CN100467493C - Producing process for low molecular weight calcium heparin - Google Patents
Producing process for low molecular weight calcium heparin Download PDFInfo
- Publication number
- CN100467493C CN100467493C CNB2007100614766A CN200710061476A CN100467493C CN 100467493 C CN100467493 C CN 100467493C CN B2007100614766 A CNB2007100614766 A CN B2007100614766A CN 200710061476 A CN200710061476 A CN 200710061476A CN 100467493 C CN100467493 C CN 100467493C
- Authority
- CN
- China
- Prior art keywords
- value
- calcium
- minutes
- heparin
- sodium
- 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
- 229920000669 heparin Polymers 0.000 title claims abstract description 28
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 239000011575 calcium Substances 0.000 title claims abstract description 27
- 229910052791 calcium Inorganic materials 0.000 title claims abstract description 27
- 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 title claims abstract description 14
- 229960002897 heparin Drugs 0.000 title claims abstract description 14
- 238000000034 method Methods 0.000 title claims description 16
- 230000008569 process Effects 0.000 title claims description 9
- 230000001858 anti-Xa Effects 0.000 claims abstract description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- 239000007788 liquid Substances 0.000 claims description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 15
- 238000001556 precipitation Methods 0.000 claims description 12
- 239000008213 purified water Substances 0.000 claims description 12
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 10
- 239000000047 product Substances 0.000 claims description 10
- 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 description 9
- 229960001008 heparin sodium Drugs 0.000 claims description 9
- 238000004108 freeze drying Methods 0.000 claims description 8
- 239000012528 membrane Substances 0.000 claims description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 8
- 239000012279 sodium borohydride Substances 0.000 claims description 8
- 235000010288 sodium nitrite Nutrition 0.000 claims description 8
- 238000005303 weighing Methods 0.000 claims description 8
- 238000000108 ultra-filtration Methods 0.000 claims description 7
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 6
- 239000001110 calcium chloride Substances 0.000 claims description 6
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 102000011759 adducin Human genes 0.000 claims description 5
- 108010076723 adducin Proteins 0.000 claims description 5
- 238000011146 sterile filtration Methods 0.000 claims description 4
- 229940095529 heparin calcium Drugs 0.000 claims description 3
- 239000003055 low molecular weight heparin Substances 0.000 claims description 3
- 238000005374 membrane filtration Methods 0.000 claims description 3
- 230000003647 oxidation Effects 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- 241000143437 Aciculosporium take Species 0.000 claims description 2
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 claims description 2
- 208000012826 adjustment disease Diseases 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000001914 filtration Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 22
- 230000000694 effects Effects 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 208000007536 Thrombosis Diseases 0.000 description 5
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 208000032843 Hemorrhage Diseases 0.000 description 3
- 230000004087 circulation Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000008676 import Effects 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 206010014522 Embolism venous Diseases 0.000 description 2
- 208000001132 Osteoporosis Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 230000023555 blood coagulation Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000005352 clarification Methods 0.000 description 2
- 238000012691 depolymerization reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000002045 lasting effect Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 208000004043 venous thromboembolism Diseases 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 102000010911 Enzyme Precursors Human genes 0.000 description 1
- 108010062466 Enzyme Precursors Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 1
- 208000006193 Pulmonary infarction Diseases 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000002170 aldosterone antagonist Substances 0.000 description 1
- 229940083712 aldosterone antagonist Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 159000000007 calcium salts Chemical group 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 238000002682 general surgery Methods 0.000 description 1
- 208000006575 hypertriglyceridemia Diseases 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 150000002832 nitroso derivatives Chemical class 0.000 description 1
- 230000010494 opalescence Effects 0.000 description 1
- 230000000399 orthopedic effect Effects 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 230000007575 pulmonary infarction Effects 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 230000008728 vascular permeability Effects 0.000 description 1
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a manufacturing method of low-molecular weight (3600-5000D) calcium heparin, which comprises the following steps: depolymerizing; reducing; transmitting calcium; filtering; condensing; obtaining the anti-Xa factor with potency at 95IU/mg-130IU/mg and pH value at 4.5-7.5 and rate of Xa and IIa at 2.5-4.0.
