CN103083253B - Acetaminophen lyophilized formulations and preparation method thereof - Google Patents
Acetaminophen lyophilized formulations and preparation method thereof Download PDFInfo
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- CN103083253B CN103083253B CN201110346693.6A CN201110346693A CN103083253B CN 103083253 B CN103083253 B CN 103083253B CN 201110346693 A CN201110346693 A CN 201110346693A CN 103083253 B CN103083253 B CN 103083253B
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- acetaminophen
- lyophilized formulations
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- injection
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- RZVAJINKPMORJF-UHFFFAOYSA-N p-acetaminophenol Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 title claims abstract description 47
- 229960005489 paracetamol Drugs 0.000 title claims abstract description 45
- 229940022659 Acetaminophen Drugs 0.000 title claims abstract description 41
- 239000000203 mixture Substances 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 238000004108 freeze drying Methods 0.000 claims abstract description 8
- 239000000463 material Substances 0.000 claims abstract description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L Sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 238000002347 injection Methods 0.000 claims description 8
- 239000007924 injection Substances 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 5
- ZGTMUACCHSMWAC-UHFFFAOYSA-L disodium;2-[2-[carboxylatomethyl(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetate Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 5
- 235000010265 sodium sulphite Nutrition 0.000 claims description 5
- 239000000243 solution Substances 0.000 claims description 5
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 claims description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 3
- 239000012528 membrane Substances 0.000 claims description 2
- 238000004806 packaging method and process Methods 0.000 claims description 2
- 238000007789 sealing Methods 0.000 claims description 2
- RTAQQCXQSZGOHL-UHFFFAOYSA-N titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 2
- 229910052719 titanium Inorganic materials 0.000 claims description 2
- 239000010936 titanium Substances 0.000 claims description 2
- 239000003643 water by type Substances 0.000 claims description 2
- 239000008215 water for injection Substances 0.000 claims description 2
- IYNDLOXRXUOGIU-UHFFFAOYSA-M potassium;3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate Chemical compound [K+].O=C1N2C(C([O-])=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 IYNDLOXRXUOGIU-UHFFFAOYSA-M 0.000 claims 2
- 239000001301 oxygen Substances 0.000 abstract description 6
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 abstract description 6
- 229910052760 oxygen Inorganic materials 0.000 abstract description 6
- 230000003078 antioxidant Effects 0.000 abstract description 5
- 239000003963 antioxidant agent Substances 0.000 abstract description 5
- HTIQEAQVCYTUBX-UHFFFAOYSA-N Amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 abstract description 4
- 238000005286 illumination Methods 0.000 abstract description 4
- 239000002904 solvent Substances 0.000 abstract description 4
- 238000005516 engineering process Methods 0.000 abstract description 3
- 239000003002 pH adjusting agent Substances 0.000 abstract description 2
- 239000000843 powder Substances 0.000 description 7
- 239000003814 drug Substances 0.000 description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000003110 anti-inflammatory Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- IYNDLOXRXUOGIU-UHFFFAOYSA-N potassium;3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound [K+].O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 IYNDLOXRXUOGIU-UHFFFAOYSA-N 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- DIIASMSSGMRMQF-UHFFFAOYSA-N 1-(2-amino-3-hydroxyphenyl)ethanone Chemical class CC(=O)C1=CC=CC(O)=C1N DIIASMSSGMRMQF-UHFFFAOYSA-N 0.000 description 1
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Natural products CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 1
- 229940069078 Citric Acid / sodium citrate Drugs 0.000 description 1
- 229960001305 Cysteine Hydrochloride Drugs 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 206010072736 Rheumatic disease Diseases 0.000 description 1
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 1
- 208000004371 Toothache Diseases 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N Trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- QIJRTFXNRTXDIP-JIZZDEOASA-N [(1R)-1-carboxy-2-sulfanylethyl]azanium;chloride;hydrate Chemical group O.Cl.SC[C@H](N)C(O)=O QIJRTFXNRTXDIP-JIZZDEOASA-N 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- -1 acetophenone amine Chemical class 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000000202 analgesic Effects 0.000 description 1
- 239000003907 antipyretic analgesic agent Substances 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 235000019636 bitter flavor Nutrition 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000005712 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 239000000820 nonprescription drug Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000000149 penetrating Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000955 prescription drug Substances 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical group [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
Abstract
The present invention relates to acetaminophen lyophilized formulations; this lyophilized formulations is obtained by following material is lyophilised, including 0.5 ~ 5% acetaminophen, 0.5 ~ 30% freeze drying protectant, 0.01 ~ 5% chelating agen, 0.01 5% pH adjusting agent, 0.01 5% antioxidant and remaining as solvent.Acetaminophen lyophilized formulations that the present invention provides and preparation method thereof, overcome in background technology acetaminophen lyophilized formulations exist stable under, easily affected by factors such as moisture, oxygen, pH, temperature, illumination, it is provided that the acetaminophen lyophilized formulations that a kind of good stability, security performance are high.
