CN102603510A - Sodium valproate crystal form as well as preparation method and application thereof - Google Patents
Sodium valproate crystal form as well as preparation method and application thereof Download PDFInfo
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- CN102603510A CN102603510A CN2012100288382A CN201210028838A CN102603510A CN 102603510 A CN102603510 A CN 102603510A CN 2012100288382 A CN2012100288382 A CN 2012100288382A CN 201210028838 A CN201210028838 A CN 201210028838A CN 102603510 A CN102603510 A CN 102603510A
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- sodium valproate
- crystal form
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- valproate
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- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 title claims abstract description 73
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 title claims abstract description 71
- 229940084026 sodium valproate Drugs 0.000 title claims abstract description 70
- 239000013078 crystal Substances 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000002347 injection Methods 0.000 claims abstract description 17
- 239000007924 injection Substances 0.000 claims abstract description 17
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 3
- 239000000843 powder Substances 0.000 claims description 9
- 230000008014 freezing Effects 0.000 claims description 7
- 238000007710 freezing Methods 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 5
- 238000009472 formulation Methods 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 239000001961 anticonvulsive agent Substances 0.000 claims description 4
- 229960003965 antiepileptics Drugs 0.000 claims description 4
- 238000001291 vacuum drying Methods 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 abstract description 6
- 238000010521 absorption reaction Methods 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 4
- 230000007012 clinical effect Effects 0.000 abstract description 3
- 238000000034 method Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 206010015037 epilepsy Diseases 0.000 description 4
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 4
- 206010010904 Convulsion Diseases 0.000 description 3
- 206010034759 Petit mal epilepsy Diseases 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 229960000604 valproic acid Drugs 0.000 description 3
- 239000007788 liquid Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 206010000117 Abnormal behaviour Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000033001 Complex partial seizures Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940028937 divalproex sodium Drugs 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 208000028316 focal seizure Diseases 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229940023568 magnesium valproate Drugs 0.000 description 1
- LKLLHOIUJVEAGU-UHFFFAOYSA-L magnesium;2-propylpentanoate Chemical compound [Mg+2].CCCC(C([O-])=O)CCC.CCCC(C([O-])=O)CCC LKLLHOIUJVEAGU-UHFFFAOYSA-L 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 239000013618 particulate matter Substances 0.000 description 1
- 208000001297 phlebitis Diseases 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940102566 valproate Drugs 0.000 description 1
- OMOMUFTZPTXCHP-UHFFFAOYSA-N valpromide Chemical compound CCCC(C(N)=O)CCC OMOMUFTZPTXCHP-UHFFFAOYSA-N 0.000 description 1
- 229960001930 valpromide Drugs 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000004552 water soluble powder Substances 0.000 description 1
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Abstract
The invention discloses a sodium valproate crystal form II as well as a preparation method and application thereof, wherein characteristic absorption peaks appear at diffraction angles of (2theta)=6.3-6.5 DEG, 7.12-7.32 DEG, 7,3-7.5 DEG, 16.95-17.15 DEG, 18.15-18.35 DEG, 18.88-19.08 DEG and 19.17-19.37 DEG in a powder x-ray diffraction pattern of the crystal. The sodium valproate crystal form II provided by the invention has the advantages that the hygroscopicity is significantly reduced and lower water content of the product is guaranteed to ensure that the quality of the sodium valproate is more stable in storage period; while the hygroscopicity is reduced, the dissolution time of the product is significantly shortened and the dissolvability of the product is improved to ensure that the curative effect and very good safety of the sodium valproate are guaranteed in clinical application, the injection pain is also significantly relieved, compliance of patients is increased during treatment and very good clinical effect of the treatment is obtained.
Description
Technical field
The invention provides Sodium Valproate new crystal II, belong to pharmaceutical field.