Description
Technical field
The present invention relates to the calciparine production technique, be specifically related to the production technique of low molecular weight calcium heparin.
Background technology
The biological activity heparin is from being found in the existing last 100 years history of clinical application, it is prevention operation back thrombosis and the acute venothrombotic choice drug of treatment, in addition, heparin and derivative thereof also are widely used in transfers blood fat, anti-inflammatory, antianaphylaxis and immunomodulatory etc., it is still one of most important biochemical drug up till now, also is China's main exit one of medicine of earning foreign exchange.
Calciparine all can delay or stop blood coagulation in vivo and in vitro, its anti-freezing mechanism complexity, each link to blood coagulation all has effect, comprises that the anticoagulant proenzyme changes zymoplasm, anticoagulant enzymic activity into, hinders Fibrinogen to change scleroproein into, prevent platelet aggregation.But calciparine is blood fat reducing also, reduces LDL and VLDL, and rising HDL changes the blood viscosity, the protection vascular endothelial cell, and prevention of arterial is atherosis, promotes blood flow, improves effects such as coronary artery circulation.Because it is to play a role in vivo with calcium salt forms, after subcutaneous injection, slowly diffusion in blood circulation, can not reduce the calcium colloid of capillary vessel between local cells, do not change vascular permeability yet, almost do not have the side effect that the heparin sodium subcutaneous injection causes local hemorrhage, be applicable to prevention and treatment thrombus-thrombotic disease and thrombosis, calciparine also has more tangible anti-feritin and aldosterone antagonist activity, thereby also can be used for kidney machine, artificial liver and extracorporeal circulation use.But in clinical use, find, many negative impacts can occur behind unassorted heparin of common molecular weight and the derivative life-time service thereof, as hemorrhage, cause osteoporosis, induced platelet minimizing etc., and when using, need detect platelet count.
Summary of the invention
The present invention aims to provide a kind of low molecular heparin calcium production technique, to overcome the defective that prior art exists.
For realizing the object of the invention, producing process for low molecular weight calcium heparin of the present invention is characterized in that it comprises the following steps:
A. take by weighing required component by following weight part: heparin sodium 2000～4000, Sodium Nitrite 50～100, sodium borohydride 2～4;
B. add heparin sodium and the Sodium Nitrite that is taken by weighing in the retort of 20000～40000 weight part purified water, stir and make dissolving fully, pH value and the temperature of controlling solution with concentrated hydrochloric acid are respectively 2.7～2.9 and 15～20 ℃;
C. stablize when constant when above-mentioned reacting liquid pH value, under keeping warm mode, continue to stir 25～35 minutes, adjust pH value to 7.8～8.3 of reaction solution with sodium hydroxide solution again after, restir obtains depolymerization liquid after 25～35 minutes;
D. in above-mentioned depolymerization liquid, added the sodium borohydride that is taken by weighing one by one in 30 minutes at every interval under room temperature and the whipped state, continue to stir after 13～16 hours, the pH value of adjusting reaction solution is 3.5～4.0, stir after 25～35 minutes, with pH value to 6.8～7.2 of sodium hydroxide solution adjustment reaction solution, restir obtained reduced liquid in 15～20 minutes;
E. at room temperature use the above-mentioned reduced liquid of uviolizing 15～30 minutes of 245nm wavelength;
F. after adjusting pH value to 10.0～11.0 of above-mentioned reaction solution with sodium hydroxide solution, reacting liquid temperature is controlled between 30～31 ℃, added the hydrogen peroxide rear oxidation 2～3 hours;
G. pH value to 6.9～7.1 backs of adjusting above-mentioned reaction solution add the sodium-chlor dissolving of 40～80 weight parts, add the ethanol of 30000～60000 weight parts under whipped state again, staticly settle then 45～50 hours;
H. after the purified water of 10 times of amounts of adding makes the throw out dissolving in the throw out of g step, 5% of lasting adding 100～200 weight parts calcium chloride water under whipped state, continue again to stir after 22～26 hours, add 95% ethanol of 1.5～2.5 times of amounts, staticly settle then and made the calcium precipitation thing in 45～50 hours;
I. after repeating the operation of a h step, throw out dissolves with the purified water of 10 times of amounts, 1% the calcium chloride water that adds 20～40 weight parts then, filter, the pH value of adjusting reaction solution is between 6.2～6.3, stirred 25～35 minutes, and then add 95% ethanol of 1.5～2.5 times of amounts, staticly settle and made secondary calcium precipitation thing in 45～55 hours;
J. after the secondary calcium precipitation thing dissolving of purified water with 10～15 times of amounts, use sheet frame and 0.2 μ m membrane filtration successively, and then filtrate is used 1000D ultra-filtration membrane ultrafiltration and concentration the i step;
K. with the concentrated solution of above-mentioned J step with 0.1 μ m filter membrane Sterile Filtration after, filtrate is gone into the Freeze Drying Equipment freeze-drying and is made finished product.
