to continuous production.
(2) present invention has innovatively used reverse phase absorption enrichment, has turned the obtained polypeptide sterling of salt, desalination one-step method, optimization
Production technology is suitble to industrialization continuous production.The removal rate of impurity is higher in Octreotide crude product solution, obtains Octreotide sterling
Purity it is higher.
(3) more recent application of the water-fast filler of excess of export is designed, column equilibration stage, reverse phase concentration stage and reverse phase turn salt phase
Eluent is aqueous solution, environment friendly and pollution-free, and efflux is immediately discharged to Sewage Disposal, the recoverable after simple process,
The yield of dangerous waste liquid, economical environment-protective greatly reduces in relatively traditional preparation process.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient
The selection of product specification.
Resistance to water packing used in embodiment is purchased from Suzhou Nano-Micro Bio-technology Co., Ltd.ODS-AQ is super
Resistance to water packing, aperture 10nm, 10 μm of partial size.
HPLC method detects Octreotide crude product and after purification product solution purity:
Instrument: 1200 high performance liquid chromatograph of Agilent
Splitter: Waters XBridge-C18,4.6 × 150mm, 5 μm
Mobile phase: A is 50% acetonitrile/water solution of percent by volume, and B is 0.02M KH2PO43.0 aqueous solution of pH, flow velocity are
1.0ml/min Detection wavelength 220nm, room temperature detection, 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 | 28~28.1min | 100%A → 35%A+65%B |
| 5 | 28.1~32min | 35%A+65%B |
In following embodiments, the Octreotide crude product solution be synthesis in solid state reduced form Octreotide crude product through dissolution,
Dilution is aoxidized and is obtained.The solid-phase synthesis includes the following steps: using Rink Amide MBHA resin as starting material, with
Fmoc-protected amino acid successively connects amino acid using HOBt/DIC as condensing agent for monomer one by one；Peptide reagent progress is cut in addition
Peptide is cut, methyl tertiary butyl ether(MTBE) is added and is precipitated, reduced form Octreotide crude product is obtained.It is described that cut peptide reagent be volume ratio is 90:
The TFA/TIS/H of 7.5:2.52O.Described is dissolved as being dissolved with the acetic acid/water solution that percent by volume is 50%.It is described
Be diluted to be diluted with water.The pH of the reduced form Octreotide crude product solution is adjusted to by described being oxidized to alkaline matter
7.0-9.0 is added the hydrogen peroxide that percent by volume is 30% and carries out oxidation process.The dosage of the hydrogen peroxide be 0.5mL/1g also
Prototype Octreotide crude product；The alkaline matter is NaOH.
1 internal diameter 50mm L&L4002 of embodiment prepares column filling:
With Load&Lock dynamic axial compression and static locking technology, filler isODS-AQ, aperture
10nm 10 μm of partial size, is filled to column bed pressure 1000psi, using Varian chromatography loading system, 300g dry powder filler, 600ml
After isopropanol stirring homogenate, pours into internal diameter 50mm L&L4002 and prepare column, compression ratio 1.5:1, carrier gas N2, adjust carrier gas pressure
Power make oil pressure meter pressure be 1500psi, dynamic axial compression to column bed height 25cm, as reverse phase enrichment, reverse phase turn salt and
Column is prepared used in reverse phase purification schemes.
The reverse phase enrichment of 2 Octreotide crude product solution of embodiment, reverse phase turn salt and reverse phase purifying
Instrument: Varian SD-1 high pressure liquid phase preparation system
Chromatographic column: 1 self-chambering of embodiment prepares column 50 × 250mm of Load&Lock4002,ODS-AQ 10μ
m 10nm
The structural formula of Octreotide isReduced form Octreotide crude product solution
The concentration of middle reduced form Octreotide crude product is 1mg/ml, and the solvent in Octreotide crude product solution is the water containing trifluoroacetic acid and acetic acid
Solution.
It is 0.02% acetic acid/water that mobile phase A, which is percent by volume, Mobile phase B be percent by volume be 0.02% acetic acid/
Acetonitrile, sample C1 are Octreotide crude product solution, and the HPLC purity according to the Octreotide crude product solution of HPLC method measurement is
77.53%, mobile phase C2 are the NH of 10mM4Ac-NH4OH pH7.5 aqueous solution.