Background technology
Sodium Valproate is an a kind of line wide spectrum antiepileptic drug.Chemical structural formula is following:
Sodium Valproate chemistry valproate by name, molecular formula: C
8H
15NaO
2Molecular weight is 166.2; For the water-soluble powder of white odorless crystalloid, be a kind of antiepileptic drug preferably, be applicable to the prevention and the treatment [Chinese Journal of Pharmaceuticals 1999 of the personality behavior disorder that various epilepsies (petit mal, focal seizure, psychomotor attack and mixing outbreak) and epilepsy cause; 30 (9): 389-390], can be prepared into oral prepns and injection formulations.The oral prepns specification has tablet at present: 100mg, 200mg, syrup: 5ml:200mg, 500mg.Sodium Valproate can be used as the intravenous drip administration; The complex partial seizures of the complicated part epilepsy of the independent outbreak of treatment or assisting therapy or the other types epilepsy that occurs together also be applicable to the simple or complicacy epilepsy petit mal of independent treatment or assisting therapy, and assisting therapy comprises the broad variety epileptic seizures (Han Rong of epilepsy petit mal separately; Deng; The Sodium Valproate injection liquid, " clinical drug therapy journal, 2006 43 phases of volume).
Usually commercially available Sodium Valproate is in the solid preparation technological process, because Sodium Valproate is prone to moisture absorption, powder flowbility is relatively poor, is prone to sticking, and face shaping is poor, and the product after the absorption may expedite product be degraded, and produces impurity, and its stability is reduced; Its injection solubility is poor, water cut is bigger than normal, so Sodium Valproate injection practical clinical difference on effect is bigger.
Because very easily moisture absorption of Sodium Valproate; At present reduce its water absorbability, for example divalproex sodium (Sodium Valproate/valproic acid 1: 1), Magnesium Valproate, valproic acid calcium, valpromide and Sodium Valproate/valproic acid (3: 1) etc. through the form of adding other components or preparing other valproates.But reducing the hygroscopic while; Also reduced the solvability of product; For powder injection, deliquescent reduction can cause the product solubility relatively poor, makes that medicine dissolution is slow or dissolving is incomplete; Cause diseases such as angiemphraxis, blood supply insufficiency, phlebitis, thrombus, local tissue necrosis easily, pain when also causing patient injection easily simultaneously.(US4988731; Liang Chenfang, etc., particulate matter is investigated in the power for intravenous injection agent, " Liuzhou medical science ", 2006 19 1 phases of volume)
At present crystalline is discovered that same compound all can two or more crystalline states exist.Identical but the crystal formation of molecular structure might have different bioavailabilities, solubleness, dissolution rate, chemical physical stability, fusing point, color, filtrability, density and flowability not simultaneously.
Number of patent application: 201110038689.3; This application discloses a kind of Sodium Valproate crystal form II I; In the diffractogram of this crystalline powder X-ray line diffraction, located charateristic avsorption band angle of diffraction (2 θ)=5.40 °, 6.31 ± 0.1 °, 7.28 °, 76.86 °, 18.10 °.In this invention, Sodium Valproate crystal form II I favorable solubility has solved the problem of existing Sodium Valproate powder injection solubility difference, but has not related in this patent the hygroscopic research of Sodium Valproate.
At present, also do not see through changing the Sodium Valproate crystal formation and reduce the hygroscopic relevant report of Sodium Valproate.
Summary of the invention
The object of the present invention is to provide the low Sodium Valproate new crystal of water absorbability.
The invention provides a kind of Sodium Valproate crystal form II, located charateristic avsorption band angle of diffraction (2 θ)=6.40 ° ± 0.1 °, 7.22 ° ± 0.1 °, 7.40 ° ± 0.1 °, 17.05 ° ± 0.1 °, 18.25 ° ± 0.1 °, 18.98 ° ± 0.1 °, 19.27 ° ± 0.1 ° in this crystalline powder x ray diffration pattern x.
Wherein, in the crystallization differential scanning calorimetric analysis, endotherm(ic)peak is arranged at 91.21 ℃ ± 3 ℃, 143.01 ℃ ± 3 ℃ and 239.04 ℃ ± 3 ℃.
Further preferably, this crystalline powder x-ray diffraction is as shown in Figure 1.
The present invention also provides the preparation method of above-mentioned Sodium Valproate crystal form II, and it comprises the steps:
Sodium Valproate is dissolved in the water,, starts freeze drier in-42 ℃～-30 ℃ after freezing 13～24 hours, vacuum-drying, whole drying process does not heat up to shelf, dry fully after, promptly get the Sodium Valproate crystal form II.