The concentration of described hydrogen peroxide is 0.4～0.6%, and described alcohol concn is 90～95%, and described concentrated hydrochloric acid concentration is 35～36%.
Handicraft product of the present invention and relevant comparative data of country such as following table with the import standard:
| Handicraft product of the present invention | National standard | The import standard | |
| Proterties | Colourless clear liquid | Colourless or faint yellow clear liquid | Clarification or opalescence or faint yellow clear liquid |
| The pH value | 4.5～7.5 | 5.5～8.0 | 4.5～7.5 |
| Anti-Xa factor is tired | 95-130IU/mg | Be not less than 70IU/mg | 95-130IU/mg |
| Xa/IIa | 2.5～4.0 | ≥1.5 | 2.5～4.0 |
| Molecular weight | 3600～5000 | <8000 | 3600～5000 |
| Molecular weight distribution | ＜8000 component〉75% | ＜8000 component〉60% | ＜8000 component〉75% |
The technical progress that the present invention obtains:
(1). owing to adopt production technique of the present invention, ultrafiltration membrane technique is applied to the separation of different molecular weight section, the solvent precipitation classification and the expensive gel adsorption method of separation that fall behind have been changed, obtained that anti-Xa factor tires that 95IU/mg～130IU/mg, pH value are 4.5～7.5, Xa/IIa ratio is 2.5～4.0, molecular-weight average is the calciparine product of 3600～5000D, its quality product is far above national standard and import standard.
(2). the molecular-weight average that production technique of the present invention obtains is that the Low molecular heparin calcium product of 3600～5000D can effectively prevent venous thromboembolism and pulmonary infarction disease, can be used for preventing before the art of general surgery, orthopedics, Neurological Surgery and the thrombosis of postoperative; Can effectively prevent the venous thromboembolism of Ischemic Apoplexy Patients, can reduce the risk that suffers stroke greatly, what can prevent effectively that the blood extracorporeal circulation from causing solidifies; Death that can more effective minimizing unstable coronary syndrome patient, heart failure, recurrent stenocardia etc., and can reduce hypertriglyceridemia, can effectively solve side effects such as be prone to behind unassorted heparin of common molecular weight and the derivative life-time service thereof hemorrhage, osteoporosis, induced platelet minimizing, have very big utilization and extention prospect.
Description of drawings
Fig. 1 is a process flow diagram of the present invention.
