CN105237657A - Preparation method for low-molecular heparin originated from new species - Google Patents
Preparation method for low-molecular heparin originated from new species Download PDFInfo
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- CN105237657A CN105237657A CN201510728035.1A CN201510728035A CN105237657A CN 105237657 A CN105237657 A CN 105237657A CN 201510728035 A CN201510728035 A CN 201510728035A CN 105237657 A CN105237657 A CN 105237657A
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Abstract
The invention relates to a preparation method for low-molecular heparin originated from a new species. The preparation method comprises the following steps: (1) fully dissolving heparin sodium prepared from raw materials bovine lungs, ox intestines and/or goat intestines in water, and adding a benzethonium chloride solution to prepare heparin benzethonium chloride salt; (2) dissolving the heparin benzethonium chloride salt in dichloromethane, adding benzyl chloride, stirring the mixture to react, reducing the temperature and adding a sodium acetate methanol solution to prepare heparin benzyl ester; (3) dissolving the heparin benzyl ester in water, adding sodium hydroxide, reducing the temperature after reaction, adjusting the pH to neutral, adding sodium chloride, and then adding alcohol to prepare an enoxaparin sodium crude product; and (4) dissolving the enoxaparin sodium coarse product in water, and purifying and drying the mixture to obtain enoxaparin sodium. According to the preparation method provided by the invention, the condition that the low-molecular heparin can be obtained by heparin sodium prepared from bovine lungs, ox intestines and goat intestines is found for the first time, and the prepared low-molecular heparin is lower in molecular weight compared with that of existing low-molecular heparin, so that the biological activity is higher and the low-molecular heparin has a wide market application prospect.
Description
Technical field
The present invention relates to the preparation method of a kind of new species source Low molecular heparin, particularly one utilizes Niu Laiyuan (ox lung, Roll) and sheep source (sheep intestines) heparin to prepare the method for Low molecular heparin, belongs to bulk drug preparing technical field
Background technology
Heparin and Low molecular heparin belong to anticoagulation glycosaminoglycan clinical medicine, and Low molecular heparin is the novel antithrombotic reagent be prepared from through physical method, chemical process or enzymolysis process by heparin.Relative heparin, Low molecular heparin has higher biological activity, longer transformation period and less side effect, and Low molecular heparin class medicine has now become the first-selection of antithrombotic anticoagulant.Heparin can extract from mucosal tissues such as chitterlings, ox lung, Roll, sheep small intestine, heparin class clinical medicine is in history primarily of the source of species of pig and Niu Zuowei heparin, but due to the impact of the end of the eighties in last century " mad cow disease " and " scrapie ", current clinical pharmaceutical heparin class medicine avoids using the heparin in ox and sheep source only to adopt pig to originate heparin as raw material.The corner on the market of pig source heparin has become the main latency of heparin class pharmaceutical market instability, once safety problem appears in pig source heparin, without other alternative source of species, then heparin class anticoagulant market will directly collapse.And at present " mad cow disease " pathogenesis has been studied to confirm as and infected primarily of Protein virus and cause, there is effective ablation method in Protein virus, and the popular of " mad cow disease " is effectively controlled.National governments also must carry out the certification existed without infective virus by pharmacopeia clear stipulaties heparin, namely utilize the purification technique of existing various advanced person can ensure the safety of ox and sheep source heparin.
The whole world butchers a large amount of oxen, sheep every year, can provide abundant ox, sheep heparin resource.And along with the arrival in aging epoch, to the demand of Low molecular heparin class medicine also by increasing.Therefore be trend of the times using ox, sheep as the source of species that Low molecular heparin class medicine is new.U.S. RobertLinhardt teaches laboratory to the heparin comparative study in pig, ox and sheep source, and the molecular weight of three kinds of heparin, degree, degree of acetylation and biological activity all exist significant difference.For studying the pharmaceutical use of the Low molecular heparin prepared by ox, sheep heparin further, first need prepare ox, sheep Low molecular heparin with ox, sheep heparin for raw material, then carrying out comparing of structure and activity difference with commercially available Low molecular heparin standard substance.
Summary of the invention
The present invention is directed to the problem that single, the obtained Molecular Weight of Low Molecular Weight Heparin of existing Low molecular heparin class medicament sources species is still larger, the preparation method that a kind of new species originates Low molecular heparin is provided.
