CN102382204B - Low-molecular-weight polysaccharide sulfate and preparation method and application thereof - Google Patents
Low-molecular-weight polysaccharide sulfate and preparation method and application thereof Download PDFInfo
- Publication number
- CN102382204B CN102382204B CN 201110253845 CN201110253845A CN102382204B CN 102382204 B CN102382204 B CN 102382204B CN 201110253845 CN201110253845 CN 201110253845 CN 201110253845 A CN201110253845 A CN 201110253845A CN 102382204 B CN102382204 B CN 102382204B
- Authority
- CN
- China
- Prior art keywords
- molecular
- low
- weight
- weight polysaccharide
- preparation
- 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
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a low-molecular-weight polysaccharide sulfate and a preparation method and application of the low-molecular-weight polysaccharide sulfate. The constitutional formula of the low-molecular-weight polysaccharide sulfate includes that the molecular skeleton of the constitutional formula is a binary linear block polymer composed of beta-D-(1,4)-mannuronic acid and alpha-L-(1,4)-guluronic acid. In the constitutional formula, R=Na or CH2CHOHCH3, R1=H or SO3Na, in each saccharide link, at least one R1=SO3Na, m+n is smaller than or equal to 25, the weight-average molecular weight of the low-molecular-weight polysaccharide sulfate ranges from 3kDa to 9kDa, and dispersion of molecular weight distribution ranges from 1.20 to 1.70. The low-molecular-weight polysaccharide sulfate can be applied to treatment of anticoagulation and anti-thrombus diseases, reduces risk of haemorrhagia and avoids anaphylaxis, and supplies raw materials for wide bioactivity of a series of low-molecular-weight PSS (polysaccharide sulfate) products.
Description
Technical field
The present invention relates to antithrombotic and anticoagulation medicine field, relate in particular to a kind of low-molecular-weight polysaccharide and its preparation method and application.
Background technology
Propylene glycol alginate sodium sulfate (Propylene glycol alginate sodium sulfate; PSS) be on the basis of oligomeric sodium alginate molecule; introduce respectively the propylene glycol ester group and sulfonyl is modified a class heparinoid drug that forms on the hydroxyl of sugar ring 6-position carboxyl and 2,3-position; wherein the weight average molecular weight of PSS crude drug is generally 10-20kDa; molecular weight distribution width＜1.80, organic sulfur content are 9%-13%.As a kind of heparinoid drug, PSS has and reduces blood viscosity, anticoagulation, blood fat reducing, improves the effect such as microcirculation, has brought into play important effect aspect the preventing and treating of the hypercoagulable diseases such as ischemic cardio cerebrovascular diseases, high blood viscosity syndrome.Along with the further investigation of clinical practice is found, PSS also has certain curative effect for chronic glomerulonephritis, diabetes, hepatitis, cancer etc.PSS extensive use has clinically been confirmed it and has been had the action and efficacy of the many target spots of multicomponent.Process for producing of the prior art has determined that PSS is a multi-component complex system that is made of different molecular weight homologue, therefore has similar traditional Chinese compound medicine multicomponent, the effect characteristics of many target spots.Also Just because of this, PSS is just seeming weaker aspect the basic research such as its effective substance, quality control and structure activity relationship, so that the multiformity that has caused drug effect in the PSS clinical practice, even produce untoward reaction, PSS can produce the side effect such as hemorrhage, thrombocytopenia and some anaphylactic reactions in its strong anticoagulant effect in performance.Therefore, advantage and the above-mentioned problems in the prior art for PSS, further exploitation has PSS product and the corresponding drug effect target spot thereof of the different weight average molecular weight of narrow distribution, find anticoagulation that it is more excellent and antithrombotic acitivity and other medical value widely, further reduce its side effect and improve the bioavailability tool being of great significance.
Summary of the invention
The present invention is directed to the propylene glycol alginate sodium sulfate that consisted of by different molecular weight homologue in prior art in the produced simultaneously side effect of its anticoagulant effect of performance, a kind of low-molecular-weight polysaccharide and its preparation method and application is provided, the low-molecular-weight polysaccharide that the present invention prepares can be applied to the treatment of anticoagulation and anti embolus disease, reduce simultaneously its bleeding risk, avoid anaphylactic reaction, but also be the support of supplying raw materials of biological activity widely of a series of low-molecular-weight PSS products of exploitation.
