CN104877042B - A kind of preparation method of heparan - Google Patents
A kind of preparation method of heparan Download PDFInfo
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- CN104877042B CN104877042B CN201510316035.0A CN201510316035A CN104877042B CN 104877042 B CN104877042 B CN 104877042B CN 201510316035 A CN201510316035 A CN 201510316035A CN 104877042 B CN104877042 B CN 104877042B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B45/00—Formation or introduction of functional groups containing sulfur
- C07B45/02—Formation or introduction of functional groups containing sulfur of sulfo or sulfonyldioxy groups
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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
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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
- C08B37/0069—Chondroitin-4-sulfate, i.e. chondroitin sulfate A; Dermatan sulfate, i.e. chondroitin sulfate B or beta-heparin; Chondroitin-6-sulfate, i.e. chondroitin sulfate C; Derivatives thereof
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Abstract
The invention discloses a kind of preparation method of heparan, including：Using chondroitin sulfate as raw material, sulfonated post-reaction treatment obtains heparan；The solvent that the sulfonating reaction is used is formamide, and the sulfonating agent used is sulfur trioxide, oleum or the pyridine. sulfur trioxide of dissociating.The preparation method of heparan of the present invention, synthesis technique is simple, and production operation is easily controllable, production equipment is without particular/special requirement, molecular weight product scope is stable, physical and chemical index is controlled in the range of quality standard, while product yield is high, is adapted to large-scale industrial production.
Description
Technical field
The invention belongs to pharmaceutical technology field, more particularly to a kind of preparation method of biochemical drug heparan.
Background technology
Heparan is the material of similar heparin, be have in chemical constitution with heparin it is a certain degree of it is similar, with anti-freezing
The acidic mucopolysaccharide class material of blood activity.Oozed out with antithrombus formation, anti-inflammatory, analgesic, improvement affected part blood circulation, absorption
The effect such as thing, healing oedema and edema, promotion organization reparation.Clinic be applied to blood vessel embolism, varication, Superficial veins it is scorching,
Adenolymphitis, mastitis and softening scar.
The patent of invention document on heparan is it has been reported that for example Japanese documentation (JP, S47-30167) is adopted at present
Make under sulfonating agent, low temperature with chondroitin sulfate the reaction in pyridine with the concentrated sulfuric acid and prepare heparan, Japanese documentation (JP,
S59-133201) then use the nitration mixture with the concentrated sulfuric acid and chlorosulfonic acid to make sulfonating agent, the system of structural modification is carried out to chondroitin sulfate
Preparation Method.These methods have used the very big excessive concentrated sulfuric acid, and acid consumption is big, to production equipment seriously corroded, liquid waste processing
Difficulty, is unfavorable for environmental protection, and production technology key point is difficult to control to, and the molecular weight ranges of products therefrom are unstable, because
And the performance indications such as activity of product are also difficult to control to.
European patent document (EP1634893) is reported using chlorosulfonic acid as sulfonating agent, is reacted and is prepared in formamide solvent
The method of heparan, although the most of physical and chemical index of heparan prepared by this method is easily controllable, but " total nitrogen " index is difficult to control
System is in critical field, and chlorosulfonic acid is dangerous material, and it is blast to meet water, is unfavorable for transporting and stores, heat release in course of reaction
And a large amount of smog are produced, there is very big potential safety hazard in production operation.In addition, when applicant repeats the method for above-mentioned document,
The yield of product is relatively low, and production cost is higher, thus is not suitable for large-scale industrial production.
The content of the invention
In view of the shortcomings of the prior art, a species is provided it is an object of the invention to improve the defect of prior art presence
The preparation method of heparin, this method environmental protection, and product yield is high.
In order to realize the purpose of the present invention there is provided main technical schemes it is as follows, specific steps include：
A kind of preparation method of heparan, including：Using chondroitin sulfate as raw material, sulfonated post-reaction treatment obtains class liver
Element；The solvent that the sulfonating reaction is used is formamide, and the sulfonating agent used is sulfur trioxide (gaseous state or liquid), the smoke of dissociating
Sulfuric acid or pyridine. sulfur trioxide.