Summary of the invention
The present invention utilizes the heparin extracted in ox, sheep body to prepare Enoxaparin Sodium according to methods involving, and by carrying out comparing of structure and anticoagulating active respectively with USP standard substance, thus determine the clinical value of above Low molecular heparin class medicine.
Detailed Description Of The Invention
Technical solution of the present invention is as follows:
A preparation method for new species source Low molecular heparin, step is as follows:
(1) be dissolved in the water completely by the heparin sodium prepared by raw material ox lung, Roll and/or sheep intestines, add benzethonium chloride solution, the mass ratio of benzethonium chloride and heparin sodium is 2 ~ 4 times, solid-liquid separation, dry, obtained heparin benzethonium chloride salt;
(2) the heparin benzethonium chloride salt that step (1) is obtained is dissolved in methylene dichloride, add Benzyl Chloride, the mass volume ratio of heparin benzethonium chloride salt and Benzyl Chloride is 1 ~ 2, unit is g/mL, 25 ~ 40 DEG C of stirring reactions 12 ~ 20 hours, lower the temperature and add the sodium-acetate methanol solution that isopyknic mass concentration is 8 ~ 10%, solid-liquid separation, drying, obtained heparin benzyl ester;
(3) by soluble in water for the heparin benzyl ester that step (2) is obtained, under 55 ~ 65 DEG C of conditions, add sodium hydroxide, make naoh concentration be 0.05 ~ 0.1M, react 20 ~ 90 minutes, be cooled to 18 ~ 22 DEG C, adjust pH to neutral, add sodium-chlor and make sodium-chlor mass concentration be 8 ~ 10%, adding the alcohol of reaction solution 3 ~ 5 times of volumes, solid-liquid separation, dry, obtained Enoxaparin Sodium crude product;
(4) by soluble in water, purified for the Enoxaparin Sodium crude product that step (3) is obtained, dry, obtained Enoxaparin Sodium.
Preferred according to the present invention, in described step (1), the mass volume ratio of heparin sodium and water is 0.1 ~ 0.3, unit: g/mL.
Preferred according to the present invention, in described step (1) ~ (3), solid-liquid separation is filtration or centrifugal.
Preferred according to the present invention, in described step (2), the mass volume ratio of heparin benzethonium chloride salt and methylene dichloride is 1:(2 ~ 5), unit g/mL.
Preferred according to the present invention, in described step (3), the mass volume ratio of heparin benzyl ester and water is 1:(20 ~ 25), unit g/mL.
Preferred according to the present invention, in described step (3), alcohol is methyl alcohol or ethanol.
Preferred according to the present invention, in described step (4), purifying is ultrafiltration, alcohol precipitation or dialysis; Preferably, dialysis membrane molecular weight is 1kD.
Preferred according to the present invention, in described step (4), drying is-50 ~-60 DEG C of freeze-drying.
Beneficial effect
The heparin sodium that Late Cambrian of the present invention is prepared by process ox lung, Roll and sheep intestines raw material can obtain Low molecular heparin, not only solve the problem that drug industries chain raw material sources are single, and due to the obtained more existing Molecular Weight of Low Molecular Weight Heparin of Low molecular heparin lower, therefore its biological activity is higher, has wide market application foreground.
Accompanying drawing explanation
Fig. 1, Enoxaparin Sodium high performance liquid phase gel permeation chromatography figure;
In figure: USP is molecular weight standard according to promise standard substance;
Chitling according to promise sample be comparative example 1 obtained meet the sample of USP according to promise standard substance molecular weight standard;
What ox lung obtained for comparative example 2 according to promise sample-1 does not meet the sample of USP according to promise standard substance molecular weight standard;
What ox lung obtained for embodiment 1 according to promise sample-2 meets the sample of USP according to promise standard substance molecular weight standard;
Fig. 2, sample ox lung to be composed according to promise standard substance (under figure) nuclear-magnetism H according to promise sample-2 (on figure) and USP and are compared;
Embodiment
Below in conjunction with embodiment, technical scheme of the present invention is described further, but institute of the present invention protection domain is not limited thereto.