For achieving the above object, the present invention adopts following technical proposals to be achieved:
A kind of low-molecular-weight polysaccharide, its structural formula is as follows:
Its molecular skeleton is the binary line style block polymer that β-D-(Isosorbide-5-Nitrae)-mannuronic acid (M) and α-L-(Isosorbide-5-Nitrae)-guluronic acid (G) form, R=Na or CH in formula
2CHOHCH
3, R
1=H or SO
3Na has a R at least in each sugar ring
1=SO
3Na, m+n≤25, the weight average molecular weight of low-molecular-weight polysaccharide is 3kDa-9kDa, the molecular weight distribution width is 1.20-1.70.
Further improvement to technical scheme: the organic sulfur content of described low-molecular-weight polysaccharide is 9%-13%.
The present invention also provides the preparation method of described low-molecular-weight polysaccharide, it comprises the following steps: propylene glycol alginate sodium sulfate is made into the aqueous solution that mass percentage concentration is 5%-20%, adding oxidant to oxidant final concentration in the described aqueous solution is 0.2-0.5mol/L, and adding metal ion to metal ion final concentration is 0.5-5.0mmol/L; Then reaction 0.5-1.0 hour under 30-60 ℃, after reaction terminating, after adding ethanol 85% or more that it is precipitated, centrifugalize precipitation and supernatant; To precipitate the cation exchange resin purification, accent pH is 8-9, and ethanol precipitation, washing make low-molecular-weight polysaccharide by spray drying.
Further improvement to technical scheme: described oxidant is hydrogen peroxide, hypochlorous acid and hypochlorite.
Further improvement to technical scheme: described metal ion is bivalent cupric ion or iron ion.
The present invention also provides described low-molecular-weight polysaccharide for the preparation of the application in antithrombotic and anticoagulation medicine.
Compared with prior art, advantage of the present invention and good effect are:
(1) low-molecular-weight polysaccharide of the present invention can obviously extend clotting time of mice and bleeding time, obviously reduces the thrombotic length of rats in vitro and weight, has excellent anticoagulant active.
(2) low-molecular-weight polysaccharide of the present invention also obviously extends electricity irritation rat carotid artery thrombus formation time, and the rat thrombus in vivo is had good therapeutic effect.Find out from mice thrombus in vivo experiment, compare with former propylene glycol alginate sodium sulfate, the hemorrhage side effect of low-molecular-weight propylene glycol alginate sodium sulfate obviously reduces, and has the effect of the thrombosis due to anticoagulant, can be used as antithrombotic agents and uses.
(3) low-molecular-weight polysaccharide of the present invention except weight average molecular weight and molecular weight distribution different from existing propylene glycol alginate sodium sulfate more concentrated, other are all identical with existing propylene glycol alginate sodium sulfate, comprise the basic framework of molecule, substituted radical, sulfur content etc.
(4) dissolubility of low-molecular-weight polysaccharide of the present invention is improved to some extent than the propylene glycol alginate sodium sulfate crude drug, and enough raw materials can be provided for the research of anticoagulation, antithrombotic reagent.
(5) preparation method of low-molecular-weight polysaccharide provided by the invention is simple and efficient, the product purity that obtains is high, good stability, can be used for preparing and have the low-molecular-weight polysaccharide identical with the propylene glycol alginate sodium sulfate structure, for develop a series of low-molecular-weight polysaccharide products widely biological activity supply raw materials and technical support.
The specific embodiment
Below in conjunction with the drawings and specific embodiments, technical scheme of the present invention is described in further detail.