Description
Technical field
The present invention relates to field of medicine preparations, particularly relate to lyophilized formulations field, particularly to acetaminophen lyophilizing
Preparation and preparation method thereof.
Background technology
Acetaminophen, usually prism crystallization or white crystalline powder.Odorless, mildly bitter flavor.Can be dissolved in ethanol,
Acetone and hot water, be slightly soluble in water, insoluble in petroleum ether and benzene, and its saturated aqueous solution pH value 5.5-6.5.
Chemical name: N-(4-hydroxy phenyl) acetamide；Molecular formula: C8H9NO2；Molecular weight: 151.170；CAS No:
103-90-2。
It is the most frequently used non-steroidal anti-inflammatory antipyretic analgesic, and refrigeration function is similar to aspirin, and analgesic activity is more weak,
Anti rheumatism action without antiinflammatory, is kind best in acetophenone amine drug.It is particularly suitable for applying carboxylic acids medicine
Patient.For catching a cold, the disease such as toothache.
In the U.S., acetaminophen has the nonprescription drugs of the prescription drugs sum of the compound recipe more than 600 and single component
Preparation, including tablet, caplet (a kind of oval capsule shape coating tablet designed for anti-undesirable substance dopes), suspension,
The form such as powder and suppository.
The clear liquid that paracetamol injection determined is colourless or almost colourless slightly thickness of listing at present.Injection side
Formula: intramuscular injection, 0.15g～0.25g；Preparation/specification: (1) 1ml:0.075g (2) 2ml:0.25g.
Historically, the intravenous form of aqueous stability difference and dissolubility low stopping acetaminophen
Development.In the presence of oxygen and water, acetaminophen can decompose.Along with increase or the contact light of temperature, its decomposition speed
Rate will be accelerated.The pH of solution also has tremendous influence to its stability, and this makes to produce applicable intravenously administrable and obtains acetparaminosalol
Phenol aqueous solution is faced with bigger challenge.Therefore acetaminophen intravenous formulations has to add multiple auxiliary materials to protect solution
In oxygen cause the instability of acetaminophen.
Acetaminophen is developed into injection freeze-dried powder, can be avoided as much as moisture, oxygen, pH, temperature,
The impact on acetaminophen of the factors such as illumination, improves its stability, and effectively reducing has the generation of related substance, thus reduces note
Risk when penetrating；Also play the purpose extended the shelf life simultaneously.Acetaminophen freeze-dried powder is producing and storage and transport process
In exist in the form of a powder, can be dissolved in water before use.
Summary of the invention
It is an object of the invention to provide the acetaminophen lyophilized formulations of a kind of good stability.
Another object of the present invention is to provide the preparation method of above-mentioned acetaminophen lyophilized formulations.
In order to realize foregoing invention purpose, present invention employs following technical scheme:
Acetaminophen lyophilized formulations, this lyophilized formulations is obtained by following material is lyophilised, including 0.5 ~ 5% pair of acetyl
Amino phenols, 0.5 ~ 30% freeze drying protectant, 0.01 ~ 5% chelating agen, 0.01-5% pH adjusting agent, 0.01-5% antioxidant and residue
For solvent.