The reverse phase enrichment of the present embodiment, reverse phase turns salt and reverse phase purification condition is as follows: flow velocity 100ml/min, 220nm inspection
It surveys, purifying gradient see the table below shown, and percentage is percent by volume.
Collecting retention time is the eluent of 108~114min up to Octreotide solution.Austria according to the measurement of HPLC method is bent
The purity of peptide HPLC is 99.65%, and the removal rate of impurity is 22.12% in Octreotide crude product solution.Elution step (1)~(3)
The eluent in stage is aqueous solution, and environment friendly and pollution-free, efflux is immediately discharged to Sewage Disposal, be can be recycled after simple process
It utilizes, the yield of dangerous waste liquid, economical environment-protective greatly reduces in relatively traditional preparation process.
The reverse phase enrichment of 3 Octreotide crude product solution of embodiment, reverse phase turn salt and reverse phase purifying
Instrument: Varian SD-1 high pressure liquid phase preparation system
Chromatographic column: 1 self-chambering of embodiment prepares column 50 × 250mm of Load&Lock4002,ODS-AQ 10μ
m 10nm
The structural formula of Octreotide isReduced form Octreotide crude product solution
The concentration of middle reduced form Octreotide crude product is 1.5mg/ml, and the solvent in Octreotide crude product solution is containing trifluoroacetic acid and acetic acid
Aqueous solution.
Mobile phase A is that percent by volume is 0.05% acetic acid/water, and Mobile phase B is that percent by volume is 0.05% acetic acid/second
Nitrile, sample C1 are Octreotide crude product solution, and the purity according to the Octreotide crude product solution HPLC of HPLC method measurement is 73.63%,
Mobile phase C2 is the NH of 20mM4Ac-NH4OH pH8.5 aqueous solution.
The reverse phase enrichment of the present embodiment, reverse phase turns salt and reverse phase purification condition is as follows: flow velocity 100ml/min, 220nm inspection
It surveys, purifying gradient see the table below shown, and percentage is percent by volume.
Collecting retention time is the eluent of 108~114min up to Octreotide solution.Austria according to the measurement of HPLC method is bent
The purity of peptide HPLC is 99.54%.The removal rate of impurity is 25.91% in the Octreotide crude product solution of the present embodiment.
The reverse phase enrichment of 4 Octreotide crude product solution of embodiment, reverse phase turn salt and reverse phase purifying
Instrument: Varian SD-1 high pressure liquid phase preparation system
Chromatographic column: 1 self-chambering of embodiment prepares column 50 × 250mm of Load&Lock4002,ODS-AQ 10μ
m 10nm
The structural formula of Octreotide isReduced form Octreotide crude product solution
The concentration of middle reduced form Octreotide crude product is 0.8mg/ml, and the solvent in Octreotide crude product solution is containing trifluoroacetic acid and acetic acid
Aqueous solution.
Mobile phase A is that percent by volume is 0.05% acetic acid/water, and Mobile phase B is that percent by volume is 0.05% acetic acid/second
Nitrile, sample C1 are Octreotide crude product solution, and the purity according to the Octreotide crude product solution HPLC of HPLC method measurement is 76.46%,
Mobile phase C2 is the NH of 20mM4Ac-NH4OH pH7.5 aqueous solution.
The reverse phase enrichment of the present embodiment, reverse phase turns salt and reverse phase purification condition is as follows: flow velocity 100ml/min, 220nm inspection
It surveys, purifying gradient see the table below shown, and percentage is percent by volume.
Collecting retention time is the eluent of 108~114min up to Octreotide solution.Austria according to the measurement of HPLC method is bent
The purity of peptide HPLC is 99.66%.The removal rate of impurity is 23.2% in the Octreotide crude product solution of the present embodiment.
The Mass Spectrometer Method of 5 Octreotide of embodiment
It is obtained using Waters micromass ZQ substance level four bars electrospray ionization mass spectrum (ESI-MS) measurement embodiment 2,3 and 4
The Octreotide arrived, test condition are as follows: the source electrospray ionisation (ESI) is used, in positive ion electrospray from being analyzed by mass spectrometry under mode, hair
Tubule ionization voltage 3.0kV samples orifice potential 35kv；115 DEG C of ion source temperature, 350 DEG C of desolventizing temperature, desolventizing nitrogen
Flow velocity 700L/h, taper hole blowback nitrogen 50L/h, 50.0~1500m/z of level four bars surface sweeping range.