Embodiment 1: the preparation of low-molecular-weight polysaccharide
Take 9g propylene glycol alginate sodium sulfate (weight average molecular weight is about 14kDa) and be dissolved in the 120mL distilled water, be made into mass fraction and be 7.5% alginate diester sodium solution.Add 0.1molL
-1FeSO
4Solution and 30% H
2O
2Aqueous solution makes Fe in reaction system
2+And H
2O
2Concentration reach the appointment final concentration shown in table 1.Airtight oscillating reactions 0.5h under 60 ℃.After reaction finishes, according to 3mgmL
-1The amount of reaction system adds ascorbic acid to consume H
2O
2Cessation reaction, and cooling rapidly, add 3 times of volume 95% ethanol, 4 ℃ of lower hold over night.The centrifugal 20min of 3000rmin-1, precipitation separation and supernatant.Precipitation is dissolved in a small amount of water, crosses 732 cation exchange resin desalting and purifyings, sample is converted into the H type; Transfer pH to 8-9 with 6molL-1 NaOH after solution after purification is concentrated, adding 95% ethanol to transfer to the ethanol final concentration is 85%, the centrifugalize precipitation, precipitate 3 times with 85% washing with alcohol, lyophilization namely gets the low-molecular-weight polysaccharide of different molecular weight, i.e. FP-9K, FP-6K, FP-4K, FP-3K.
The structural formula of the described low-molecular-weight polysaccharide that makes is as follows:
R=Na or CH in formula
2CHOHCH
3, R
1=H or SO
3Na, and have a R at least in each sugar ring
1=SO
3Na, m+n≤25, molecular skeleton is β-D-(1,4)-mannuronic acid (Mannuronic acid, M) and α-L-(Isosorbide-5-Nitrae)-guluronic acid (Guluronic acid, G) the binary line style block polymer that forms, the weight average molecular weight of low-molecular-weight polysaccharide is 3kDa-9kDa, and organic sulfur content is 9%-13%, and the molecular weight distribution width is 1.20-1.70.
As standard, record the weight average molecular weight of the low-molecular-weight polysaccharide of acquisition with TOSOH TSK GEL3000PWXL column chromatography (7.8mm*300mm, 6 μ m) and dextran standard substance (Nat'l Pharmaceutical ﹠ Biological Products Control Institute).Weight average molecular weight and breadth coefficient according to the low-molecular-weight polysaccharide of the present invention preparation are as shown in table 1.
Relation between table 1Fenton amount of reagent and response time and propylene glycol alginate sodium sulfate weight average molecular weight
Embodiment 2: the main pharmacologically active experiment of low-molecular-weight polysaccharide
The main pharmacologically active experimental result of the low-molecular-weight polysaccharide that application the method for the invention makes is as follows, and following result all by the method for national regulation, obtains through system experimentation research.
A: the anticoagulant active test of low-molecular-weight polysaccharide
The capillary glass-tube is inserted mice endocanthion ball rear vein beard get blood, record the time of blood clotting silk occurs for testing the index of clotting time from taking a blood sample to; With after mice docking, record blood flows out to time that blood stops naturally index for the test bleeding time naturally.Utilize above two indexs to detect and compare anticoagulant effect and the bleeding risk of the low-molecular-weight polysaccharide of different molecular weight, test result is as shown in table 2.
Table 2: low-molecular-weight polysaccharide is on clotting time of mice (CT) and the impact in bleeding time (BT) (± s, n=10)
*: P＜0.05, compare with the blank group * *: P＜0.01
Test result shows, various low-molecular-weight propylene glycol alginate sodium sulfate intraperitoneal injections all can obviously extend clotting time of mice and bleeding time.Along with the rising of propylene glycol alginate sodium sulfate weight average molecular weight, its anticoagulant active raises gradually, but bleeding risk also can raise to some extent.
B: low-molecular-weight polysaccharide is on the thrombotic impact of rats in vitro
Utilize external artificial thrombosis device, the low-molecular-weight polysaccharide of detection and comparison different molecular weight is the impact of anticoagulant effect on rats in vitro thrombosis, and test result is as shown in table 3.
