CN106565784A - Purification method for ceftaroline fosamil disodium salt - Google Patents
Purification method for ceftaroline fosamil disodium salt Download PDFInfo
- Publication number
- CN106565784A CN106565784A CN201610929015.5A CN201610929015A CN106565784A CN 106565784 A CN106565784 A CN 106565784A CN 201610929015 A CN201610929015 A CN 201610929015A CN 106565784 A CN106565784 A CN 106565784A
- Authority
- CN
- China
- Prior art keywords
- ceftaroline fosamil
- disodium salt
- purification process
- nanofiltration
- purification method
- 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.)
- Granted
Links
- 229960004828 ceftaroline fosamil Drugs 0.000 title claims abstract description 41
- -1 ceftaroline fosamil disodium salt Chemical class 0.000 title claims abstract description 27
- 238000000746 purification Methods 0.000 title claims abstract description 26
- 238000000034 method Methods 0.000 title abstract description 13
- 238000001728 nano-filtration Methods 0.000 claims abstract description 19
- ZCCUWMICIWSJIX-NQJJCJBVSA-N ceftaroline fosamil Chemical compound S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OCC)C=2N=C(NP(O)(O)=O)SN=2)CC=1SC(SC=1)=NC=1C1=CC=[N+](C)C=C1 ZCCUWMICIWSJIX-NQJJCJBVSA-N 0.000 claims abstract description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000003756 stirring Methods 0.000 claims abstract description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- 239000000706 filtrate Substances 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 239000012528 membrane Substances 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims 1
- 230000014759 maintenance of location Effects 0.000 claims 1
- 159000000000 sodium salts Chemical class 0.000 claims 1
- 239000007788 liquid Substances 0.000 abstract description 6
- 238000004440 column chromatography Methods 0.000 abstract description 4
- 239000002904 solvent Substances 0.000 abstract description 4
- 239000002351 wastewater Substances 0.000 abstract description 4
- 239000002253 acid Substances 0.000 abstract description 3
- 239000003513 alkali Substances 0.000 abstract description 3
- 238000005516 engineering process Methods 0.000 abstract description 2
- 238000002425 crystallisation Methods 0.000 abstract 1
- 230000008025 crystallization Effects 0.000 abstract 1
- 238000001914 filtration Methods 0.000 abstract 1
- 238000001514 detection method Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 5
- 239000012043 crude product Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 150000003952 β-lactams Chemical class 0.000 description 2
- ITHCSGCUQDMYAI-ZMIZWQJLSA-N 2-carboxy-D-arabinitol 1,5-bisphosphate Chemical compound OP(=O)(O)OC[C@@H](O)[C@@H](O)[C@](O)(COP(O)(O)=O)C(O)=O ITHCSGCUQDMYAI-ZMIZWQJLSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 201000001178 Bacterial Pneumonia Diseases 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 102100021486 Protein S100-G Human genes 0.000 description 1
- 101710122252 Protein S100-G Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001782 cephems Chemical group 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000011027 product recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000001223 reverse osmosis Methods 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940036731 teflaro Drugs 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65613—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system (X = CH2, O, S, NH) optionally with an additional double bond and/or substituents, e.g. cephalosporins and analogs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention relates to a purification method for ceftaroline fosamil disodium salt. The ceftaroline fosamil disodium salt is dissolved in water, activated carbon is added for filtration, and filter liquor is obtained; after pH of the above filter liquor is adjusted, nanofiltration is performed; and an organic solvent is added into the obtained nanofiltration liquid under the condition of stirring, crystallization is performed, and the purified ceftaroline fosamil disodium salt is obtained. The nanofiltration technology is adopted for the purification method to purify ceftaroline fosamil, and replaces a traditional high-expense and complex-process column chromatography purification method. The purification method has the characteristics that operation can be performed under high temperature, acid, alkali and other harsh conditions, and pollution resistance is achieved; the purity degree of the ceftaroline fosamil can be substantially improved; and the using amount of the solvent is reduced, and the waste water amount is reduced.
Description
Technical field
The present invention relates to a kind of purification process of Ceftaroline Fosamil disodium salt, belongs to technical field of medicine synthesis.
Background technology
Ceftaroline Fosamil is developed by Japanese Takeda Pharmaceutical Company Limited, and U.S. Forest Laboratories obtain market and authorize.
In the Nikkei United States drug food control office approval listing of October 29 in 2010.Medicine trade name Teflaro, is CPT
Prodrug (i.e. N- phosphorylateds CPT), belongs to the 5th generation cephalosporinses antimicrobial drug.