It is obtained using waters micromass ZQ substance level four bars electrospray ionization mass spectrum (ESI-MS) measurement embodiment 2,3,4
The molecular mass peak [M+1] of the Octreotide arrived+Measured value 1019.30, leading ion fragment peak [M+2]2+Measured value 510.17, all
Meeting the theoretical value i.e. molecular weight of Octreotide is 1019.26.
Claims (10)
1. a kind of refining methd of Octreotide, which is characterized in that it includes the following steps: to use efficient liquid phase RP chromatography will
Octreotide crude product solution successively carries out reverse phase enrichment, reverse phase turns salt, reverse phase purifying；
The filler of the efficient liquid phase RP chromatography is super resistance to water packing；
The reverse phase is enriched with, reverse phase turns salt, reverse phase purifying is completed in a step reverse phase elution process, and the reverse phase is rich
It is as follows that collection, reverse phase turn salt, the condition of reverse phase purifying:
Wherein, mobile phase A is the acetic acid/water that percent by volume is 0.005~0.1%, and Mobile phase B is that percent by volume is
0.005~0.1% acetic acid/acetonitrile, sample C1 are the Octreotide crude product solution, and mobile phase C2 is 5~50mM NH4Ac-
NH4OH aqueous solution, the pH of the mobile phase C2 are 7.0~9.0, and flow velocity is 80~100ml/min；
Collecting retention time is the eluent of 108~114min up to Octreotide solution.
2. the refining methd of Octreotide as described in claim 1, it is characterised in that: the Octreotide crude product solution is solid phase
The reduced form Octreotide crude product of synthesis through dissolution, dilution, oxidation and obtain.
3. the refining methd of Octreotide as described in claim 1, it is characterised in that: the reduced form Octreotide crude product is through molten
It solves, dilute to obtain reduced form Octreotide crude product solution, reduced form Octreotide crude product in the reduced form Octreotide crude product solution
Concentration is 0.1~4mg/ml, preferably 0.5~2mg/ml；The solvent for dissolving the reduced form Octreotide crude product is volume hundred
Divide the acetic acid/water solution than being 50%.
4. the refining methd of Octreotide as described in claim 1, it is characterised in that: Octreotide in the Octreotide crude product solution
Structural formula beSolvent in the Octreotide crude product solution is containing trifluoro
The aqueous solution of acetic acid and acetic acid.
5. the refining methd of Octreotide as described in claim 1, it is characterised in that: the super resistance to water packing is
The super resistance to water packing of ODS-AQ.
6. the refining methd of Octreotide as described in claim 1, it is characterised in that: the aperture of the super resistance to water packing be 7~
10nm, partial size are 10 μm.
7. the refining methd of Octreotide as described in claim 1, it is characterised in that: the efficient liquid phase RP chromatography
Detection wavelength is 220nm.
8. the refining methd of Octreotide as described in claim 1, it is characterised in that: the mobile phase A is percent by volume
For 0.02~0.05% acetic acid/water solution；
And/or the Mobile phase B is acetic acid/acetonitrile that percent by volume is 0.02~0.05%；
And/or the mobile phase C2 is 10~20mM NH4Ac-NH4OH aqueous solution；
And/or the pH of the mobile phase C2 is 7.5~8.5；
And/or the HPLC purity of the Octreotide crude product solution is 60~85%, preferably 70%~85%, more preferably
It is 70%~80%.
9. the refining methd of Octreotide as described in claim 1, it is characterised in that: during 45~46min, described is washed
De- liquid is changed to mobile phase C2 by sample C1 completely；During 65~66min, completely more by mobile phase C2 by the eluent
It is changed to mobile phase A.