Table 3: various low-molecular-weight polysaccharides are on the thrombotic impact of rats in vitro (± s, n=8)
*: P＜0.05, compare with the blank group * *: P＜0.01
Test result shows, the administration of various low-molecular-weight propylene glycol alginate sodium sulfate vena femoralis injection all has a significant effect to thrombosis length and the weight that rat blood forms in simulation thrombosis instrument.The low-molecular-weight polysaccharide of weight average molecular weight 3kD namely can significantly suppress the formation of rats in vitro thrombosis, weight average molecular weight is that the low-molecular-weight polysaccharide of 4kD, 6KD, 9KD also can significantly suppress the formation of rats in vitro thrombosis, and has compared extremely significant difference with the blank group.Simultaneously, along with the rising of propylene glycol alginate sodium sulfate weight average molecular weight, rats in vitro thrombosis length and weight reduce gradually, and its anticoagulant active raises gradually.
C: low-molecular-weight polysaccharide is on the thrombotic impact of rat carotid artery
Utilize the electricity irritation rat carotid artery to cause rat thrombus in vivo formation model, detect and compare the low-molecular-weight polysaccharide of different molecular weight to the therapeutical effect of rat thrombus in vivo formation, test result is as shown in table 4.
The various low-molecular-weight polysaccharides of table 4 are on the thrombotic impact of electricity irritation rat carotid artery (± s, n=8)
*: P＜0.05, compare with the blank group * *: P＜0.01
Test result shows, various low-molecular-weight propylene glycol alginate sodium sulfate intravenous administrations all have obvious prolongation effect to electricity irritation rat carotid artery thrombus formation time (off-period, Occlusion Time, OT).Weight average molecular weight is the i.e. obvious prolong rats thrombus in vivo formation time of low-molecular-weight polysaccharide of 3kDa, and has compared significant difference with the blank group, and other each groups are compared with the blank group the extremely difference of significance.Simultaneously, along with the rising of propylene glycol alginate sodium sulfate weight average molecular weight, it suppresses the also obviously prolongation of thrombotic time.
D: low-molecular-weight polysaccharide is on thrombotic impact in Mice Body
Utilize collagen and epinephrine induced platelet to assemble hyperamization bolt thromboembolism model, detect and compare the low-molecular-weight polysaccharide of different molecular weight to the impact of mice thrombus in vivo generation, namely on the impact of platelet aggregation, test result is as shown in table 5.
The various low-molecular-weight polysaccharides of table 5 are on thrombotic impact in Mice Body
*: P＜0.05, compare with the blank group * *: P＜0.01
Test result shows, various low-molecular-weight propylene glycol alginate sodium sulfate intraperitoneal injections can obviously improve the thromboembolism mouse survival and recover number of elements.In conjunction with other test result analysis, although the anticoagulant active of propylene glycol alginate sodium sulfate is higher than low-molecular-weight propylene glycol alginate sodium sulfate, but its hemorrhage side effect is also more serious, find that by dissecting mice the PSS group has the subcutaneous hemorrhage phenomenon, infer that tentatively the hemorrhage side effect under this dosage causes mouse survival rate and recovery rate obviously not to promote.Therefore in this test, the recovery number of the mice of injection propylene glycol alginate sodium sulfate is injected obviously not raising of low-molecular-weight polysaccharide (FP-6K, FP-9K).Low-molecular-weight propylene glycol alginate sodium sulfate FP6K, FP9K have the effect of antiplatelet aggregation, and its side effect significantly reduces, and therefore can be used as antithrombotic agents and use.
Show through above-mentioned serial experiment, along with the rising of propylene glycol alginate sodium sulfate weight average molecular weight, its anticoagulant active raises gradually, but bleeding risk also can raise to some extent; Along with the rising of propylene glycol alginate sodium sulfate weight average molecular weight, rats in vitro thrombosis length and weight reduce gradually; Along with the rising of propylene glycol alginate sodium sulfate weight average molecular weight, it suppresses the also obviously prolongation of thrombotic time; The recovery number of the mice of injection propylene glycol alginate sodium sulfate is injected obviously not raising of low-molecular-weight polysaccharide, and low-molecular-weight propylene glycol alginate sodium sulfate has the effect of antiplatelet aggregation, and its side effect significantly reduces.
Pharmacologically active result to sum up, low-molecular-weight polysaccharide of the present invention can be used as antithrombotic, anticoagulation medicine.