Described freeze drying protectant is one or more mixing in sucrose, trehalose, glycine.Add freeze drying protectant
Not only act as the effect of lyophilizing excipient, and storage protection acetaminophen medicine after freezing dry process and lyophilizing can be played
The effect of effect.
Described chelating agen is disodiumedetate or citric acid.
Described PH regulator is sodium dihydrogen phosphate, disodium hydrogen phosphate or citric acid/sodium citrate.Adding PH regulator is
In order to pH value is controlled between 5.5 ~ 6.5, improve the stability of acetaminophen lyophilized formulations.
Described antioxidant is cysteine hydrochloride or sodium sulfite.Add antioxidant to reduce sky gas and water
Oxidation to acetaminophen, improves stability.
Described solvent is water, the tert-butyl alcohol or both mixing.
The invention also discloses the preparation method of above-mentioned acetaminophen lyophilized formulations, comprise the steps:
(1) weigh the acetaminophen of recipe quantity to be added to fill in the container of solvent dissolve and join concentrated solution, regulate pH
5.5-6.5；
(2) join 2/3 volume according to content results, add needle-use activated carbon, stirring, stand；
(3) filtration, fine straining, sample examination；
(4) add water the most molten according to content and pH；
(5) seal after subpackage, lyophilization, pack.
Acetaminophen lyophilized formulations that the present invention provides and preparation method thereof, overcomes in background technology acetyl ammonia
Under the existence of base phenol lyophilized formulations is stable, easily affected by factors such as moisture, oxygen, pH, temperature, illumination, it is provided that a kind of stable
The acetaminophen lyophilized formulations that property is good, security performance is high.
Detailed description of the invention
Below by specific embodiment, the present invention is described further.
Embodiment 1: prepare 100 bottles of acetaminophen lyophilized formulations, uses following material:
Acetaminophen 0.75g
Mannitol 3g
EDTA-2Na 0.2g
Sodium sulfite 0.5g
Disodium hydrogen phosphate is appropriate
Water is to 1000ml
Make 100 bottles
Preparation process:
1, weigh the acetaminophen of recipe quantity to be added to fill in the container of 80 DEG C of waters for injection dissolve and join concentrated solution, adjust
Joint pH 5.5-6.5；
2, join 2/3 volume according to content results, add the needle-use activated carbon of 0.1%, 80 DEG C of insulated and stirred 30 minutes, stand；
3,1 μm titanium rod coarse filtration, 0.45 μm filter membrane fine straining；
4, sample examination；
5, add water the most molten according to content and pH；
6, cillin bottle subpackage；
7, lyophilization；
8, cillin bottle sealing, packaging.
The present embodiment, in preparing acetaminophen lyophilized formulations, adds freeze drying protectant mannitol, chelating agen
EDTA-2Na and antioxidant sodium sulfite, and with disodium hydrogen phosphate regulation pH value 5.5 ~ 6.5 so that prepare
The good stability of acetaminophen lyophilizing, be susceptible to the impact of the factors such as moisture, oxygen, pH, temperature, illumination, effectively
The drug effect of the medicine ensured and the safety of use.
Embodiment 2: prepare 100 bottles of acetaminophen lyophilized formulations, uses following material:
Acetaminophen 7.5g
Mannitol 5g
EDTA-2Na 0.5g
Sodium sulfite 0.5g
Disodium hydrogen phosphate is appropriate
The tert-butyl alcohol is to 1000ml
Make 100 bottles
Preparation method is identical with embodiment 1.
Stability below by stability experiment checking acetaminophen lyophilized formulations.
1. test: experimental technique
(1) paracetamol injection determined: preparation paracetamol injection determined, concentration: 7.5mg/ml, in different condition
Lower storage, and measure its content, pH；
(2) acetaminophen freeze-dried powder: store under different condition, water for injection dissolves, and is configured to concentration:
7.5mg/ml, measures its content, pH.