The last handling process generally comprises removing impurity by means of precipitation, ion exchange resin desalination, is concentrated under reduced pressure except amine, hydrogen peroxide
Decolourize and freezing dry process obtains heparan.
Further, above-mentioned preparation method comprises the following steps：
(1) sulfonating reaction：In the formamide that chondroitin sulfate is dissolved in 5~10 times of volumes, sulfonating agent is added, in 0~
Stirring reaction 3~12 hours at a temperature of 80 DEG C, then add organic solvent terminating reaction, and standing sedimentation collects sediment；
(2) removing impurity by means of precipitation：The sediment that step (1) is obtained is made into the aqueous solution of 10~20%W/V concentration, adjusts water-soluble
The pH value of liquid is to 6~8, and the organic solvent for adding 2~3 times of volumes is allowed to precipitate；Sediment is made into 20~40%W/V again dense
The aqueous solution of degree, the organic solvent for adding 2~3 times of volumes is allowed to precipitate, and collects sediment；
(3) ion exchange resin desalination：The sediment that step (2) is finally obtained is made into the water of 10~30%W/V concentration
Solution, successively through storng-acid cation exchange resin, strong-base anion-exchange resin, carries out ion-exchange demineralization, collects pH
Part of the value less than 4, is then adjusted to 6.5~7.5 by the pH value of collection liquid；
(4) it is concentrated under reduced pressure except amine：The collection liquid that step (3) is obtained is heated to 35~45 DEG C, and being concentrated under reduced pressure, it is organic to boil off
Solvent, then adjust pH value to 10.5~12, be heated to 45~55 DEG C, be concentrated under reduced pressure removing part water and take out of residual it is organic molten
Agent, obtains concentrate；
(5) hydrogen peroxide decolourizes and is freeze-dried：The pH value for the concentrate that step (4) is obtained is adjusted to 10~12, warp
After hydrogen peroxide decolourizes, the pH value of regulation system is freeze-dried to obtain heparan to 6~7.
In the preparation method of above-mentioned heparan, raw materials used chondroitin sulfate is in pig, the cartilaginous tissue of ox, production
Product exist in the form of sodium salt.Purchase producer limited including Jiaxing Hengjie Bio-Pharmaceutical Co., Ltd., the emerging biotechnology of Zhejiang Australia
The limited public affairs of woods bioengineering are contained in company, four tendril-leaved fritillary bulb Biology Pharmacy Co., Ltd difficult to understand, Shandong Yi Bao biological products Co., Ltd, Jinan
Si Deng companies.
In above-mentioned steps (1), reaction temperature is preferably 0~60 DEG C, and the reaction time is preferably 3~6 hours.Preferably,
In step (1), when the sulfonating agent be pyridine. sulfur trioxide when, sulfonating reaction temperature be 45~55 DEG C, the reaction time be 3.5~
4.5 hour.When the sulfonating agent is oleum, sulfonating reaction temperature is 20~30 DEG C, and the reaction time is 5~6 hours.When
When the sulfonating agent is free sulfur trioxide (gaseous state or liquid), sulfonating reaction temperature is 0~10 DEG C, the reaction time is 2.5~
3.5 hour.During using above-mentioned technical proposal, it is to avoid use a large amount of sulfuric acid, while environmental protection pressure is small, improve the final of product
Yield, relative to prior art, it is possible to increase more than 10% yield.As further preferred, the sulfonating agent is pyridine three
Sulfur oxide, during using the technical scheme, yield is more preferable, and up to more than 95%, and simple to operate, convenient post-treatment.Preferably,
In step (1), the organic solvent of terminating reaction is at least one of methanol, ethanol, acetone.