Wherein, the amount ratio of Sodium Valproate and water is 1: (10～20) w/v; In-42 ℃～-30 ℃ after freezing 18～24 hours, dry again.
Further, the amount ratio of Sodium Valproate and water is 1: (15～20) w/v; In-42 ℃～-40 ℃ after freezing 18～20 hours, dry again.
The present invention also provides a kind of pharmaceutical composition, and it contains above-mentioned Sodium Valproate crystal form II.
Wherein, said pharmaceutical composition is oral prepns, injection formulations.
Further, described injection formulations is a powder injection.
The present invention also provides the purposes of above-mentioned Sodium Valproate crystal form II in the preparation antiepileptic drug.
Sodium Valproate crystal form II provided by the invention, its water absorbability significantly reduces, and has guaranteed the water cut that product is lower, makes that Sodium Valproate quality in storage period is more stable; Reducing the hygroscopic while; Also significantly shortened the dissolution time of product; Improved the solubility of product, its good solubility has guaranteed the curative effect of Sodium Valproate when clinical application and well security, has also reduced pain on injection significantly; Improved the compliance during the patient, made treatment obtain the good clinical effect.
Obviously, according to foregoing of the present invention,,, can also make modification, replacement or the change of other various ways not breaking away under the above-mentioned basic fundamental thought of the present invention prerequisite according to the ordinary skill knowledge and the customary means of this area.
Below through embodiment the present invention is made further detailed description; But do not limit the present invention; Those skilled in the art can make various changes and distortion according to the present invention, only otherwise break away from spirit of the present invention, all should belong to the scope of accompanying claims of the present invention.
Description of drawings
Fig. 1 crystal form II P-XRD collection of illustrative plates
Fig. 2 crystal form II DSC collection of illustrative plates
Embodiment
The preparation method of embodiment 1 Sodium Valproate crystal form II of the present invention
Take by weighing the 10g Sodium Valproate, add the 66.6ml purified water ,-40 ℃ of quick freezing 18 hours start freeze drier, vacuum-drying, whole drying process does not heat up to shelf, the crystal form II Sodium Valproate.In the whole drying process, shelf is not heated up, promptly in the drying process, temperature remains unchanged, and has guaranteed the working method higher repeatability.
The P-XRD collection of illustrative plates of crystal form II is seen Fig. 1, and the DSC collection of illustrative plates is seen Fig. 2.
Wherein, In the X diffracting spectrum, (2 θ)=6.40 °, 7.22 °, 7.40 °, 17.05 °, 18.25 °, 18.98 °, 19.27 ° ± 0.1 ° located charateristic avsorption band (also can be expressed as 6.40 ° ± 0.1 °, 7.22 ° ± 0.1 °, 7.40 ° ± 0.1 °, 17.05 ° ± 0.1 °, 18.25 ° ± 0.1 °, 18.98 ° ± 0.1 °, 19.27 ° ± 0.1 °).
Among the present invention, be used to prepare the Sodium Valproate raw material of crystal form II, can obtain, also can prepare, for example CN102241582A through existing preparation method through buying the commercial goods.
Embodiment 2 preparation of drug combination methods of the present invention
Under aseptic condition, adopt embodiment 1 preparation Sodium Valproate crystal form II after, crystal form II is packed in the vial, seal, promptly get the powder injection of Sodium Valproate crystal form II.
Below specify beneficial effect of the present invention through Test Example.
Test Example 1 Sodium Valproate crystal form II of the present invention and currently available products draw moist comparative studies
Get product 1g, draw moist test (2010 editions second appendix XIX J of Pharmacopoeia of People's Republic of China medicine draws moist test direction principle).
About drawing the defining standard of moist weightening finish:
Deliquescence: absorb enough water and divide formation liquid
Have draw moist: drawing wet weightening finish and being not less than 15%
Have draw moist: drawing wet weightening finish less than 15% but be not less than 2%
Slightly draw moist: drawing wet weightening finish less than 2% but be not less than 0.2%
Do not have or almost do not have draw moist: drawing wet the weightening finish less than 0.2%
The Sodium Valproate crystal form II is prepared by the embodiment of the invention 1, and the Sodium Valproate currently available products prepares with reference to existing document (CN102241582A) disclosed method.