Embodiment
Embodiment 1: as shown in Figure 1, it is standby that a. at first takes by weighing 3kg heparin sodium (injection stage is removed DS), 75g Sodium Nitrite, 3g sodium borohydride;
B. in the retort of 30L purified water, add 3kg heparin sodium, 75g Sodium Nitrite successively, and stirring makes it to dissolve fully, fluid temperature in the control retort is between 15～20 ℃, concentrated hydrochloric acid with 35～36% is adjusted the pH value of reaction solution between 2.7～2.9, test paper color and pH value were write down with potassium iodide starch test paper survey primary first-order equation liquid in 15 minutes in every interval;
C. when the pH of above-mentioned reaction solution value stabilization was constant, when potassium iodide starch test paper was colourless, above depolymerization reaction finished.Continue then to stir 25～35 minutes under keeping warm mode, adjust between pH value to 7.8～8.3 of reaction solution with sodium hydroxide, restir stops depolymerization reaction and obtains depolymerization liquid after 25～35 minutes;
D. the sodium borohydride that is taken by weighing is mixed with 1% the aqueous solution, every interval 30 minutes is divided it to add in the above-mentioned depolymerization liquid for three times and is carried out reduction reaction under room temperature and whipped state then, continue to stir after 13～16 hours, concentrated hydrochloric acid with 35～36% is adjusted the pH value of reaction solution between 3.5～4.0, behind the restir 25～35 minutes, adjust with sodium hydroxide between pH value to 6.8～7.2 of reaction solution, restir obtained reduced liquid in 15～20 minutes;
E. at room temperature use the above-mentioned reaction solution of uviolizing 15～30 minutes of 245nm wavelength, to eliminate nitroso compound in the solution and residual nitrite;
F. after adjusting pH value to 10.0～11.0 of above-mentioned reaction solution with sodium hydroxide, reacting liquid temperature is controlled between 30～31 ℃, adds the hydrogen peroxide oxidation 2～3 hours of 30～60ml 0.4～0.6% then;
G. add the 60g solid sodium chloride again after adjusting pH value to 6.9～7.1 of above-mentioned reaction solution with 35～36% concentrated hydrochloric acid, add the ethanol of 45L90～95% again under whipped state, staticly settle then until the supernatant clarification, required time is about 48 hours;
H. after the purified water of 10 times of amounts of adding makes the throw out dissolving in the throw out of g step, 5% of lasting adding 100～200 weight parts calcium chloride water obtains changeing calcium liquid under whipped state, continue to stir after 22～26 hours, in changeing calcium liquid, add 95% ethanol of 1.5～2.5 times of amounts, staticly settle then and made the calcium precipitation thing in 45～50 hours;
I. after repeating once the operation of above-mentioned h step, supernatant liquor is reclaimed, after the purified water dissolving of throw out with 10～15 times of amounts, 1% the calcium chloride water that adds 20～40ml obtains secondary is changeed calcium liquid, filter the back and adjust the pH value of secondary commentaries on classics calcium liquid between 6.2～6.3 with 35%～36% concentrated hydrochloric acid, stir and add 1.5～2.5 times of ethanol of 95% after 25～35 minutes again, staticly settle and made secondary calcium precipitation thing in 45～55 hours to g step throw out amount;
J. supernatant is reclaimed, secondary calcium precipitation thing enters the control region, after with 10～15 times of purified water secondary calcium precipitation thing being dissolved then, use sheet frame and 0.2 μ m membrane filtration successively, and then filtrate is used 1000D ultra-filtration membrane ultrafiltration and concentration to secondary calcium precipitation thing amount;
K. the concentrated bacteria-removing liquid that the concentrated solution of above-mentioned J step is obtained after with 0.1 μ m filter membrane Sterile Filtration is gone into the Freeze Drying Equipment freeze-drying and is made finished product.
K. with the concentrated solution of above-mentioned J step with 0.1 μ m filter membrane Sterile Filtration after, filtrate is gone into the Freeze Drying Equipment freeze-drying and is made finished product.
Embodiment 2: the present embodiment difference from Example 1 is that heparin sodium is 2kg, Sodium Nitrite 50g, sodium borohydride 2g.
Embodiment 3: the present embodiment difference from Example 1 is that heparin sodium is 4kg, Sodium Nitrite 100g, sodium borohydride 4g.