In the present invention, using the removing impurity by means of precipitation of step (2), it is mainly used in removing unnecessary sulfuric acid in the aqueous solution, while entering one
Step removes the formamide of residual.Organic solvent described in step (2) is at least one of methanol, ethanol, acetone.
As further preferred, in step (1) and step (2), described organic solvent is identical, is acetone.
In above-mentioned steps (3), described storng-acid cation exchange resin, strong-base anion-exchange resin and sulfuric acid are soft
The volume mass ratio of ossein is 2~6ml/g.Highly acid (polystyrene, propylene may be selected in the storng-acid cation exchange resin
Sour system, phenolic aldehyde system, epoxy, vinylpyridine system, ureaformaldehyde system) cationic ion-exchange resin, the strong-base anion-exchange resin
Strong basicity (polystyrene, acrylic acid series, phenolic aldehyde system, epoxy, vinylpyridine system, ureaformaldehyde system) anion exchange tree may be selected
Fat.
Preferably, described storng-acid cation exchange resin, strong-base anion-exchange resin and chondroitin sulfate
Volume mass ratio be 3~4ml/g.The preferred strongly acidic styrene's cation of storng-acid cation exchange resin exchanges tree
Fat, the preferred strong-basicity styrene series anion exchange resin of strong-base anion-exchange resin
Preferably, in step (3), the pH value of collection liquid is adjusted to 7 ± 0.2.The step mainly removes what is be mingled with product
Salt, reduces chlorinity.
Preferably, in step (4), being concentrated under reduced pressure and boiling off organic solvent, then pH to 11.5 ± 0.2 is adjusted with alkali.Should
In step, during concentration, 2/3~3/4 volume of condensate precursor product is concentrated into.The step is mainly removal organic solvent.
Preferably, in step (5), the pH value for the concentrate that step (4) is obtained is adjusted to 11.0 ± 0.5.
In the present invention, for adjusting pH alkali for 20~30% sodium hydrate aqueous solutions.Acid can be using sulfuric acid etc..
The preparation method of heparan of the present invention, synthesis technique is simple, and production operation is easily controllable, production equipment without
Particular/special requirement, molecular weight product scope is stable, physical and chemical index is controlled in the range of quality standard, while product yield is high, is adapted to
Large-scale industrial production.
Embodiment
Further illustrate how the present invention realizes with reference to specific embodiment, following examples help to understand
The present invention, but it is not intended to limit the present invention.
Embodiment 1：
(1) 100g chondroitin sulfates (Jiaxing Hengjie Bio-Pharmaceutical Co., Ltd., EP7.0 standards) are dissolved in 1000ml's
In formamide, 150g pyridine. sulfur trioxide solids are added, 50 DEG C are heated to, then stirring reaction 4 hours adds 2000ml
Acetone terminating reaction, standing sedimentation collects sediment；
(2) above-mentioned sediment 800ml purified waters are dissolved, with the aqueous solution of the mass percent concentration for 30% NaOH
Regulation system pH value is to 7 ± 0.5, and the acetone for adding 2 times of volumes is allowed to precipitate；Sediment 400ml purified waters are dissolved again,
The acetone for adding 2 times of volumes is allowed to precipitate, and collects sediment；
(3) above-mentioned sediment 800ml purified waters are dissolved, successively through 400ml storng-acid cation exchange resins (Shanghai
Kai Ping resins Co., Ltd, model：001 × 7), 400ml strong-base anion-exchange resins (Shanghai Kai Ping resins Co., Ltd,
Model：201 × 7), ion-exchange demineralization is carried out, the part that pH value is less than 4 is collected, is then 30% with mass percent concentration
The NaOH aqueous solution pH value of collection liquid is adjusted to 7 ± 0.2；
(4) above-mentioned collection liquid is heated to 40 DEG C, is concentrated under reduced pressure and boils off the acetone of residual, then use mass percent concentration
For 30% NaOH the aqueous solution regulation remaining liq pH value to 11.5 ± 0.2, be heated to 50 DEG C, be concentrated under reduced pressure into about remain
400ml concentrates；
(5) aqueous solution of the mass percent concentration for 30% hydrogen peroxide is added in the concentrate obtained to step (4)
20ml, adjusts system pH to 11.0 ± 0.5,30 DEG C of stirrings to decolourize 1~2 hour, system pH is adjusted with sulfuric acid with 30% NaOH
To 6.5 ± 0.5, heparan 98g is freeze-dried to obtain, is calculated according to mass yield, total recovery is 98%.