Table 1 Sodium Valproate crystal form II of the present invention and currently available products draw moist comparative studies
Visible by table 1, the moisture absorption weightening finish of Sodium Valproate crystal form II of the present invention is starkly lower than existing Sodium Valproate product, shows that Sodium Valproate crystal form II of the present invention has significantly reduced the water absorbability of Sodium Valproate, makes that Sodium Valproate quality in storage period is more stable.
The solubility comparative studies of Test Example 2 Sodium Valproate crystal form IIs of the present invention and currently available products
Take by weighing product 0.4g, add water for injection 4mL, jolting, dissolution time should be less than 60 seconds.
The Sodium Valproate crystal form II is prepared by the embodiment of the invention 1, and the Sodium Valproate currently available products prepares with reference to existing document (CN102241582A) disclosed method.
The solubility comparative studies of table 1 crystal form II and currently available products
Visible by table 2; Sodium Valproate crystal form II of the present invention is compared with currently available products, and the redissolution time has shortened more than 34%, shows that the Sodium Valproate crystal form II is reducing the hygroscopic while of Sodium Valproate; Can also significantly improve the solvability of Sodium Valproate, thereby improve the compliance during the patient.
In sum, Sodium Valproate crystal form II provided by the invention, its water absorbability significantly reduces, and has guaranteed the water cut that product is lower, makes that Sodium Valproate quality in storage period is more stable; Reducing the hygroscopic while; Also significantly shortened the dissolution time of product; Improved the solubility of product, its good solubility has guaranteed the curative effect of Sodium Valproate when clinical application and well security, has also reduced pain on injection significantly; Improved the compliance during the patient, made treatment obtain the good clinical effect.
Claims (10)
1. Sodium Valproate crystal form II; It is characterized in that: in this crystalline powder x ray diffration pattern x, located charateristic avsorption band angle of diffraction 2 θ=6.40 ° ± 0.1 °, 7.22 ° ± 0.1 °, 7.40 ° ± 0.1 °, 17.05 ° ± 0.1 °, 18.25 ° ± 0.1 °, 18.98 ° ± 0.1 °, 19.27 ° ± 0.1 °.
2. Sodium Valproate crystal form II according to claim 1 is characterized in that: in the crystallization differential scanning calorimetric analysis, at 91.21 ℃ ± 3 ℃, 143.01 ℃ ± 3 ℃ and 239.04 ℃ ± 3 ℃ endotherm(ic)peak is arranged.
3. Sodium Valproate crystal form II according to claim 1 and 2 is characterized in that: this crystalline powder x-ray diffraction is as shown in Figure 1.
4. the preparation method of any said Sodium Valproate crystal form II of claim 1-3, it comprises the steps:
Sodium Valproate is dissolved in the water,, starts freeze drier in-42 ℃～-30 ℃ after freezing 13～24 hours, vacuum-drying, whole drying process does not heat up to shelf, dry fully after, promptly get the Sodium Valproate crystal form II.
5. preparation method according to claim 4 is characterized in that: the amount ratio of Sodium Valproate and water is 1: (10～20) w/v; In-42 ℃～-30 ℃ after freezing 18～24 hours, dry again.
6. preparation method according to claim 5 is characterized in that: the amount ratio of Sodium Valproate and water is 1: (15～20) w/v; In-42 ℃～-40 ℃ after freezing 18～20 hours, dry again.
7. pharmaceutical composition, it is characterized in that: it contains any described Sodium Valproate crystal form II of claim 1-3.
8. pharmaceutical composition according to claim 7 is characterized in that: said pharmaceutical composition is oral prepns, injection formulations.
9. pharmaceutical composition according to claim 8 is characterized in that: described injection formulations is a powder injection.
10. any described Sodium Valproate crystal form II of claim 1-3 is in the purposes of preparation in the antiepileptic drug.
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| CN201210028838.2A CN102603510B (en) | 2011-02-25 | 2012-02-09 | Sodium valproate crystal form as well as preparation method and application thereof |
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| CN201110045689 | 2011-02-25 | ||
| CN201110045689.6 | 2011-02-25 | ||
| CN201210028838.2A CN102603510B (en) | 2011-02-25 | 2012-02-09 | Sodium valproate crystal form as well as preparation method and application thereof |
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| CN201210028529.5A Active CN102531878B (en) | 2011-02-25 | 2012-02-09 | Novel crystal form of sodium valproate, and preparation method and application thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105017007A (en) * | 2014-04-16 | 2015-11-04 | 四川科瑞德制药有限公司 | Sodium valproate compound |
| CN114853595A (en) * | 2022-06-01 | 2022-08-05 | 广州茂丰药业有限公司 | Preparation method of sodium valproate and valproic acid eutectic crystal and product thereof |
| CN114853595B (en) * | 2022-06-01 | 2024-04-26 | 广州茂丰药业有限公司 | Preparation method of sodium valproate and valproic acid eutectic and product thereof |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111349003B (en) * | 2018-12-20 | 2023-10-03 | 四川科瑞德制药股份有限公司 | Preparation method of sodium valproate |
| CN114685304B (en) * | 2020-12-28 | 2024-01-09 | 湖南省湘中制药有限公司 | Preparation of valproimide spherical crystal and application of valproimide spherical crystal in tablets |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102079699A (en) * | 2010-02-11 | 2011-06-01 | 成都科瑞德医药投资有限责任公司 | New crystal form for sodium valproate and preparation method and usage thereof |
| CN102241582A (en) * | 2010-05-10 | 2011-11-16 | 山东方明药业股份有限公司 | Synthesis technology of sodium valproate |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4988731A (en) * | 1979-08-20 | 1991-01-29 | Abbott Laboratories | Sodium hydrogen divalproate oligomer |
-
2012
- 2012-02-09 CN CN201210028838.2A patent/CN102603510B/en active Active
- 2012-02-09 CN CN201210028529.5A patent/CN102531878B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102079699A (en) * | 2010-02-11 | 2011-06-01 | 成都科瑞德医药投资有限责任公司 | New crystal form for sodium valproate and preparation method and usage thereof |
| CN102241582A (en) * | 2010-05-10 | 2011-11-16 | 山东方明药业股份有限公司 | Synthesis technology of sodium valproate |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105017007A (en) * | 2014-04-16 | 2015-11-04 | 四川科瑞德制药有限公司 | Sodium valproate compound |
| CN105017007B (en) * | 2014-04-16 | 2019-04-16 | 四川科瑞德制药股份有限公司 | A kind of sodium vedproate compound |
| CN114853595A (en) * | 2022-06-01 | 2022-08-05 | 广州茂丰药业有限公司 | Preparation method of sodium valproate and valproic acid eutectic crystal and product thereof |
| CN114853595B (en) * | 2022-06-01 | 2024-04-26 | 广州茂丰药业有限公司 | Preparation method of sodium valproate and valproic acid eutectic and product thereof |
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| CN102531878B (en) | 2014-08-20 |
| CN102531878A (en) | 2012-07-04 |
| CN102603510B (en) | 2014-04-23 |
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| CP03 | Change of name, title or address | ||
| CP03 | Change of name, title or address |
Address after: 646100 Industrial Park, Fu Zhen Town, Luzhou, Sichuan, Luxian County Patentee after: Luzhou kered Pharmaceutical Co.,Ltd. Address before: 646106 Industrial Park, Fu Zhen Town, Luzhou, Sichuan, Luxian County Patentee before: SICHUAN CREDIT CHEMWERTH PHARMACEUTICAL Co.,Ltd. |
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| CP03 | Change of name, title or address | ||
| CP03 | Change of name, title or address |
Address after: 646100 Industrial Park, Fu Zhen Town, Luzhou, Sichuan, Luxian County Patentee after: Sichuan Tiandao Pharmaceutical Co.,Ltd. Country or region after: China Address before: 646100 Industrial Park, Fu Zhen Town, Luzhou, Sichuan, Luxian County Patentee before: Luzhou kered Pharmaceutical Co.,Ltd. Country or region before: China |