Claims (5)
1. a producing process for low molecular weight calcium heparin is characterized in that it comprises the following steps:
A. take by weighing required component by following weight part: heparin sodium 2000～4000, Sodium Nitrite 50～100, sodium borohydride 2～4;
B. add heparin sodium and the Sodium Nitrite that is taken by weighing in the retort of 20000～40000 weight part purified water, stir and make dissolving fully, pH value and the temperature of controlling solution with concentrated hydrochloric acid are respectively 2.7～2.9 and 15～20 ℃;
C. stablize when constant when above-mentioned reacting liquid pH value, under keeping warm mode, continue to stir 25～35 minutes, adjust pH value to 7.8～8.3 of reaction solution with sodium hydroxide solution again after, restir obtains depolymerization liquid after 25～35 minutes;
D. in above-mentioned depolymerization liquid, added the sodium borohydride that is taken by weighing one by one in 30 minutes at every interval under room temperature and the whipped state, continue to stir after 13～16 hours, the pH value of adjusting reaction solution is 3.5～4.0, stir after 25～35 minutes, with pH value to 6.8～7.2 of sodium hydroxide solution adjustment reaction solution, restir obtained reduced liquid in 15～20 minutes;
E. at room temperature use the above-mentioned reduced liquid of uviolizing 15～30 minutes of 245nm wavelength;
F. after adjusting pH value to 10.0～11.0 of above-mentioned reaction solution with sodium hydroxide solution, reacting liquid temperature is controlled between 30～31 ℃, added the hydrogen peroxide rear oxidation 2～3 hours;
G. pH value to 6.9～7.1 backs of adjusting above-mentioned reaction solution add the sodium-chlor dissolving of 40～80 weight parts, add the ethanol of 30000～60000 weight parts under whipped state again, staticly settle then 45～50 hours;
H. after the purified water of 10 times of amounts of adding makes the throw out dissolving in the throw out of g step, under whipped state, continue to add the 100-200 weight part calcium chloride water, continue again to stir after 22～26 hours, add 95% ethanol of 1.5～2.5 times of amounts, staticly settle then and made the calcium precipitation thing in 45～50 hours;
I. after repeating the operation of a h step, throw out dissolves with the purified water of 10 times of amounts, 1% the calcium chloride water that adds the 20-40 weight part then, filter, the pH value of adjusting reaction solution is between 6.2～6.3, stirred 25～35 minutes, and then add 95% ethanol of 1.5～2.5 times of amounts, staticly settle and made secondary calcium precipitation thing in 45～55 hours;
J. after the secondary calcium precipitation thing dissolving of purified water with 10～15 times of amounts, use sheet frame and 0.2 μ m membrane filtration successively, and then filtrate is used 1000D ultra-filtration membrane ultrafiltration and concentration the i step;
K. with the concentrated solution of above-mentioned J step with 0.1 μ m filter membrane Sterile Filtration after, filtrate is gone into the Freeze Drying Equipment freeze-drying and is made finished product.
2. producing process for low molecular weight calcium heparin according to claim 1 is characterized in that described hydrogen peroxide concentration is 0.4～0.6%.
3. producing process for low molecular weight calcium heparin according to claim 1 is characterized in that described concentrated hydrochloric acid concentration is 35～36%.
4. producing process for low molecular weight calcium heparin according to claim 1, the alcohol concn that it is characterized in that described g step is 90～95%.