Embodiment 2：
100g chondroitin sulfates are dissolved in 900ml formamide, it is 60% to be slowly added dropwise to mass percent concentration
Oleum 160ml, then 20~30 DEG C of temperature control, stirring reaction 6 hours add 1800ml acetone terminating reactions, and it is heavy to stand
Drop, collects sediment；
Embodiment 1 is shown in post processing, is finally freeze-dried to obtain heparan product 95g, total recovery is 95%.
Embodiment 3：
100g chondroitin sulfates are dissolved in 950ml formamide, sulfur trioxide gas, temperature control are slowly passed through under stirring
0~10 DEG C, then insulation reaction 3 hours adds 1900ml acetone terminating reactions, and standing sedimentation collects sediment；
Embodiment 1 is shown in post processing, is finally freeze-dried to obtain heparan product 95g, total recovery is 95%.
The main physical and chemical index for the heparan product that 1-3 of the embodiment of the present invention is prepared is as follows：
Outward appearance：White or yellowish white powder
pH：6.0~7.5
Specific rotation：- 11.7 °~-14.7 °
Loss on drying：≤ 6%
Residue on ignition：38%~48%
Electrophoresis：1.07~1.16
Total nitrogen：1.6%~2.0%
Inherent viscosity：0.09~0.18
Organic sulfate radical：25.8%~37.3%
Free sulphur：≤ 13%
D-Glucose aldehydic acid：19%~24%
Hyaluronidase：14%~29%
Total chlorine：＜ 0.178%
Comparative example 1：
The pyridine. sulfur trioxide in embodiment 1 is replaced using the chlorosulfonic acid of same mole, after being carried out according to identical step
Continuous reaction, is finally freeze-dried to obtain heparan product 83g, and yield is 83% yield well below the embodiment of the present invention 1.
Comparative example 2
The pyridine. sulfur trioxide in embodiment 1 is replaced using the sulfur trioxide of same mole, isometric pyridine generation is utilized
For formamide as solvent, subsequent reactions are carried out according to identical step, heparan product 73g, yield is finally freeze-dried to obtain
For 73% yield well below the embodiment of the present invention 1.
Comparative example 3：
The step (3) in embodiment 1 is omitted, remaining step be the same as Example 1 is finally freeze-dried to obtain heparan product
100g, but chlorinity is more than 0.178%, it is impossible to meet product physical and chemical index requirement.
The foregoing is only a specific embodiment of the invention, and protection scope of the present invention is not limited thereto, any ripe
Know those skilled in the art the invention discloses technical scope in, the change or replacement that can be readily occurred in should all be contained
Cover within protection scope of the present invention.Therefore, the protection domain that protection scope of the present invention should be defined with claim
It is defined.