Ceftaroline Fosamil is used to treat the acquired bacterial pneumonia in Adults Community (CABP) and acute bacterial skin and soft
Infection caused by tissue infection (ABSSSI), including methicillin-resistant staphylococcus aureus (MRSA).Both indications all belong to
In the infection of serious and possible life-threatening, especially community acquired pneumonia M ＆ M is all higher.With other heads
Spore bacteriums antibiotic is the same, and in the chemical constitution of Ceftaroline Fosamil, bicyclic a combination with a beta-lactam nucleus constitutes one
Individual cephem ring.CPT is to the activity of MRSA just because of its 1,3- sulfur azole.CPT can also be effective
Combined with PBP-2a, this albumen is generally produced and be difficult and present clinical widely used beta-lactam antibiosis by MRSA
Element is combined.Therefore, CPT for MRSA has effective antibacterial activity, better than other beta-lactam antibiotics.
Ceftaroline Fosamil is injection stage medicine, higher to impurity component requirement, and the fewer side effect of impurity is less.At present
For the method for purification of Ceftaroline Fosamil is rarely reported, patent CN1462275A is reported and carried using macroporous adsorption resin chromatography method
Pure Ceftaroline Fosamil.But column chromatography scale is difficult to expand, eluting control requirement is strictly operated and quantity of solvent is big, energy expenditure is big,
Product recovery rate is low, the serious problems such as contaminated wastewater.
Nanofiltration is a kind of new molecule fractionation technique between ultrafiltration and reverse osmosiss, can be used to separating inorganic salts with
Molecular weight, between the low-molecular-weight organic matter of 100-2000 dalton, is a kind of filter method of separation different size molecule.
In nanofiltration, although the shape of molecule, size, electric charge, valence state have certain impact on separation, but the molecular weight of molecule is most important
Effect.By the NF membrane of PSPP, the effect of purification can be reached to Ceftaroline Fosamil.
The content of the invention
It is an object of the invention to provide a kind of purification process of Ceftaroline Fosamil disodium salt, using nanofiltration to cephalo Lip river
Woods ester carries out purification, instead of traditional costly, loaded down with trivial details column chromatography purification process of technique.It is characteristic of the invention that can be in height
Carry out under the harsh conditions such as temperature, acid, alkali, anti-pollution；The purity of Ceftaroline Fosamil can be increased substantially；Reduce solvent load, drop
Low wastewater flow rate.
The purification process of Ceftaroline Fosamil disodium salt of the present invention, comprises the steps：
Ceftaroline Fosamil disodium salt is dissolved in into water, adds activated carbon to be filtrated to get filtrate；
(1) above-mentioned filtrate is adjusted and carry out nanofiltration after pH；
(2) organic solvent, crystallize is added to obtain the CPT of purification in the case of stirring the nanofiltration solution of acquisition
Ester disodium salt.
The structural formula of Ceftaroline Fosamil disodium salt of the present invention is as follows：
The Ceftaroline Fosamil disodium salt that the process for purification of present invention offer is targeted is the synthetic method being currently known
Ceftaroline Fosamil disodium salt obtained by CN1462275A.
The following specifically describes the present invention：
In the step (1) of the present invention, described activated carbon dosage is the 0%-20% of the quality of compound I, preferably
1%-10%.
In the step (2) of the present invention, it is 4.0-8.0, preferably 5.0-7.0 that described filtrate adjusts pH scopes.
In the step (2) of the present invention, described nanofiltration temperature is 0-50 DEG C, preferably 5-30 DEG C.
In the step (2) of the present invention, described nanofiltration retaining molecular weight is less than 1300 dalton, preferably retains molecule
Amount is in 1200-800 dalton.
In the step (3) of the present invention, described organic solvent is ethanol, methanol, acetone, butanone, acetonitrile or therein
Mixed solvent, preferred alcohol, acetone.
In the step (3) of the present invention, recrystallization temperature is -10 DEG C -30 DEG C, preferably 0 DEG C -10 DEG C.
Compared with prior art, the invention has the advantages that：
The purification process of Ceftaroline Fosamil disodium salt of the present invention, the present invention is carried out pure using nanofiltration to Ceftaroline Fosamil
Change, instead of traditional costly, loaded down with trivial details column chromatography purification process of technique.It is characteristic of the invention that can be severe in high temperature, acid, alkali etc.