10. the refining methd of Octreotide as described in claim 1, it is characterised in that: the elution step (4) and elution step
Suddenly the conversion rate of the eluent in (5) is the process at the uniform velocity changed.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910375961.3A CN109942678B (en) | 2019-05-07 | 2019-05-07 | Refining method of octreotide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910375961.3A CN109942678B (en) | 2019-05-07 | 2019-05-07 | Refining method of octreotide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109942678A true CN109942678A (en) | 2019-06-28 |
| CN109942678B CN109942678B (en) | 2021-04-13 |
Family
ID=67017201
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910375961.3A Active CN109942678B (en) | 2019-05-07 | 2019-05-07 | Refining method of octreotide |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109942678B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106188218A (en) * | 2016-07-14 | 2016-12-07 | 江苏诺泰生物制药股份有限公司 | A kind of method improving polypeptide raw material drug stabilisation |
| CN106749528A (en) * | 2017-01-03 | 2017-05-31 | 上海上药第生化药业有限公司 | A kind of preparation method of Octreotide |
| WO2017175107A1 (en) * | 2016-04-04 | 2017-10-12 | Emcure Pharmaceuticals Limited | Process for preparation of octreotide acetate |
-
2019
- 2019-05-07 CN CN201910375961.3A patent/CN109942678B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017175107A1 (en) * | 2016-04-04 | 2017-10-12 | Emcure Pharmaceuticals Limited | Process for preparation of octreotide acetate |
| CN106188218A (en) * | 2016-07-14 | 2016-12-07 | 江苏诺泰生物制药股份有限公司 | A kind of method improving polypeptide raw material drug stabilisation |
| CN106749528A (en) * | 2017-01-03 | 2017-05-31 | 上海上药第生化药业有限公司 | A kind of preparation method of Octreotide |
Non-Patent Citations (4)
| Title |
|---|
| YOUSEF AKHLAGHI等: "A rapid hydrolysis method and DABS‑Cl derivatization for complete amino acid analysis of octreotide acetate by reversed phase HPLC", 《AMINO ACIDS》 * |
| 刘作家: "醋酸奥曲肽的合成研究", 《中国优秀硕士学位论文全文数据库》 * |
| 张怡轩: "《生物药物分析》", 31 December 2015, 中国医药科技出版社 * |
| 李俊锁: "《兽药残留分析》", 28 February 2002, 上海科学技术出版社 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109942678B (en) | 2021-04-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103980351A (en) | Method for preparing vasopressin and vasopressin tannate | |
| CN106699851B (en) | A kind of preparation method of pitressin deamidation impurity | |
| CN104672308A (en) | Method for preparing vasopressin tannate | |
| CN106749541B (en) | Preparation method of vasopressin [5-Asp ] | |
| CN106518978B (en) | Preparation method of vasopressin [4-Glu,5-Asp ] | |
| CN110016072A (en) | A kind of refining methd of oxytocin | |
| CN103965291B (en) | Octreotide, the preparation method of octreotide acetate | |
| CN109438561A (en) | A kind of purification process of Triptorelin | |
| CN109929010A (en) | A kind of refining methd of pitressin | |
| CN109942678A (en) | A kind of refining methd of Octreotide | |
| CN106518975B (en) | A kind of preparation method of pitressin | |
| CN110016071A (en) | A kind of refining methd of pitressin [4-Glu] impurity | |
| CN110016070A (en) | A kind of refining methd of pitressin [+Gly] impurity | |
| CN110028556B (en) | Method for refining oxytocin impurity [ -NH2] | |
| CN110041405A (en) | A kind of refining methd of oxytocin [5-Asp] impurity | |
| CN110078796B (en) | Method for refining oxytocin [4-Glu,5-Asp ] impurity | |
| CN109942686B (en) | Purification method of vasopressin acetylated impurities | |
| CN110003313B (en) | Vasopressin [ -NH ]2]Method for purifying impurities | |
| CN110078795B (en) | Method for refining vasopressin [4-Glu,5-Asp ] impurity | |
| CN109929011B (en) | Method for refining vasopressin [5-Asp ] impurity | |
| CN110078797A (en) | A kind of refining methd of oxytocin [4-Glu] impurity | |
| CN110041406B (en) | Method for refining oxytocin [ + Gly ] impurity | |
| CN110066319A (en) | A kind of refining methd of oxytocin acetylation impurity | |
| CN106749528A (en) | A kind of preparation method of Octreotide | |
| CN103965296B (en) | Method for preparing angiotensin and angiotensin acetate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |