CN101942038B - Production method of dalteparin sodium - Google Patents
Production method of dalteparin sodium Download PDFInfo
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- CN101942038B CN101942038B CN2010102871225A CN201010287122A CN101942038B CN 101942038 B CN101942038 B CN 101942038B CN 2010102871225 A CN2010102871225 A CN 2010102871225A CN 201010287122 A CN201010287122 A CN 201010287122A CN 101942038 B CN101942038 B CN 101942038B
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 9
- 229940018872 dalteparin sodium Drugs 0.000 title abstract 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 50
- 229920000669 heparin Polymers 0.000 claims abstract description 33
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 claims abstract description 12
- 229960001008 heparin sodium Drugs 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 8
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims description 21
- 229960002897 heparin Drugs 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 16
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 16
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 14
- 230000008021 deposition Effects 0.000 claims description 14
- 238000000151 deposition Methods 0.000 claims description 14
- 238000004062 sedimentation Methods 0.000 claims description 13
- 239000008213 purified water Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 9
- 238000005374 membrane filtration Methods 0.000 claims description 8
- 235000010288 sodium nitrite Nutrition 0.000 claims description 8
- 238000006297 dehydration reaction Methods 0.000 claims description 7
- 101100136092 Drosophila melanogaster peng gene Proteins 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 230000018044 dehydration Effects 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- 230000003647 oxidation Effects 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- 230000001105 regulatory effect Effects 0.000 claims description 4
- 239000000047 product Substances 0.000 abstract description 23
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 abstract description 3
- 239000002253 acid Substances 0.000 abstract description 3
- 230000002378 acidificating effect Effects 0.000 abstract description 3
- 238000001291 vacuum drying Methods 0.000 abstract description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical class OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 abstract description 2
- 230000009615 deamination Effects 0.000 abstract description 2
- 238000006481 deamination reaction Methods 0.000 abstract description 2
- 238000004108 freeze drying Methods 0.000 abstract description 2
- 239000003960 organic solvent Substances 0.000 abstract description 2
- 230000001590 oxidative effect Effects 0.000 abstract description 2
- 238000006462 rearrangement reaction Methods 0.000 abstract description 2
- JCZPMGDSEAFWDY-SQOUGZDYSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanamide Chemical group NC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO JCZPMGDSEAFWDY-SQOUGZDYSA-N 0.000 abstract 2
- 239000012043 crude product Substances 0.000 abstract 2
- 230000007547 defect Effects 0.000 abstract 1
- 230000000640 hydroxylating effect Effects 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 235000019441 ethanol Nutrition 0.000 description 13
- 208000005156 Dehydration Diseases 0.000 description 6
- 230000002950 deficient Effects 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- WQZGKKKJIJFFOK-PQMKYFCFSA-N alpha-D-mannose Chemical compound OC[C@H]1O[C@H](O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-PQMKYFCFSA-N 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000010835 comparative analysis Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 239000003055 low molecular weight heparin Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
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- Polysaccharides And Polysaccharide Derivatives (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a production method of dalteparin sodium. The production method comprises the following steps: adding methylic organic solvent into heparin sodium solution; under specific temperature and acidic conditions, reacting with nitrous acid to cause deamination on N-sulfuric-base aminoglucose residues, so that rearrangement reaction occurs, thereby causing glycosidic bond rupture between aminoglucose and uronic acid and forming 2,5-dehydrated mannitose terminal residue; carrying out further treatment to obtain stable 2,5-dehydrated mannitol terminal, thereby obtaining the crude product of dalteparin sodium of which the molecular weight is 5600-6400 Daltons; and decoloring the crude product of dalteparin sodium by oxidizing and hydroxylating, settling with ethanol, and freeze drying or vacuum drying to obtain the finished product of dalteparin sodium. The invention overcomes the defects of disqualified product structure and poor product stability in the traditional production technique; the product of the invention has the uniform structure and properties as the European standard sample structure; and the invention has the advantages of simple operation, high stability and high product yield, and can realize industrial production.
Description
One, technical field:
The present invention relates to a kind of preparation method of biochemical drug, particularly a kind of reaching for the heparin working method.
Two, background technology:
Reaching for heparin is a kind of anti-freezing and antithrombotic reagent, is a kind of of Low molecular heparin.Reaching for heparin is raw material with the heparin, and through the depolymerization of acid Sodium Nitrite, sodium borohydride reduction and ultraviolet are modified, and produce to such an extent that reach for heparin through decolouring.The preparation method is more single in the world, is the nitrous acid aqueous solution degraded, but as condition, the product internal structure is destroyed, and structural confirmation is defective.Common working method is at present: the heparin sodium raw material is dissolved in 1% acetum, adds a certain amount of sodium nitrite solution, control the pH value in 2.3～4.0 scopes, stirring reaction 1～4h under the certain temperature.Transfer pH to 6.5～7.0 with the 5mol/L sodium hydroxide solution, and add the absolute ethyl alcohol deposition of 2.5 times of volumes of reaction solution, in about 4 ℃, place 12～16h, remove supernatant, add 2～3 times of volume acetone dehydrations in the deposition and grind 2～3 times, in P
2O
5Vacuum-drying promptly gets.Traditional method has only selected heparin and to produce low molecule by nitrous acid degraded, and output object is through ir spectra and nucleus magnetic resonance and reach for the comparative analysis of heparin standard substance, and the front has lacked methyl signals, and product stability is poor.
Three, summary of the invention:
The object of the invention is exactly the above-mentioned defective that exists to prior art; Providing a kind of reaches for the heparin working method; Having overcome traditional technology, to produce product structure defective, the defective of product stability difference, the product of production have reach for heparin European standard article structure consistent with character; And good stability, product yield is high.
Technical scheme of the present invention is: in heparin sodium aqua, add methylic organic solvent, under certain temperature and acidic conditions, with nitrite reaction; Cause the deamination on the N-sulfate glucosamine residue, and then the generation rearrangement reaction causes the glycosidic link fracture between glucosamine and the uronic acid, formation 2; 5-dehydration seminose terminal residue further handles obtaining stablely 2 then, and 5-dehydration N.F,USP MANNITOL is terminal; Obtain molecular weight 5600～6400 daltonian reaching for the heparin bullion; Reach for the heparin bullion through the hydrogen peroxide oxidative decoloration above-mentioned, ethanol sedimentation, freezing or vacuum-drying must arrive for the heparin finished product.
Concrete production stage of the present invention is (according to weight percent) as follows: heparin sodium is added purified water be dissolved into 3%～10% concentration; Using the hydrochloric acid adjusting pH of 2～6mol/L is 1.0～3.0; What add 0.5～2.0 times of liquor capacity then contains the organic kind solvent of methyl signals, during adjustment temperature to 10～30 ℃, adds Sodium Nitrite; Stirring reaction 30～90min, temperature is controlled at 10～30 ℃; Regulating pH after degraded is accomplished is 8～10, adds Peng Qinghuana then, stirring reaction 15h; Regulate pH to 3.0～4.0 with hydrochloric acid then, re-adjustment pH is 6～8 behind reaction 5～30min, adds ethanol sedimentation, places 6～24h; The gained deposition is added purified water be dissolved into 5%～20% concentration, regulate pH to 6～8, use membrane filtration, shine 5～10min in the filtrating input ultraviolet Sterilizers, add 1.5～3 times of amount ethanol sedimentation depositions and placed 6～24 hours; Above-mentioned throw out is added purified water be dissolved into 10%～20% concentration, transfer pH to 9～12, added hydrogen peroxide oxidation 6～12 hours, use membrane filtration, add the ethanol sedimentation deposition and placed 6～12 hours; Throw out is dissolved into 10%～15% concentration, lyophilize or throw out through ethanol dehydration in below 50 ℃, dry must reaching below the vacuum tightness 0.095Mpa for the heparin finished product.
The consumption of above-mentioned Sodium Nitrite is 1.0%～3.0% of a heparin sodium weight, is weight and weight ratio.
Above-mentioned Peng Qinghuana consumption is 0.5%～2% of a heparin sodium weight, is weight and weight ratio.
Above-mentioned hydrogen peroxide consumption is 0.2%～1% of a liquor capacity, is weightmeasurement ratio.
What add 0.5～2.0 times of liquor capacity contains the organic kind solvent of methyl signals, contains the organic kind solvent of methyl signals and can adopt glycol dimethyl ether.
Filtrating is shone 5～10min in the ultraviolet Sterilizers, carry out product structure and modify.
The invention has the beneficial effects as follows: in the certain solution of heparin sodium aqua, under specified temp and acidic conditions, with nitrite reaction; Modify through reduction and uv irradiating, must arrive for the heparin product through the decolouring freeze-drying, it is defective to have overcome traditional technology production product structure; The defective of product stability difference; The product of producing have reach for heparin European standard article structure consistent with character, and good stability, product yield height.
Four, description of drawings:
Accompanying drawing 1 is the schema of products production of the present invention.