Heparin sodium laboratory purifying prepared by embodiment and the raw material ox lung described in comparative example obtains
Heparin sodium prepared by the raw material chitling described in comparative example is purchased from the biochemical pharmaceutcal corporation, Ltd of Changshan
Embodiment 1
A preparation method for new species source Low molecular heparin, step is as follows:
(1) the heparin sodium 1g prepared by raw material ox lung is dissolved in 10mL water completely, slowly drips the benzethonium chloride solution 10mL of 20%, filter, dry, obtained heparin benzethonium chloride salt;
(2) the heparin benzethonium chloride salt 2.5g that step (1) is obtained is dissolved in 6mL methylene dichloride, drip 2.5mL Benzyl Chloride, 35 DEG C of stirring reactions 15 hours, lower the temperature and add the sodium-acetate methanol solution that isopyknic mass concentration is 8%, filter, dry, obtained heparin benzyl ester;
(3) the 1g heparin benzyl ester that step (2) is obtained is dissolved in 25mL water, under 60 DEG C of conditions, add sodium hydroxide, make naoh concentration be 0.07M, react 30 minutes, be cooled to 20 DEG C, adjust pH to neutral, add sodium-chlor and make sodium-chlor mass concentration be 10%, add the methyl alcohol of 75mL, filter, dry, obtained Enoxaparin Sodium crude product;
(4) by soluble in water for the Enoxaparin Sodium crude product that step (3) is obtained, dialyse after 48 hours, through-60 DEG C of freeze-drying, obtained ox lung Enoxaparin Sodium, is designated as ox lung according to promise sample-2.
Embodiment 2
A preparation method for new species source Low molecular heparin, step is as follows:
(1) the heparin sodium 1g prepared by raw material Roll is dissolved in 20mL water completely, slowly drips the benzethonium chloride solution 15mL of 20%, filter, dry, obtained heparin benzethonium chloride salt;
(2) the heparin benzethonium chloride salt 2.5g that step (1) is obtained is dissolved in 10mL methylene dichloride, drip 4mL Benzyl Chloride, 40 DEG C of stirring reactions 12 hours, lower the temperature and add the sodium-acetate methanol solution that isopyknic mass concentration is 10%, filter, dry, obtained heparin benzyl ester;
(3) the 1g heparin benzyl ester that step (2) is obtained is dissolved in 25mL water, under 55 DEG C of conditions, add sodium hydroxide, make naoh concentration be 0.1M, react 30 minutes, be cooled to 20 DEG C, adjust pH to neutral, add sodium-chlor and make sodium-chlor mass concentration be 10%, adding the ethanol of reaction solution 70mL, filter, dry, obtained Enoxaparin Sodium crude product;
(4) by soluble in water for the Enoxaparin Sodium crude product that step (3) is obtained, dialyse after 48 hours, through-60 DEG C of freeze-drying, obtained Roll Enoxaparin Sodium.
Embodiment 3
A preparation method for new species source Low molecular heparin, step is as follows:
(1) the heparin sodium 1g prepared by raw material sheep intestines is dissolved in 30mL water completely, slowly drips the benzethonium chloride solution 20mL of 20%, filter, dry, obtained heparin benzethonium chloride salt;
(2) heparin benzethonium chloride salt 2.5g obtained for step (1) is dissolved in 12mL methylene dichloride, drips 5mL Benzyl Chloride, 30 DEG C of stirring reactions 20 hours, lower the temperature and add the sodium-acetate methanol solution that isopyknic mass concentration is 9%, filter, dry, obtained heparin benzyl ester;
(3) the 1g heparin benzyl ester that step (2) is obtained is dissolved in 25mL water, under 65 DEG C of conditions, add sodium hydroxide, make naoh concentration be 0.06M, react 60 minutes, be cooled to 20 DEG C, adjust pH to neutral, add sodium-chlor and make sodium-chlor mass concentration be 10%, adding the methyl alcohol of reaction solution 80mL, filter, dry, obtained Enoxaparin Sodium crude product;
(4) by soluble in water for the Enoxaparin Sodium crude product that step (3) is obtained, dialyse after 48 hours, through-60 DEG C of freeze-drying, obtained sheep intestines Enoxaparin Sodium.
Comparative example 1
(1) the heparin sodium 1g prepared by raw material chitling is dissolved in 10mL water completely, slowly drips the benzethonium chloride solution 15mL of 20%, filter, dry, obtained heparin benzethonium chloride salt;
(2) the heparin benzethonium chloride salt 2.5g that step (1) is obtained is dissolved in 15mL methylene dichloride, drip 3mL Benzyl Chloride, 35 DEG C of stirring reactions 20 hours, lower the temperature and add the sodium-acetate methanol solution that isopyknic mass concentration is 10%, filter, dry, obtained heparin benzyl ester;
(3) the 1g heparin benzyl ester that step (2) is obtained is dissolved in 25mL water, under 65 DEG C of conditions, add sodium hydroxide, make naoh concentration be 0.07M, react 30 minutes, be cooled to 20 DEG C, adjust pH to neutral, add sodium-chlor and make sodium-chlor mass concentration be 10%, adding the methyl alcohol of reaction solution 75mL, filter, dry, obtained Enoxaparin Sodium crude product;
(4) by soluble in water for the Enoxaparin Sodium crude product that step (3) is obtained, dialyse after 48 hours, through-60 DEG C of freeze-drying, obtained chitling is according to promise sample.