Above embodiment is only in order to illustrating technical scheme of the present invention, but not is limited; Although with reference to previous embodiment, the present invention is had been described in detail, for the person of ordinary skill of the art, still can modify to the technical scheme that previous embodiment is put down in writing, perhaps part technical characterictic wherein is equal to replacement; And these modifications or replacement do not make the essence of appropriate technical solution break away from the spirit and scope of the present invention's technical scheme required for protection.
Claims (4)
1. the preparation method of a low-molecular-weight polysaccharide, it is characterized in that it comprises the following steps: propylene glycol alginate sodium sulfate is made into the aqueous solution that mass percentage concentration is 5%-20%, adding oxidant to oxidant final concentration in the described aqueous solution is 0.2-0.5mol/L, and adding metal ion to metal ion final concentration is 0.5-5.0mmol/L; Then reaction 0.5-1.0 hour under 30-60 ℃, after reaction terminating, after adding ethanol 85% or more that it is precipitated, centrifugalize precipitation and supernatant; To precipitate the cation exchange resin purification, accent pH is 8-9, and ethanol precipitation, washing make low-molecular-weight polysaccharide by spray drying;
The structural formula of described low-molecular-weight polysaccharide is as follows:
Its molecular skeleton is the binary line style block polymer that β-D-(Isosorbide-5-Nitrae)-mannuronic acid (M) and α-L-(Isosorbide-5-Nitrae)-guluronic acid (G) form, R=Na or CH in formula
2CHOHCH
3, R
1=H or SO
3Na has a R at least in each sugar ring
1=SO
3Na, m+n≤25, the weight average molecular weight of low-molecular-weight polysaccharide is 3kDa-9kDa, the molecular weight distribution width is 1.20-1.70.
2. the preparation method of low-molecular-weight polysaccharide according to claim 1, it is characterized in that: described oxidant is hydrogen peroxide, hypochlorous acid or hypochlorite.
3. the preparation method of low-molecular-weight polysaccharide according to claim 1, it is characterized in that: described metal ion is bivalent cupric ion or iron ion.
According to claim 1 the low-molecular-weight polysaccharide that makes of preparation method for the preparation of the application in antithrombotic and anticoagulation medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110253845 CN102382204B (en) | 2011-08-31 | 2011-08-31 | Low-molecular-weight polysaccharide sulfate and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110253845 CN102382204B (en) | 2011-08-31 | 2011-08-31 | Low-molecular-weight polysaccharide sulfate and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102382204A CN102382204A (en) | 2012-03-21 |
| CN102382204B true CN102382204B (en) | 2013-06-26 |
Family
ID=45822088
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201110253845 Active CN102382204B (en) | 2011-08-31 | 2011-08-31 | Low-molecular-weight polysaccharide sulfate and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102382204B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB201322777D0 (en) | 2013-12-20 | 2014-02-05 | Algipharma As | Use of alginate oligomers as blood anticoagulants |
| CN104774278A (en) * | 2015-04-22 | 2015-07-15 | 青岛正大海尔制药有限公司 | Method for preparing polysaccharide sulfate by virtue of electrochemical reaction |
| CN104744607A (en) * | 2015-04-22 | 2015-07-01 | 青岛正大海尔制药有限公司 | Method for preparing polysaccharide sulfate through nanofiltration technology |
| CN109200058B (en) * | 2017-07-03 | 2020-09-04 | 青岛海洋生物医药研究院股份有限公司 | Application of poly (propyl guluronate) sulfate in preparation of anticoagulant drugs |
-
2011
- 2011-08-31 CN CN 201110253845 patent/CN102382204B/en active Active
Non-Patent Citations (5)
| Title |
|---|
| 张晶晶.注射用褐藻多糖硫酸酯的制备及理化性质研究.《中国优秀硕士学位论文医药卫生科计辑》.2009, |
| 林长征等.藻酸双酯钠的超滤分级及分级产物抗凝血活性的比较研究.《中国药学杂志》.2007,第42卷(第22期), |