5. producing process for low molecular weight calcium heparin according to claim 1, the anti-Xa factor of low molecular heparin calcium that the it is characterized in that described finished product 95IU/mg～130IU/mg that tires, the pH value is 4.5～7.5, Xa/IIa ratio is 2.5～4.0.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007100614766A CN100467493C (en) | 2007-02-01 | 2007-02-01 | Producing process for low molecular weight calcium heparin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007100614766A CN100467493C (en) | 2007-02-01 | 2007-02-01 | Producing process for low molecular weight calcium heparin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101012289A CN101012289A (en) | 2007-08-08 |
| CN100467493C true CN100467493C (en) | 2009-03-11 |
Family
ID=38700029
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2007100614766A Active CN100467493C (en) | 2007-02-01 | 2007-02-01 | Producing process for low molecular weight calcium heparin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100467493C (en) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102050888B (en) * | 2010-12-13 | 2011-12-07 | 河北常山生化药业股份有限公司 | Method for preparing enoxaparin sodium |
| CN102603923B (en) * | 2012-03-02 | 2013-12-11 | 海南灵康制药有限公司 | Heparin calcium compound and preparation method thereof |
| CN103382232B (en) * | 2012-05-04 | 2015-11-18 | 常州泰康制药有限公司 | The preparation of nadroparin calcium and purifying process |
| CN103012622B (en) * | 2012-12-13 | 2014-08-27 | 南通天龙畜产品有限公司 | Entirely-stirring tank used for heparin sodium extraction process |
| 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 |
| GB2515315A (en) * | 2013-06-19 | 2014-12-24 | Dilafor Ab | New Processes |
| CN103408676A (en) * | 2013-07-15 | 2013-11-27 | 河北常山生化药业股份有限公司 | Nadroparin calcium preparation technology |
| CN103315951B (en) * | 2013-07-17 | 2014-10-08 | 海南通用同盟药业有限公司 | Low-molecular-weight heparin calcium injection |
| CN104072638B (en) * | 2014-07-07 | 2016-08-31 | 兆科药业（合肥）有限公司 | A kind of preparation method of nadroparin calcium |
| CN104072639B (en) * | 2014-07-16 | 2015-04-22 | 南京健友生化制药股份有限公司 | Production method for nadroparin calcium |
| CN104086673B (en) * | 2014-07-28 | 2016-07-06 | 常州千红生化制药股份有限公司 | A kind of preparation technology of nadroparin calcium |
| CN104804110B (en) * | 2015-05-08 | 2017-04-12 | 深圳赛保尔生物药业有限公司 | High-purity nadroparin calcium |
| CN108409890A (en) * | 2018-03-16 | 2018-08-17 | 湖北亿诺瑞生物制药有限公司 | A method of producing calciparine from heparin sodium crude |
| CN110894246A (en) * | 2019-12-31 | 2020-03-20 | 湖北亿诺瑞生物制药有限公司 | Method for increasing calcium content in low molecular weight heparin calcium |
-
2007
- 2007-02-01 CN CNB2007100614766A patent/CN100467493C/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN101012289A (en) | 2007-08-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN100467493C (en) | Producing process for low molecular weight calcium heparin | |
| CN102558393B (en) | Preparation process of dalteparin sodium | |
| CN102050888B (en) | Method for preparing enoxaparin sodium | |
| DE60307366T3 (en) | Soluble hyperbranched polymers and process for their preparation | |
| JP6432709B2 (en) | Method for producing polysulfate pentosan | |
| JP6281659B1 (en) | Polysulfate pentosan, pharmaceutical composition and anticoagulant | |
| MX2008011064A (en) | Soluble, highly branched glucose polymers for enteral and parenteral nutrition and for peritoneal dialysis. | |
| CN104086673A (en) | Preparation process of nadroparin calcium | |
| CN103232558A (en) | Preparation method of high-quality low-molecular weight dalteparin sodium | |
| CN102070727A (en) | Extraction method of sodium heparin | |
| CN102585038A (en) | Islamic enoxaparin sodium and method for producing and purifying same | |
| CN104622896A (en) | Method for preparing sodium-potassium-magnesium-calcium glucose injection | |
| JP2022180509A (en) | Pentosan polysulfate and method for producing pentosan polysulfate | |
| WO2019124363A1 (en) | Pentosan polysulfate and medicine containing pentosan polysulfate | |
| CN102276742A (en) | Method for cleanly producing MMW (medium molecular weight) hydroxyethyl starches | |
