CN106832061A - A kind of Enoxaparin Sodium preparation technology - Google Patents
A kind of Enoxaparin Sodium preparation technology Download PDFInfo
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- CN106832061A CN106832061A CN201611197430.2A CN201611197430A CN106832061A CN 106832061 A CN106832061 A CN 106832061A CN 201611197430 A CN201611197430 A CN 201611197430A CN 106832061 A CN106832061 A CN 106832061A
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- sodium
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- enoxaparin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/727—Heparin; Heparan
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
- C08B37/0078—Degradation products
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Abstract
The invention discloses a kind of Enoxaparin Sodium preparation technology, including heparin sodium aqua is prepared, depolymerized heparin liquid is prepared, is prepared reducing solution, prepares the step such as crude product, refined, lyophilized.Products obtained therefrom weight average molecular weight is 5000 ~ 6000, and peak molecular weight is 3000 ~ 6000, and component of the molecular weight less than 3000 is not more than 11%, and component of the molecular weight more than 8000 is not more than 13%, Anti-Xa activity >=135IU/mg.
Description
Technical field
The invention belongs to biological technical field, in particular to Enoxaparin process for producing sodium.
Background technology
Enoxaparin Sodium is low molecular sodium salt, and it is mainly used in pre- anticoagulant in haemodialysis and DVT
Treatment, unstable coronary artery disease treatment and the prevention thrombosis relevant with operation.Heparin (heparin) is deposited extensively
It is a kind of glycosaminoglycan in the tissue such as animal organ and mucous membrane of small intestine, lung, with anti-freezing, anti-inflammatory, antiallergy, disease-resistant
Various pharmacological activity such as poison, anticancer, regulation blood fat.
LMWHs is used in addition to possessing unfractionated heparin whole pharmacological action as anticoagulation, generally short-term medication, and
Therapeutic index is high.U.S. FDA has been approved by Enoxaparin Sodium as the prophylactic after low level limbs displacement technique.
The method of the product degraded of current domestic production LMWHs class mainly has natrium nitrosum edman degradation Edman, hydrogen peroxide
The methods such as edman degradation Edman, enzyme edman degradation Edman.But hydrogen peroxide degradation may introduce foreign matter, quality is not easily controlled；Enzyme degradation products end
There is unsaturated group at end, and stability is poor, high cost；On removal of impurities discoloration method, the country mainly has under condition of different pH at present
Potassium permanganate and hydrogen peroxide Two-step anodization or hydrogen peroxide oxidation process.The shortcoming of potassium permanganate and hydrogen peroxide Two-step anodization is
The manganese dioxide of generation is more difficult to be leached, and manganese dioxide has suction-operated to portioned product, reduces product recovery rate；In product
On purification technique, mainly there are the methods such as gel chromatography, ultrafiltration the country, difficult although the product quality that gel chromatography is obtained is higher
It is in large-scale production and relatively costly.
The content of the invention
The present invention is intended to provide a kind of Enoxaparin process for producing sodium, and the Enoxaparin prepared with this technique and
Its quality standard, with the defect for overcoming prior art to exist.
To realize the object of the invention, Enoxaparin process for producing sodium of the present invention comprises the following steps：
1st, heparin sodium aqua is prepared
After the purified water for adding 5~7 mass times in liquaemin, dissolved after stirring 4~5 hours at normal temperatures；
2nd, depolymerized heparin liquid is prepared
After the pH value 2~2.5 of the heparin sodium aqua obtained with hydrochloric acid regulating step 1, addition weight is liquaemin 1.0%~2.0%
Natrium nitrosum, then 2~3h of stirring reaction at 20~30 DEG C, then obtain depolymerized heparin liquid after standing 20~24h；
3rd, reducing solution is prepared
After adjusting the pH value 9~10 of above-mentioned depolymerized heparin liquid with sodium hydroxide solution, 0.8%~1.2% times of liquaemin weight is added
10~12h of sodium borohydride reduction, then again with sodium hydroxide solution adjust pH value to 6.8~7.2, obtain reducing solution；
4th, precipitate reduction thing is prepared
The ethanol for adding 2~3 volumes to measure again in above-mentioned reducing solution, collects after being sufficiently stirred for and obtains precipitate reduction thing；
5th, Enoxaparin Sodium crude product is prepared
After adding pure water stirring and dissolving in the precipitate reduction thing collected, the hydrogen peroxide for adding 0.6%~1.0% volume to measure again exists
At 25~30 DEG C aoxidize 20~24h, then add the ethanol that 2~3 volumes are measured again, after being sufficiently stirred for collect sediment obtain according to
Promise heparin sodium crude；
6th, Enoxaparin Sodium fine work is prepared
Purified water is added to be dissolved into 1%~2% the Enoxaparin Sodium crude product precipitation of above-mentioned collection（w/w）Solution, respectively with point
Son measures the milipore filter that cutoff value is 3000 and 8000 and carries out ultrafiltration, then Enoxaparin Sodium fine work solution is obtained after aseptic filtration；
7th, freeze
Enoxaparin sodium solution obtained in above-mentioned steps is freezed at 25~30 DEG C, that is, obtains Enoxaparin Sodium finished product.