Five, embodiment:
In conjunction with accompanying drawing, the present invention is done further description:
Embodiment 1: get refined heparin sodium; Add purified water and be dissolved into 3%～10% concentration, using the hydrochloric acid adjusting pH of 2～6mol/L is 1.0～3.0, adds the glycol dimethyl ether of 0.5～2.0 times of liquor capacity then; During adjustment temperature to 10～30 ℃; The Sodium Nitrite of adding 1.0%～3.0%, stirring reaction 30～90min, temperature is controlled at 10～30 ℃; Regulating pH after degraded is accomplished is 8～10, adds 0.5%～2% Peng Qinghuana then, stirring reaction 15h.Regulate pH to 3.0～4.0 with hydrochloric acid then, re-adjustment pH is 6～8 behind reaction 5～30min, adds 1.5～3 times of amount 92% ethanol sedimentations, places 6～24h.The gained deposition is added purified water be dissolved into 5%～20% concentration, regulate pH6～8, use the 0.65um membrane filtration, shine 5～10min in the filtrating input ultraviolet Sterilizers, add 1.5～3 times of amount 92% ethanol sedimentation depositions and placed 6～24 hours.Above-mentioned throw out is added purified water be dissolved into 10%～20% concentration, transfer pH9～12, the hydrogen peroxide oxidation of adding 0.2%～1% 6～12 hours is used the 0.22um membrane filtration, adds 2.7 times of amount 92% ethanol sedimentations depositions and places 6～12 hours.Throw out is dissolved into 10%～15% concentration, lyophilize or throw out through ethanol dehydration in below 50 ℃, dry must reaching below the vacuum tightness 0.095Mpa for the heparin finished product.
Embodiment 2: reach and realize through following technology for heparin; Heparin sodium is added purified water be dissolved into 3%～10% concentration, using the hydrochloric acid adjusting pH of 4mol/L is 1.0～3.0, adds the glycol dimethyl ether of 0.5～2.0 times of liquor capacity then; During adjustment temperature to 10～30 ℃; The Sodium Nitrite of adding 1.0%～3%, stirring reaction 30～90min, temperature is controlled at 10～30 ℃; Regulating pH after degraded is accomplished is 8～10, adds 0.5%～2% Peng Qinghuana then, stirring reaction 15h.Regulate pH to 3.0～4.0 with hydrochloric acid then, re-adjustment pH is 6～8 behind reaction 5～30min, adds 1.5～3 times of amount concentration 90%～95% ethanol sedimentations, places 6～24h.The gained deposition is added purified water be dissolved into 5%～20% concentration, regulate pH6～8, use the 0.65um membrane filtration, shine 5～10min in the filtrating input ultraviolet Sterilizers, add 1.5～3 times of amount concentration 90%～95% ethanol sedimentation depositions and placed 6～24 hours.Above-mentioned throw out is added purified water be dissolved into 10%～20% concentration, transfer pH9～12, the hydrogen peroxide oxidation of adding 0.2%～1% 6～12 hours is used the 0.22um membrane filtration, adds 2～3 times of amount concentration 90%～92% ethanol sedimentations depositions and places 6～12 hours.Throw out is dissolved into 10%～15% concentration, lyophilize or throw out through ethanol dehydration in below 50 ℃, dry must reaching under the negative pressure state for the heparin finished product.The present invention meets the European Pharmacopoeia quality standard, and is consistent with European Pharmacopoeia standard substance structure, and good stability, and product yield is high.
Claims (2)
1. one kind reaches for the heparin working method, it is characterized in that production stage is following, according to weight percent:
Heparin sodium is added purified water be dissolved into 3%～10% concentration; Using the hydrochloric acid adjusting pH of 2～6mol/L is 1.0～3.0; What add 0.5～2.0 times of liquor capacity then contains the organic kind solvent of methyl signals, during adjustment temperature to 10～30 ℃, adds Sodium Nitrite; Stirring reaction 30～90min, temperature is controlled at 10～30 ℃; Regulating pH after degraded is accomplished is 8～10, adds Peng Qinghuana then, stirring reaction 15h; Regulate pH to 3.0～4.0 with hydrochloric acid then, re-adjustment pH is 6～8 behind reaction 5～30min, adds ethanol sedimentation, places 6～24h; The gained deposition is added purified water be dissolved into 5%～20% concentration, regulate pH to 6～8, use membrane filtration, shine 5～10min in the filtrating input ultraviolet Sterilizers, add 1.5～3 times of amount ethanol sedimentation depositions and placed 6～24 hours; Above-mentioned throw out is added purified water be dissolved into 10%～20% concentration, transfer pH to 9～12, added hydrogen peroxide oxidation 6～12 hours, use membrane filtration, add the ethanol sedimentation deposition and placed 6～12 hours; Throw out is dissolved into 10%～15% concentration, lyophilize or throw out through ethanol dehydration in below 50 ℃, dry must reaching below the vacuum tightness 0.095MPa for the heparin finished product; The consumption of described Sodium Nitrite is the 1.0%-3.0% of heparin sodium weight, is weight and weight ratio; Described Peng Qinghuana consumption is the 0.5%-2% of heparin sodium weight, is weight and weight ratio; Described hydrogen peroxide consumption is the 0.2%-1% of liquor capacity, is weightmeasurement ratio; Contain the organic kind solvent of methyl signals and adopt glycol dimethyl ether.