Comparative example 2
(1) the heparin sodium 1g prepared by raw material ox lung is dissolved in 10mL water completely, slowly drips the benzethonium chloride solution 15mL of 20%, filter, dry, obtained heparin benzethonium chloride salt;
(2) the heparin benzethonium chloride salt 2.5g that step (1) is obtained is dissolved in 15mL methylene dichloride, drip 3mL Benzyl Chloride, 35 DEG C of stirring reactions 20 hours, lower the temperature and add the sodium-acetate methanol solution that isopyknic mass concentration is 10%, filter, dry, obtained heparin benzyl ester;
(3) the 1g heparin benzyl ester that step (2) is obtained is dissolved in 25mL water, under 60 DEG C of conditions, add sodium hydroxide, make naoh concentration be 0.12M, react 90 minutes, be cooled to 20 DEG C, adjust pH to neutral, add sodium-chlor and make sodium-chlor mass concentration be 10%, adding the methyl alcohol of reaction solution 75mL, filter, dry, obtained Enoxaparin Sodium crude product;
(4) by soluble in water for the Enoxaparin Sodium crude product that step (3) is obtained, dialyse after 48 hours, through-60 DEG C of freeze-drying, obtained ox lung is according to promise sample-1.
Experimental example
Sample prepared by embodiment 1, comparative example 1 and comparative example 2 is carried out chromatogram and detect analysis, chromatographic parameter is as follows:
Chromatographic column: Superdex
tMpeptide10/300GL
Moving phase: 0.2MNH
4hCO
3
Flow velocity: 0.4mL/min
Sample concentration: 20mg/mL
Sample size: 10 μ L
Detector: Composition distribution
After testing, result as shown in Figure 1.
The sample embodiment 1 prepared adopts gpc analysis method, utilizes standard equation to calculate weight-average molecular weight and to Enoxaparin Sodium activity test method (with reference to USP), result is as shown in table 1:
Table 1. molecular weight analyte and Activity determination result
Adopt nuclear-magnetism determination method to detect the sample of embodiment 1 preparation, detection method is with reference to Chinese Pharmacopoeia annex IX, and detected result as shown in Figure 2.
Interpretation of result
As can be seen from above data, adopt raw material of the present invention to obtain Low molecular heparin, more existing Molecular Weight of Low Molecular Weight Heparin is lower, and the Molecular Weight of Low Molecular Weight Heparin distribution of different genera determined by respective heparin raw material respectively with structure.
Table 2. each animal tissues source molecule amount GPC-MALLS detects analytical results
Claims (8)
1. a preparation method for new species source Low molecular heparin, it is characterized in that, step is as follows:
(1) be dissolved in the water completely by the heparin sodium prepared by raw material ox lung, Roll and/or sheep intestines, add benzethonium chloride solution, the mass ratio of benzethonium chloride and heparin sodium is 2 ~ 4 times, solid-liquid separation, dry, obtained heparin benzethonium chloride salt;
(2) the heparin benzethonium chloride salt that step (1) is obtained is dissolved in methylene dichloride, add Benzyl Chloride, the mass volume ratio of heparin benzethonium chloride salt and Benzyl Chloride is 1 ~ 2, unit is g/mL, 25 ~ 40 DEG C of stirring reactions 12 ~ 20 hours, lower the temperature and add the sodium-acetate methanol solution that isopyknic mass concentration is 8 ~ 10%, solid-liquid separation, drying, obtained heparin benzyl ester;
(3) by soluble in water for the heparin benzyl ester that step (2) is obtained, under 55 ~ 65 DEG C of conditions, add sodium hydroxide, make naoh concentration be 0.05 ~ 0.1M, react 20 ~ 90 minutes, be cooled to 18 ~ 22 DEG C, adjust pH to neutral, add sodium-chlor and make sodium-chlor mass concentration be 8 ~ 10%, adding the alcohol of reaction solution 3 ~ 5 times of volumes, solid-liquid separation, dry, obtained Enoxaparin Sodium crude product;
(4) by soluble in water, purified for the Enoxaparin Sodium crude product that step (3) is obtained, dry, obtained Enoxaparin Sodium.