Claims (6)
1. a kind of preparation method of heparan, it is characterised in that specifically include following steps：
(1) chondroitin sulfate is dissolved in the formamide of 5~10 times of volumes, adds sulfonating agent, carry out sulfonating reaction, Ran Houjia
Enter organic solvent terminating reaction, standing sedimentation collects sediment；When the sulfonating agent is pyridine. sulfur trioxide, sulfonating reaction temperature
Spend for 45~55 DEG C, the reaction time is 3.5~4.5 hours；The sulfonating agent be oleum when, sulfonating reaction temperature be 20~
30 DEG C, the reaction time is 5~6 hours；When the sulfonating agent is free sulfur trioxide, sulfonating reaction temperature is 0~10 DEG C, reaction
Time is 2.5~3.5 hours；
(2) sediment for obtaining step (1) is made into the aqueous solution of 10~20%W/V concentration, adjust the pH value of the aqueous solution to 6~
8, add the organic solvent of 2~3 times of volumes, sediment separate out；Sediment is made into the water-soluble of 20~40%W/V concentration again
Liquid, adds the organic solvent of 2~3 times of volumes, collects sediment；
(3) sediment for finally obtaining step (2) is made into the aqueous solution of 10~30%W/V concentration, successively through highly acid sun from
Sub-exchange resin, strong-base anion-exchange resin, carry out ion-exchange demineralization, collect the part that pH value is less than 4, then will receive
The pH value of liquid collecting is adjusted to 6.5~7.5；Described storng-acid cation exchange resin, strong-base anion-exchange resin and sulfuric acid
The volume mass ratio of chondroitin is 2~6ml/g；
(4) collection liquid for obtaining step (3) is heated to 35~45 DEG C, is concentrated under reduced pressure and boils off organic solvent, then adjusts pH value
To 10.5~12,45~55 DEG C are heated to, is concentrated under reduced pressure and removes part water and take residual organic solvent out of, obtain concentrate；
(5) pH value for the concentrate for obtaining step (4) is adjusted to 10~12, after being decolourized through hydrogen peroxide, the pH of regulation system
Value is freeze-dried to obtain heparan to 6~7；
For adjusting pH alkali for 20~30% sodium hydrate aqueous solutions, acid is sulfuric acid.
2. the preparation method of heparan according to claim 1, it is characterised in that raw materials used chondroitin sulfate comes from
In pig, the cartilaginous tissue of ox, product exists in the form of sodium salt.
3. the preparation method of heparan according to claim 1, it is characterised in that the sulfonating agent is that pyridine three is aoxidized
Sulphur.
4. the preparation method of heparan according to claim 1, it is characterised in that in step (1), terminating reaction it is organic
Solvent is at least one of methanol, ethanol, acetone.
5. the preparation method of heparan according to claim 1, it is characterised in that in step (2), precipitation it is organic molten
Agent is at least one of methanol, ethanol, acetone.
6. the preparation method of heparan according to claim 1, it is characterised in that the storng-acid cation exchange resin
For strongly acidic styrene type cation exchange resin；The strong-base anion-exchange resin is strong-basicity styrene series anion
Exchanger resin.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510316035.0A CN104877042B (en) | 2015-06-10 | 2015-06-10 | A kind of preparation method of heparan |
| DE112016001603.4T DE112016001603T5 (en) | 2015-06-10 | 2016-05-18 | Production process of heparinoid |
| KR1020177032344A KR101966435B1 (en) | 2015-06-10 | 2016-05-18 | Process for the preparation of helianidides |
| JP2018507767A JP6486554B2 (en) | 2015-06-10 | 2016-05-18 | Method for producing heparinoid |