2. working method according to claim 1 is characterized in that: filtrating is shone 5～10min in the ultraviolet Sterilizers, carries out product structure and modifies.
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| CN2010102871225A CN101942038B (en) | 2010-09-16 | 2010-09-16 | Production method of dalteparin sodium |
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| CN2010102871225A CN101942038B (en) | 2010-09-16 | 2010-09-16 | Production method of dalteparin sodium |
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| CN101942038B true CN101942038B (en) | 2012-08-29 |
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103275246B (en) * | 2013-06-07 | 2015-08-26 | 山东辰中生物制药有限公司 | A kind of nadroparin calcium production method |
| CN104045744B (en) * | 2014-06-26 | 2016-01-06 | 常州千红生化制药股份有限公司 | The preparation method of dalteparin sodium |
| CN106749769B (en) * | 2016-12-26 | 2021-08-24 | 海南通用同盟药业有限公司 | Improved low molecular weight heparin calcium bulk drug and preparation thereof |
| US11492421B2 (en) * | 2018-02-14 | 2022-11-08 | Biological E Limited | Process for the preparation of Dalteparin sodium |
| CN110845641A (en) * | 2019-11-07 | 2020-02-28 | 中国药科大学 | Heparin oligosaccharide and application thereof in preparation of anti-angiogenesis drugs |
| CN111019014A (en) * | 2019-11-22 | 2020-04-17 | 苏州二叶制药有限公司 | Preparation process of nadroparin calcium |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1554671A (en) * | 2003-12-24 | 2004-12-15 | 合肥兆峰科大药业有限公司 | Process for preparing low moledule heparin calcium of low nitrite content |
| CN1847268A (en) * | 2005-04-11 | 2006-10-18 | 丘比株式会社 | Low molecule heparin and salt thereof, pharmaceutical composition comprising same and producing method thereof |
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| US20060040896A1 (en) * | 2004-08-18 | 2006-02-23 | Paringenix, Inc. | Method and medicament for anticoagulation using a sulfated polysaccharide with enhanced anti-inflammatory activity |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1554671A (en) * | 2003-12-24 | 2004-12-15 | 合肥兆峰科大药业有限公司 | Process for preparing low moledule heparin calcium of low nitrite content |
| CN1847268A (en) * | 2005-04-11 | 2006-10-18 | 丘比株式会社 | Low molecule heparin and salt thereof, pharmaceutical composition comprising same and producing method thereof |
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Effective date of registration: 20120914 Address after: 257000 Shandong District of Dongying city in Dongying Province North Road No. 726 in the building Patentee after: SHANDONG HI-TECH CHEMICAL GROUP Co.,Ltd. Patentee after: DONGYING TIANDONG PHARMACEUTICAL Co.,Ltd. Address before: 257000 Shandong District of Dongying city in Dongying Province North Road No. 726 in the building Patentee before: SHANDONG HI-TECH CHEMICAL GROUP Co.,Ltd. Patentee before: DONGYING TIANDONG BIOCHEMICAL INDUSTRY Co.,Ltd. |
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Address after: 257000 West of HaoChun Road, Dongying District, Dongying City, Shandong Province Patentee after: Shandong Haike Chemical Co.,Ltd. Patentee after: DONGYING TIANDONG PHARMACEUTICAL Co.,Ltd. Address before: 257000 Shandong District of Dongying city in Dongying Province North Road No. 726 in the building Patentee before: SHANDONG HI-TECH CHEMICAL GROUP Co.,Ltd. Patentee before: DONGYING TIANDONG PHARMACEUTICAL Co.,Ltd. |
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Effective date of registration: 20201030 Address after: 257000 No. two, 1236 South Road, Dongying District, Shandong, Dongying Patentee after: DONGYING TIANDONG PHARMACEUTICAL Co.,Ltd. Address before: 257000 West of HaoChun Road, Dongying District, Dongying City, Shandong Province Patentee before: Shandong Haike Chemical Co.,Ltd. Patentee before: DONGYING TIANDONG PHARMACEUTICAL Co.,Ltd. |
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