2. preparation method as claimed in claim 1, it is characterized in that, in described step (1), the mass volume ratio of heparin sodium and water is 0.1 ~ 0.3, unit: g/mL.
3. preparation method as claimed in claim 1, is characterized in that, in described step (1) ~ (3), solid-liquid separation is filtration or centrifugal.
4. preparation method as claimed in claim 1, it is characterized in that, in described step (2), the mass volume ratio of heparin benzethonium chloride salt and methylene dichloride is 1:(2 ~ 5), unit g/mL.
5. preparation method as claimed in claim 1, it is characterized in that, in described step (3), the mass volume ratio of heparin benzyl ester and water is 1:(20 ~ 25), unit g/mL.
6. preparation method as claimed in claim 1, it is characterized in that, in described step (3), alcohol is methyl alcohol or ethanol.
7. preparation method as claimed in claim 1, it is characterized in that, in described step (4), purifying is ultrafiltration, alcohol precipitation or dialysis; Preferably, dialysis membrane molecular weight is 1kD.
8. preparation method as claimed in claim 1, it is characterized in that, in described step (4), drying is-50 ~-60 DEG C of freeze-drying.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106467577A (en) * | 2015-08-21 | 2017-03-01 | 苏州融析生物科技有限公司 | A kind of pulmonis Bovis seu Bubali Enoxaparin Sodium and preparation method and application |
| CN109485749A (en) * | 2018-10-31 | 2019-03-19 | 江西浩然生物医药有限公司 | A method of chromatography and Ultrafiltration Membrane prepare Enoxaparin Sodium |
| RU2725545C1 (en) * | 2020-01-30 | 2020-07-02 | федеральное государственное бюджетное образовательное учреждение высшего образования "МИРЭА-Российский технологический университет" | Method of producing low-molecular heparin |
| RU2749424C1 (en) * | 2020-06-10 | 2021-06-10 | Федеральное государственное унитарное предприятие "Московский эндокринный завод" | Method for obtaining drug with anti-coagulant activity |
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| CN102585038A (en) * | 2012-03-13 | 2012-07-18 | 麦科罗夫（南通）生物制药有限公司 | Islamic enoxaparin sodium and method for producing and purifying same |
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| CN102585038A (en) * | 2012-03-13 | 2012-07-18 | 麦科罗夫（南通）生物制药有限公司 | Islamic enoxaparin sodium and method for producing and purifying same |
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| 傅立: "生物工程肝素与低分子量肝素的酶法制备、结构鉴定与构效关系研究", 《中国博士学位论文全文数据库 工程科技Ⅰ辑》 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106467577A (en) * | 2015-08-21 | 2017-03-01 | 苏州融析生物科技有限公司 | A kind of pulmonis Bovis seu Bubali Enoxaparin Sodium and preparation method and application |
| CN106467578A (en) * | 2015-08-21 | 2017-03-01 | 苏州融析生物科技有限公司 | A kind of Intestinum Bovis seu Bubali mucosa Enoxaparin Sodium and preparation method and application |
| WO2017032276A1 (en) * | 2015-08-21 | 2017-03-02 | 苏州融析生物科技有限公司 | Bovine intestinal mucosa enoxaparin sodium, preparation method therefor, and application thereof |
| WO2017032277A1 (en) * | 2015-08-21 | 2017-03-02 | 苏州融析生物科技有限公司 | Bovine lung enoxaparin sodium, preparation method therefor, and application thereof |
| WO2017032275A1 (en) * | 2015-08-21 | 2017-03-02 | 苏州融析生物科技有限公司 | Sheep enoxaparin sodium, preparation method therefor, and application thereof |
| CN109485749A (en) * | 2018-10-31 | 2019-03-19 | 江西浩然生物医药有限公司 | A method of chromatography and Ultrafiltration Membrane prepare Enoxaparin Sodium |
| RU2725545C1 (en) * | 2020-01-30 | 2020-07-02 | федеральное государственное бюджетное образовательное учреждение высшего образования "МИРЭА-Российский технологический университет" | Method of producing low-molecular heparin |
| RU2749424C1 (en) * | 2020-06-10 | 2021-06-10 | Федеральное государственное унитарное предприятие "Московский эндокринный завод" | Method for obtaining drug with anti-coagulant activity |
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Application publication date: 20160113 |