Carry out under the conditions of quarter, anti-pollution；The purity of Ceftaroline Fosamil can be increased substantially；Solvent load is reduced, wastewater flow rate is reduced.
Specific embodiment
With reference to embodiment, the present invention is described further.
HPLC detects the purity of Ceftaroline Fosamil：
Chromatographic condition：Agilent ZORBAX SB-Aq, chromatographic column (4.6*250mm, 5um), mobile phase be acetonitrile-
0.05mol ammonium acetate solutions (0：100)；Flow velocity 1.0ml/min；30 DEG C of column temperature；Detection wavelength 244nm, sample size 20ul.
Embodiment 1
Accurately weigh 20g Ceftaroline Fosamil disodium salt crude products to be dissolved in 200ml water, add 2g activated carbons, be stirred at room temperature half
Hour, after be filtered to remove insoluble impuritiess, filtrate adjusts pH to 5.0, and the road of model molecular cut off 1000 is used under the conditions of 20 DEG C
The NF membrane nanofiltration that you pause, filter liquor adds acetone 50ml, stirs 1 hour under the conditions of 0 DEG C, and crystallize obtains white solid 15.9g,
Liquid Detection purity is sent to be 98.6%.
Comparative example 1
The present embodiment is identical with the preparation process of embodiment 1, and difference is, NF membrane model molecular cut off used
800 dalton, concentrated crystallize obtains 15.3g white solids, send Liquid Detection its purity, and its purity is 98.3%.
Embodiment 2
Accurately weigh 30g Ceftaroline Fosamil disodium salt crude products to be dissolved in 300ml water, add 1.5g activated carbons, be stirred at room temperature
Half an hour, insoluble impuritiess are filtered to remove, filtrate adjusts pH to 6.0, and the road of model molecular cut off 1000 is used under the conditions of 20 DEG C
The NF membrane nanofiltration that you pause, filter liquor adds ethanol 100ml, stirs 1 hour under the conditions of 10 DEG C, and crystallize obtains white solid
20.9g, send Liquid Detection purity to be 99.3%.
Embodiment 3
Accurately weigh 30g Ceftaroline Fosamil disodium salt crude products to be dissolved in 300ml water, add 6g activated carbons, be stirred at room temperature 1 little
When, insoluble impuritiess are filtered to remove, filtrate adjusts pH to 8.0, and the dalton of model molecular cut off 1300 is used under the conditions of 50 DEG C
NF membrane nanofiltration, filter liquor add methanol 100ml, under the conditions of 30 DEG C stir 1 hour, crystallize obtains white solid 16.9g, send
Liquid Detection purity is 98.3%.
Embodiment 4
Accurately weigh 30g Ceftaroline Fosamil disodium salt crude products to be dissolved in 300ml water, add 0.03g activated carbons, be stirred at room temperature
1 hour, insoluble impuritiess are filtered to remove, filtrate adjusts pH to 4.0, and the dalton of model molecular cut off 800 is used under the conditions of 0 DEG C
NF membrane nanofiltration, filter liquor add ethanol 100ml, under the conditions of -10 DEG C stir 1 hour, crystallize obtains white solid 19.8g,
Liquid Detection purity is sent to be 97.8%.
Above-described embodiment is described in detail to the present invention.It should be noted that the embodiment of the above is just to illustrating
The bright present invention.On the premise of without departing from spirit and substance of the present invention, those skilled in the art can be designed that this
Bright various alternatives and improvement project, should be understood within protection scope of the present invention.
Claims (8)
1. a kind of purification process of Ceftaroline Fosamil disodium salt, it is characterised in that comprise the following steps：
(1) Ceftaroline Fosamil disodium salt is dissolved in into water, adds activated carbon to be filtrated to get filtrate；
(2) above-mentioned filtrate is adjusted and carry out nanofiltration after pH；
(3) organic solvent, crystallize is added to obtain the Ceftaroline Fosamil two of purification in the case of stirring the nanofiltration solution of acquisition
Sodium salt.
2. the purification process of Ceftaroline Fosamil disodium salt according to claim 1, it is characterised in that Ceftaroline Fosamil disodium
The structural formula of salt is：
3. the purification process of Ceftaroline Fosamil disodium salt according to claim 1, it is characterised in that described activated carbon is used
Measure the 0%-20% of the quality for compound I.
4. the purification process of Ceftaroline Fosamil disodium salt according to claim 1, it is characterised in that filtrate adjusts pH scopes
For 4.0-8.0.