The technological progress that the present invention is obtained：
1st, due to using production technology of the present invention, by application of membrane separation technology in different molecular weight section is separated, change backward
The gel molecular sieve method of solvent precipitation classification and costliness, has obtained anti-Xa potency >=135IU/mg, activity than for 2.0~
3.0, the molecular weight distribution of key component is the Enoxaparin Sodium product of 5000~6000D.
2nd, production technology of the present invention obtains the Enoxaparin Sodium product that mean molecule quantity is 5000~6000D and can effectively prevent
VTE, can be used to prevent general surgery, orthopaedic srugery, the preoperative and postoperative thrombosis of neurosurgery, can have
Effect prevents the venous thromboembolism of Ischemic Apoplexy Patients, can substantially reduce the risk that suffers stroke, can effectively anti-Hemostatic Oral Liquid it is external
The solidification that circulation causes, and unstability coronary heart disease can be effectively prevented, easily go out after effectively solving unfraction heparin long-term use
Existing bleeding, osteoporosis, induced platelet reduction etc., have broad application prospects.
3rd, of the invention to compare with existing Enoxaparin Sodium preparation technology, yield is up to 86%~97%, and weight average molecular weight is
5000~6000D, peak molecular weight is 3000~6000, and component of the molecular weight less than 3000 is not more than 11%, and molecular weight is more than
8000 component is not more than 13%；Anti-Xa activity >=135IU/mg, quality reaches the quality standard that European Pharmacopoeia specifies.Commercialization
The structure of compound reducing end is the mannitol of dehydration, and with raw material sources it is abundant, yield is high, stable and reliable product quality, pure
Degree is high, low cost, is degraded using natrium nitrosum and causes process is simple, and easy to operate, production process is easily controlled, steady quality,
Reaction is gentle, and product color is preferable, the features such as discharge without " three wastes ".Product Enoxaparin Sodium has anticoagulation, antithrombotic, resists and swell
Knurl, anti-inflammatory, antiallergy etc. act on and regulation blood fat effect, it is evident in efficacy, using in extensive range, can be used as injection, capsule
The raw material of the products such as agent, ointment, is easy to large-scale production.
Specific embodiment
With reference to specific embodiment, the invention will be further described.
Embodiment 1：
1st, weigh respectively standby after 3Kg liquaemins, 45g natrium nitrosums, 30g sodium borohydrides；
2nd, after to 3Kg liquaemins are added in 15~24L purified water retort, dissolving obtains liver after stirring 4~5 hours at normal temperatures
Plain sodium solution；
3rd, after pH=2~3 of above-mentioned heparin sodium aqua are adjusted with hydrochloric acid, weighed 45g nitrous acid is added under stirring
Sodium, then reacts 2~3h, then obtain depolymerized heparin liquid after standing 20~24h under 20~30 DEG C of insulations, stirring；
4th, after the pH value 9~10 of above-mentioned depolymerized heparin liquid is adjusted with sodium hydroxide solution, addition 30g sodium borohydride reductions 10~
12h, adjusts pH value to 6.8~7.2 with sodium hydroxide solution again after completion of the reaction, obtains reducing solution；
5th, the ethanol for adding 2~3 volumes to measure again in above-mentioned reducing solution, collects precipitate reduction thing after being sufficiently stirred for；
6th, after adding pure water stirring and dissolving in the precipitate reduction thing collected, the hydrogen peroxide of 0.6%~1.0% volume times is added to exist
20~24h is aoxidized at 25~30 DEG C, oxidation adds the ethanol that 2~3 volumes measure again and precipitated after finishing, received after being sufficiently stirred for
Collection obtains Enoxaparin Sodium sediment crude product；
7th, above-mentioned Enoxaparin Sodium crude product precipitation is added into pure water 150L~200L, after being dissolved into the solution of 1~2% concentration, is used
The milipore filter that molecular weight cut-off value is respectively 3000 and 8000 carries out ultrafiltration, then that Enoxaparin Sodium is obtained after bacteria removing is molten
Liquid；
8th, Enoxaparin Sodium finished product is obtained after Enoxaparin sodium solution obtained in above-mentioned steps is freezed at 25~30 DEG C
2.7Kg。
Embodiment 2：The present embodiment difference from Example 1 is that liquaemin is 10Kg, and natrium nitrosum is 150g, hydroboration
Sodium is 100g, and Enoxaparin Sodium finished product 9Kg is obtained after freezing.