| JP3455783B2 (en) | Intimal thickening inhibitor | |
| CN102675079B (en) | Recovery method of aliphatic calcium alpha-keto acid | |
| CN104448037B (en) | A kind of preparation technology of chondroitin sulfate potassium salt | |
| CN112321751A (en) | Refining method of high-quality enoxaparin sodium | |
| CN111943234A (en) | Method for preparing medicinal sterile sodium bicarbonate granules with large particle size | |
| CN108409890A (en) | A method of producing calciparine from heparin sodium crude | |
| EP1075839B1 (en) | Plasma expander, blood diluent and cryoprotector produced using amylopectin-rich potato starch | |
| CN109293800A (en) | Benzyl chloride taste removes method in a kind of heparin Bian ester production process | |
| CN106832061A (en) | A kind of Enoxaparin Sodium preparation technology | |
| CN112237570A (en) | Novel carbamide peroxide preparation for preparing medicine for repairing pulmonary vascular injury and preparation method thereof |
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 | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Assignee: Hebei Changshan Biochemical Pharmaceutical Co.,Ltd. Assignor: Gao Shuhua Contract fulfillment period: 2009.3.11 to 2027.1.31 Contract record no.: 2009130000032 Denomination of invention: Producing process for low molecular weight calcium heparin Granted publication date: 20090311 License type: Exclusive license Record date: 20090312 |
|
| LIC | Patent licence contract for exploitation submitted for record |
Free format text: EXCLUSIVE LICENSE; TIME LIMIT OF IMPLEMENTING CONTACT: 2009.3.11 TO 2027.1.31; CHANGE OF CONTRACT Name of requester: HEBEI CHANGSHAN BIOCHEMICAL DRUG INDUSTRY CO., LTD Effective date: 20090312 |
|
| ASS | Succession or assignment of patent right |
Owner name: HEBEI CHANGSHAN BIOCHEMICAL DRUG INDUSTRY CO., LTD Free format text: FORMER OWNER: GAO SHUHUA Effective date: 20091218 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20091218 Address after: No 9 prosperous road, Zhengding County, Hebei Patentee after: Hebei Changshan Biochemical Pharmaceutical Co.,Ltd. Address before: Changshan Biochemical Pharmaceutical Co., Ltd., 9 prosperous road, Zhengding County, Hebei Patentee before: Gao Shuhua |
|
| C56 | Change in the name or address of the patentee |
Owner name: HEBEI CHANGSHAN BIOCHEMICAL PHARMACEUTICAL CO., LT Free format text: FORMER NAME: HEBEI CHANGSHAN BIOCHEMICAL DRUG INDUSTRY CO., LTD. |
|
| CP01 | Change in the name or title of a patent holder |
Address after: No 9 prosperous road, Zhengding County, Hebei Patentee after: HEBEI CHANGSHAN BIOCHEMICAL PHARMACEUTICAL Co.,Ltd. Address before: No 9 prosperous road, Zhengding County, Hebei Patentee before: Hebei Changshan Biochemical Pharmaceutical Co.,Ltd. |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Producing process for low molecular weight calcium heparin Effective date of registration: 20190422 Granted publication date: 20090311 Pledgee: Zhengding Branch of Industrial and Commercial Bank of China Ltd. Pledgor: HEBEI CHANGSHAN BIOCHEMICAL PHARMACEUTICAL Co.,Ltd. Registration number: 2019130000006 |
|
| CP02 | Change in the address of a patent holder | ||
| CP02 | Change in the address of a patent holder |
Address after: 050800 No.71, Menglong street, South District, Zhengding high tech Industrial Development Zone, Zhengding District, China (Hebei) pilot Free Trade Zone, Shijiazhuang City, Hebei Province Patentee after: HEBEI CHANGSHAN BIOCHEMICAL PHARMACEUTICAL Co.,Ltd. Address before: 050800 No. 9, Fuqiang Road, Zhengding County, Hebei Province Patentee before: HEBEI CHANGSHAN BIOCHEMICAL PHARMACEUTICAL Co.,Ltd. |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20220426 Granted publication date: 20090311 Pledgee: Zhengding Branch of Industrial and Commercial Bank of China Ltd. Pledgor: HEBEI CHANGSHAN BIOCHEMICAL PHARMACEUTICAL Co.,Ltd. Registration number: 2019130000006 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A low molecular weight heparin calcium production process Granted publication date: 20090311 Pledgee: Langfang Bank Co.,Ltd. Shijiazhuang Branch Pledgor: HEBEI CHANGSHAN BIOCHEMICAL PHARMACEUTICAL Co.,Ltd. Registration number: Y2024980013117 |