| 林长征等.藻酸双酯钠的超滤分级及分级产物抗凝血活性的比较研究.《中国药学杂志》.2007,第42卷(第22期),第1689-1692页. |
| 注射用褐藻多糖硫酸酯的制备及理化性质研究;张晶晶;《中国优秀硕士学位论文医药卫生科计辑》;20091031;第17-18、22-24和28-29页 * |
| 藻酸双酯钠的超滤分级及分级产物抗凝血活性的比较研究;林长征等;《中国药学杂志》;20071122;第42卷(第22期);第1690页第2栏倒数第1行至第1691页第1栏第15行，表1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102382204A (en) | 2012-03-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2794666B1 (en) | Use of chemically modified heparin derivates in sickle cell disease | |
| CN102382204B (en) | Low-molecular-weight polysaccharide sulfate and preparation method and application thereof | |
| ES2277911T3 (en) | DERIVATIVES OF GLYCOSAMINOGLICANS GIVEN WITH ANTIANGIOGENIC ACTIVITY AND DESPROVISTOS OF ANTICOAGULANT EFFECT. | |
| CN104144950B (en) | The glucosaminoglycan and its medical usage of non-anti-freezing containing the disaccharide unit repeated | |
| JPH01308292A (en) | Production of ganglioside derivative | |
| CN104031170B (en) | A kind of people dextran iron material used for intravenous injection and preparation method thereof | |
| CN106349407A (en) | Low-molecular-weight fucosylated chondroitin sulfate, preparation method thereof and application of low-molecular-weight fucosylated chondroitin sulfate to preparation of medicine for resisting Trousseau syndrome | |
| KR101847846B1 (en) | High purity heparin and production method therefor | |
| CN105924544A (en) | High-sulfating chondroitin sulfate (CS) and preparing method and application thereof | |
| US9539271B2 (en) | Application of depolymerized holothurian glycosaminoglycans (DHG) in preparation of drug for prevention and treatment of thromboembolic diseases | |
| CN108350094A (en) | The improved method for producing high-purity sulfuric acid HA | |
| EP1731131A1 (en) | Hgf production accelerator containing heparin-like oligosaccharide | |
| CN107312765A (en) | A kind of glycosaminoglycan lyases for being difficult to degraded CS E and its encoding gene and application | |
| US20150337025A1 (en) | Use of fusion protein | |
| CN100341518C (en) | Use of sulfated glycosaminoglycans for establishing effective labor in women | |
| CN103804522A (en) | Method for increasing purity of heparin sodium | |
| CN110511285A (en) | A kind of recombinant fusion polypeptide and its application | |
| CN1840547A (en) | Method for preparing hydroxyethyl starch with different molecular weight and different substitution degree | |
| CN103638162B (en) | The application resisted myocardial ischemia and in reperfusion injury medicine prepared by a kind of morinda root oligosacchride 4 glycan | |
| CN104725532B (en) | A kind of method of chondroitin sulfate and dermatan sulfate content in accurate quantification control heparin/heparan | |
| CN109200058B (en) | Application of poly (propyl guluronate) sulfate in preparation of anticoagulant drugs | |
| CN113248630A (en) | Fucoidin composition, preparation method and application thereof | |
| CN103665180A (en) | Application of Morindae officinalis oligosaccharide 6 glycan in preparation of myocardial ischemia and reperfusion injury resistance medicines | |
| CN112691122A (en) | Stem cell preparation and application thereof in preparation of medicine for treating lung injury | |
| KR102298179B1 (en) | Method for producing unfractionated heparin |
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 | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20151102 Address after: 266071 Hongkong East Road, Laoshan District, Shandong, China, No. 23, No. Patentee after: Qingdao Ocean University of China Holdings Limited Address before: 266003 Shandong province Qingdao City fish Road No. 5 Patentee before: Ocean University of China |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20160510 Address after: 266071 Hongkong East Road, Laoshan District, Shandong, China, No. 23, No. Patentee after: Qingdao Haiyang biological medicine academy limited company Address before: 266071 Hongkong East Road, Laoshan District, Shandong, China, No. 23, No. Patentee before: Qingdao Ocean University of China Holdings Limited |