5. the purification process of Ceftaroline Fosamil disodium salt according to claim 1, it is characterised in that nanofiltration temperature is 0-50
℃。
6. the purification process of Ceftaroline Fosamil disodium salt according to claim 1, it is characterised in that NF membrane retention used
Molecular weight is less than 1300 dalton.
7. the purification process of Ceftaroline Fosamil disodium salt according to claim 1, it is characterised in that what nanofiltration solution was added
Organic solvent is one or more mixing in ethanol, methanol, acetone, butanone or acetonitrile.
8. the purification process of Ceftaroline Fosamil disodium salt according to claim 1, it is characterised in that in step (3), analysis
Brilliant temperature is -10 DEG C -30 DEG C.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610929015.5A CN106565784B (en) | 2016-10-31 | 2016-10-31 | The purification process of Ceftaroline Fosamil disodium salt |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610929015.5A CN106565784B (en) | 2016-10-31 | 2016-10-31 | The purification process of Ceftaroline Fosamil disodium salt |
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| Publication Number | Publication Date |
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| CN106565784A true CN106565784A (en) | 2017-04-19 |
| CN106565784B CN106565784B (en) | 2019-02-26 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110872322A (en) * | 2018-08-29 | 2020-03-10 | 上海博志研新药物技术有限公司 | Preparation method of cefaloside acetate monohydrate and intermediate thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1282335A (en) * | 1997-12-19 | 2001-01-31 | 武田药品工业株式会社 | Phosphonocephem derivatives, process for preparation of the same, and use thereof |
| CN1462275A (en) * | 2000-08-10 | 2003-12-17 | 武田药品工业株式会社 | Phosphonocephem compound |
| CN102060861A (en) * | 2010-11-04 | 2011-05-18 | 浙江工业大学 | Desalination concentration method for cephalo mother liquor |
| CN104718216A (en) * | 2012-10-19 | 2015-06-17 | 桑多斯股份公司 | Novel process for preparing ceftaroline fosamil |
| CN104725425A (en) * | 2015-04-09 | 2015-06-24 | 山东罗欣药业集团股份有限公司 | Preparation method for ceftaroline fosamil |
-
2016
- 2016-10-31 CN CN201610929015.5A patent/CN106565784B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1282335A (en) * | 1997-12-19 | 2001-01-31 | 武田药品工业株式会社 | Phosphonocephem derivatives, process for preparation of the same, and use thereof |
| CN1462275A (en) * | 2000-08-10 | 2003-12-17 | 武田药品工业株式会社 | Phosphonocephem compound |
| CN102060861A (en) * | 2010-11-04 | 2011-05-18 | 浙江工业大学 | Desalination concentration method for cephalo mother liquor |
| CN104718216A (en) * | 2012-10-19 | 2015-06-17 | 桑多斯股份公司 | Novel process for preparing ceftaroline fosamil |
| CN104725425A (en) * | 2015-04-09 | 2015-06-24 | 山东罗欣药业集团股份有限公司 | Preparation method for ceftaroline fosamil |
Non-Patent Citations (1)
| Title |
|---|
| 邬方宁: "膜分离技术在药物分离中的应用", 《天津药学》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110872322A (en) * | 2018-08-29 | 2020-03-10 | 上海博志研新药物技术有限公司 | Preparation method of cefaloside acetate monohydrate and intermediate thereof |
| CN110872322B (en) * | 2018-08-29 | 2022-08-02 | 上海博志研新药物技术有限公司 | Preparation method of cefaloside acetate monohydrate and intermediate thereof |
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| Publication number | Publication date |
|---|---|
| CN106565784B (en) | 2019-02-26 |
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Address after: 256100 No. 1 Yang drive road, Yiyuan County, Zibo, Shandong Patentee after: Ruiyang Pharmaceutical Co.,Ltd. Address before: 256100 No. 1 Yang drive road, Yiyuan County, Zibo, Shandong Patentee before: REYOUNG PHARMACEUTICAL Co.,Ltd. |
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Denomination of invention: Purification of disodium salt of cephalosporin axetil Effective date of registration: 20211209 Granted publication date: 20190226 Pledgee: Commercial Bank of China Yiyuan branch of Limited by Share Ltd. Pledgor: Ruiyang Pharmaceutical Co.,Ltd. Registration number: Y2021980014543 |
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| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20221012 Granted publication date: 20190226 Pledgee: Commercial Bank of China Yiyuan branch of Limited by Share Ltd. Pledgor: Ruiyang Pharmaceutical Co.,Ltd. Registration number: Y2021980014543 |