| PCT/CN2016/082482 WO2016197799A1 (en) | 2015-06-10 | 2016-05-18 | Method for preparing heparinoid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510316035.0A CN104877042B (en) | 2015-06-10 | 2015-06-10 | A kind of preparation method of heparan |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104877042A CN104877042A (en) | 2015-09-02 |
| CN104877042B true CN104877042B (en) | 2017-08-29 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201510316035.0A Active CN104877042B (en) | 2015-06-10 | 2015-06-10 | A kind of preparation method of heparan |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JP6486554B2 (en) |
| KR (1) | KR101966435B1 (en) |
| CN (1) | CN104877042B (en) |
| DE (1) | DE112016001603T5 (en) |
| WO (1) | WO2016197799A1 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104877042B (en) * | 2015-06-10 | 2017-08-29 | 浙江三门恒康制药有限公司 | A kind of preparation method of heparan |
| CN107987184A (en) * | 2017-12-04 | 2018-05-04 | 唐财坤 | A kind of preparation method of heparan |
| IT202000004564A1 (en) * | 2020-03-04 | 2021-09-04 | Lesaffre & Cie | PROCESS FOR DIRECT SULPHATION OF POLYSACCHARIDES IN ECOLOGICALLY ACCEPTABLE SOLVENT |
| CN111825777B (en) * | 2020-07-13 | 2022-05-27 | 山东众山生物科技有限公司 | Method for preparing heparinoids from chondroitin |
| CN112279936B (en) * | 2020-11-12 | 2023-06-30 | 上海辉文生物技术股份有限公司 | Preparation method of heparinoids |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB796737A (en) * | 1954-09-10 | 1958-06-18 | Hoffmann La Roche | A process for the production of glycan poly-(sulphuric acid esters) |
| EP1634893A1 (en) * | 2004-09-13 | 2006-03-15 | Laboratori Derivati Organici S.P.A. | Process for the sulfation of chondroitin |
| CN101717455A (en) * | 2009-12-15 | 2010-06-02 | 武汉大学 | Method for preparing heparinoid polysaccharide |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0699485B2 (en) * | 1984-08-14 | 1994-12-07 | 生化学工業株式会社 | Method for producing synthetic chondroitin polysulfate |
| US6388060B1 (en) * | 1998-11-06 | 2002-05-14 | Vascular Therapeutics Inc. | Process for the sulfation of uronic acid-containing polysaccharides |
| CN1789287A (en) * | 2005-12-20 | 2006-06-21 | 山东大学 | Poly-sulfated chondroitin sulfate and preparation method thereof |
| GB201001203D0 (en) * | 2010-01-25 | 2010-03-10 | Anamar Medical Ab | Use of pharmaceutically active compounds |
| PL2710043T3 (en) * | 2011-05-20 | 2016-11-30 | Shark-like chondroitin sulphate and process for the preparation thereof | |
| CN104877042B (en) * | 2015-06-10 | 2017-08-29 | 浙江三门恒康制药有限公司 | A kind of preparation method of heparan |
-
2015
- 2015-06-10 CN CN201510316035.0A patent/CN104877042B/en active Active
-
2016
- 2016-05-18 DE DE112016001603.4T patent/DE112016001603T5/en not_active Ceased
- 2016-05-18 JP JP2018507767A patent/JP6486554B2/en active Active
- 2016-05-18 KR KR1020177032344A patent/KR101966435B1/en active IP Right Grant
- 2016-05-18 WO PCT/CN2016/082482 patent/WO2016197799A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB796737A (en) * | 1954-09-10 | 1958-06-18 | Hoffmann La Roche | A process for the production of glycan poly-(sulphuric acid esters) |
| EP1634893A1 (en) * | 2004-09-13 | 2006-03-15 | Laboratori Derivati Organici S.P.A. | Process for the sulfation of chondroitin |
| CN101717455A (en) * | 2009-12-15 | 2010-06-02 | 武汉大学 | Method for preparing heparinoid polysaccharide |
Also Published As
| Publication number | Publication date |
|---|---|
| KR101966435B1 (en) | 2019-04-05 |
| KR20170136584A (en) | 2017-12-11 |
| JP2018514641A (en) | 2018-06-07 |
| DE112016001603T5 (en) | 2018-01-04 |
| WO2016197799A1 (en) | 2016-12-15 |
| JP6486554B2 (en) | 2019-03-20 |
| CN104877042A (en) | 2015-09-02 |
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Address after: Longxiang three county Hareon street 317100 Taizhou Road, Zhejiang province No. 1 Patentee after: Zhejiang Hengkang Pharmaceutical Co., Ltd Address before: Longxiang three county Hareon street 317100 Taizhou Road, Zhejiang province No. 1 Patentee before: ZHEJIANG SANMEN HYGECON PHARMACEUTICAL CO., LTD. |