Embodiment 3：The present embodiment difference from Example 1 is that liquaemin is 30Kg, and natrium nitrosum is 450g, hydroboration
Sodium is 300g, and Enoxaparin Sodium finished product 27Kg is obtained after freezing.
Claims (7)
1. a kind of Enoxaparin Sodium preparation technology, it is characterised in that it is comprised the following steps：
（1）, prepare heparin sodium aqua
After the purified water for adding 5~7 mass times in liquaemin, dissolved after stirring 4~5 hours at normal temperatures；
（2）, prepare depolymerized heparin liquid
After the pH value 2~2.5 of the heparin sodium aqua obtained with hydrochloric acid regulating step 1, addition weight is liquaemin 1.0%~2.0%
Natrium nitrosum, then 2~3h of stirring reaction at 20~30 DEG C, then obtain depolymerized heparin liquid after standing 20~24h；
（3）, prepare reducing solution
After adjusting the pH value 9~10 of above-mentioned depolymerized heparin liquid with sodium hydroxide solution, 0.8%~1.2% times of liquaemin weight is added
10~12h of sodium borohydride reduction, then again with sodium hydroxide solution adjust pH value to 6.8~7.2, obtain reducing solution；
（4）, prepare precipitate reduction thing
The ethanol for adding 2~3 volumes to measure again in above-mentioned reducing solution, collects after being sufficiently stirred for and obtains precipitate reduction thing；
（5）, prepare Enoxaparin Sodium crude product
After adding pure water stirring and dissolving in the precipitate reduction thing collected, the hydrogen peroxide for adding 0.6%~1.0% volume to measure again exists
At 25~30 DEG C aoxidize 20~24h, then add the ethanol that 2~3 volumes are measured again, after being sufficiently stirred for collect sediment obtain according to
Promise heparin sodium crude；
（6）, prepare Enoxaparin Sodium fine work
Purified water is added to be dissolved into 1%~2% the Enoxaparin Sodium crude product precipitation of above-mentioned collection（w/w）Solution, respectively with point
Son measures the milipore filter that cutoff value is 3000 and 8000 and carries out ultrafiltration, then Enoxaparin Sodium fine work solution is obtained after aseptic filtration；
（7）, it is lyophilized
Enoxaparin sodium solution obtained in above-mentioned steps is freezed at 25~30 DEG C, that is, obtains Enoxaparin Sodium finished product.
2. according to claim 1, it is characterised in that：Step（1）The purified water of 5~7 mass times is added, stirring 4~5 is small
When.
3. according to claim 1, it is characterised in that：Step（2）The pH value of heparin sodium aqua is 2~2.5, the Asia of addition
Sodium nitrate weight is liquaemin 1.0%~2.0%.
4. according to claim 1, it is characterised in that：Step（3）The depolymerized heparin liquid adjusted with sodium hydroxide solution
PH value 9~10, the sodium borohydride amount of addition is 0.8%~1.2% times of liquaemin weight, and the recovery time is 10~12h, uses hydrogen-oxygen
Change sodium solution and adjust pH value to 6.8~7.2.
5. according to claim 1, it is characterised in that：Step（4）Addition amount of alcohol in reducing solution for reducing solution 2~
3 volumes times.
6. according to claim 1, it is characterised in that：Step（5）It is 0.6%~1.0% that the dioxygen water volume of addition is measured again,
20~24h is aoxidized at 25~30 DEG C, adds the volume of ethanol to measure 2~3 again.
7. according to claim 1, it is characterised in that：Step（6）The molecular weight cut-off value that milipore filter carries out ultrafiltration is
3000 and 8000.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611197430.2A CN106832061A (en) | 2016-12-22 | 2016-12-22 | A kind of Enoxaparin Sodium preparation technology |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611197430.2A CN106832061A (en) | 2016-12-22 | 2016-12-22 | A kind of Enoxaparin Sodium preparation technology |
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| CN106832061A true CN106832061A (en) | 2017-06-13 |
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| CN201611197430.2A Pending CN106832061A (en) | 2016-12-22 | 2016-12-22 | A kind of Enoxaparin Sodium preparation technology |
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- 2016-12-22 CN CN201611197430.2A patent/CN106832061A/en active Pending
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