2. experimental result
Finally, the stability of acetaminophen freeze-dried powder is substantially better than paracetamol injection determined.
Claims (1)
1. acetaminophen lyophilized formulations, it is characterised in that prepare 100 bottles of acetaminophen lyophilized formulations, use following thing
Material:
Acetaminophen 0.75g
Mannitol 3g
EDTA-2Na 0.2g
Sodium sulfite 0.5g
Disodium hydrogen phosphate is appropriate
Water for injection is to 1000ml
And use following preparation process to prepare:
(1), weigh the acetaminophen of recipe quantity and be added to fill in the container of 80 DEG C of waters for injection dissolve and join concentrated solution, regulation
pH 5.5-6.5；
(2), according to content results join 2/3 volume, add the needle-use activated carbon of 0.1%, 80 DEG C of insulated and stirred 30 minutes, stand；
(3), 1 μm titanium rod coarse filtration, 0.45 μm filter membrane fine straining；
(4), sample examination；
(5), inject with water fixed molten according to content and pH；
(6), cillin bottle subpackage；
(7), lyophilization；
(8), cillin bottle sealing, packaging.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110346693.6A CN103083253B (en) | 2011-11-07 | Acetaminophen lyophilized formulations and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110346693.6A CN103083253B (en) | 2011-11-07 | Acetaminophen lyophilized formulations and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103083253A CN103083253A (en) | 2013-05-08 |
| CN103083253B true CN103083253B (en) | 2016-12-14 |
Family
ID=
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1548038A (en) * | 2003-05-22 | 2004-11-24 | 孙明杰 | New acetaminophen prepn |
| CN101147731A (en) * | 2006-11-22 | 2008-03-26 | 陈旭良 | Tramadol hydrochloride and paracetamol combined injection |
| CN101366695A (en) * | 2008-10-16 | 2009-02-18 | 江苏四环生物股份有限公司 | Tylenol injection and preparation method thereof |
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1548038A (en) * | 2003-05-22 | 2004-11-24 | 孙明杰 | New acetaminophen prepn |
| CN101147731A (en) * | 2006-11-22 | 2008-03-26 | 陈旭良 | Tramadol hydrochloride and paracetamol combined injection |
| CN101366695A (en) * | 2008-10-16 | 2009-02-18 | 江苏四环生物股份有限公司 | Tylenol injection and preparation method thereof |
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| CB02 | Change of applicant information |
Address after: Hangzhou City, Zhejiang province Binjiang District 310052 shore road 1180 China Science and Technology Park 2 Building 4 floor West Applicant after: HANGZHOU SHARPLY PHARM R&D INSTIT. Co.,Ltd. Applicant after: HAINAN POLY PHARM. Co.,Ltd. Applicant after: ZHEJIANG POLY PHARMACEUTICAL Co.,Ltd. Address before: Hangzhou City, Zhejiang province Binjiang District 310052 shore road 1180 China Science and Technology Park 2 Building 4 floor West Applicant before: HANGZHOU SHARPLY PHARM R&D INSTIT. Co.,Ltd. Applicant before: Hainan Poly Pharm Co.,Ltd. Applicant before: ZHEJIANG POLY PHARMACEUTICAL Co.,Ltd. |
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| TR01 | Transfer of patent right |
Effective date of registration: 20230117 Address after: 571127 Guilin Ocean Economic Development Zone, Meilan District, Haikou City, Hainan Province Patentee after: HAINAN POLY PHARM. Co.,Ltd. Patentee after: ZHEJIANG POLY PHARMACEUTICAL Co.,Ltd. Address before: West side of 4/F, Building 2, Huaye Science Park, No. 1180 Bin'an Road, Binjiang District, Hangzhou, Zhejiang 310052 Patentee before: HANGZHOU SHARPLY PHARM R&D INSTIT. Co.,Ltd. Patentee before: HAINAN POLY PHARM. Co.,Ltd. Patentee before: ZHEJIANG POLY PHARMACEUTICAL Co.,Ltd. |