CN104031032A - Esomeprazole sodium compound and medicine composition thereof - Google Patents
Esomeprazole sodium compound and medicine composition thereof Download PDFInfo
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- CN104031032A CN104031032A CN201410316155.6A CN201410316155A CN104031032A CN 104031032 A CN104031032 A CN 104031032A CN 201410316155 A CN201410316155 A CN 201410316155A CN 104031032 A CN104031032 A CN 104031032A
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- C07—ORGANIC CHEMISTRY
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention belongs to the field of medical chemistry and discloses an esomeprazole sodium compound and a medicine composition thereof. The composition is provided with a radial powder diffraction peak with the interplanar spacing being 21.23141 angstroms and the diffraction angle being 4.16 degrees. The esomeprazole sodium compound crystal obtained with the method has the advantages of being low in hygroscopicity and high in stability, and meets the medical requirement. The preparing technology is stable, the reproducibility is good, and large-scale industrial requirements are met.
Description
Technical field
the invention belongs to medical chemistry field, specifically, the pharmaceutical composition that relates to a kind of esomeprazole sodium compound and contain this compound.
Background technology
esomeprazole sodium (Esomeprazole sodium) (formula I compound) is a kind of novel proton pump inhibitor, can be diseases related in therapic acid, there is selectivity strongly inhibited helicobacter pylori (HP) effect., be mainly used in therapic acid diseases related, as peptide ulceration, gastro oesophageal reflux disease (GORD), Zhuo-Emhorn syndrome etc.
formula I
esomeprazole, by Astrazeneca AB's exploitation listing, is the S-optically active isomer of omeprazole, is global first isomer proton pump inhibitor (PPI), suppresses parietal cell proton pump reduce gastric acid secretion by specificity.Through a large amount of clinical experiments and drug research, confirm: its time that maintains pH>4 in stomach is longer, presses down sour efficiency higher, and curative effect is better than front two generation PPI, and individual difference is little.As PPI of new generation, the many acid related disorders of clinical treatment have now been widely used in.
injection esomeprazole press down sour ability compared with other injections PPI sooner, more effective.Dirk etc. give healthy volunteer's 40 mg esomeprazoles or 40 mg pantoprazole single dose intravenous injections, then monitoring continuously pH in stomach finds, after two groups of medications, the time length of first 6 hours pH>4 is respectively 3.4 and 2.1 hours, and within 24 hours, respective value is respectively 11.8 and 7.2 hours.Research shows, under Isodose, repeat intravenous drip esomeprazole compared with pantoprazole gastric acid inhibitory sooner, more effective.Recently research also shows, under Isodose, the effect that intravenous applications esomeprazole suppresses gastric acid secretion under base state and stimulation state compared with omeprazole sooner, more complete.
form J, K, L, M, the N of Esomeprazole sodium are disclosed; In addition, WO2007031845, WO2009047775, CN200980126581.0, CN201110224730.6, CN201110401306.4, CN201210103806.4, CN201210458464.8 etc. disclose a plurality of crystal formations and the preparation method of Esomeprazole sodium.
in prior art, disclose the multiple crystal formation of Esomeprazole sodium, but Esomeprazole sodium less stable also has stronger water absorbability, thereby affect final preparation security, validity; Therefore, need to find the new crystal of the esomeprazole sodium compound that performance is more superior.
Summary of the invention
the new crystal that the object of this invention is to provide a kind of esomeprazole sodium compound the invention also discloses the preparation method of this new crystal simultaneously, and the pharmaceutical composition that contains this crystal formation.
the formation of drug crystal forms has more multifactor, and different solvents, the differing temps crystal formation that even crystallization obtains in different vessels all may be completely different.Those skilled in the art have unexpectedly obtained a kind of new crystal of esomeprazole sodium compound by great many of experiments, new crystal have draw moist low, the feature that stability is high.
the present invention is achieved through the following technical solutions:
the invention provides a kind of esomeprazole sodium compound, its structural formula is suc as formula shown in I:
formula I
described esomeprazole sodium compound is crystalline form, and further, described esomeprazole sodium compound is the crystalline form of Esomeprazole sodium dihydrate.
according to the present invention, the X-ray powder diffraction of described crystal formation has characteristic peak at 21.2314 dust places, and diffraction angle is 4.16 degree.
preferably, the X-ray powder diffraction peak relative intensity of described crystal formation is greater than in 20% diffraction peak, and only at spacing 21.2314 dusts, diffraction angle is the First Characteristic peak of 4.16 degree.
preferably, in peak relative intensity is greater than 10% diffraction peak, in spacing, there is characteristic peak at 21.2314,10.6660,2.8147 dust places, and its corresponding diffraction angle is respectively 4.16 degree, 8.28 degree, 31.77 degree.
further, in peak relative intensity is greater than 5% diffraction peak, in spacing, there is characteristic peak at 21.2314,10.6660,2.8147,16.4208,4.8873,3.5675 dust places.Its corresponding diffraction angle is respectively 4.16 degree, 8.28 degree, 31.77 degree, 5.38 degree, 18.14 degree, 24.94 degree.
further, described X-ray powder diffraction, except peak relative intensity is greater than 5% diffraction peak, also at spacing 12.5748,10.0222,9.4844,8.2439,7.1027,5.6412,3.8015,3.7417,3.5006,3.0120 dust places, have characteristic peak, its diffraction angle is 7.02 degree, 8.82 degree, 9.32 degree, 10.72 degree, 12.45 degree, 15.70 degree, 23.38 degree, 23.76 degree, 25.42 degree, 29.64 degree.
spacing described above also can be expressed as d value.
further preferably, described esomeprazole sodium compound, has X-ray powder diffraction pattern substantially as shown in Figure 1.In Fig. 1,2 θ, d value and relative intensity data are as shown in table 1.
table 1
the new crystal of esomeprazole sodium compound provided by the invention, after vacuum-drying, is measured through K-F method, and moisture content is about 8.9%, is equivalent to containing having an appointment 2 crystal water.
the DSC collection of illustrative plates of the new crystal of esomeprazole sodium compound provided by the invention and TG collection of illustrative plates show: the endotherm(ic)peak of 76 ℃ of left and right produces for sloughing solvent, the exothermic peak of 182 ℃ of left and right shows that brilliant phenomenon has occurred to turn for it, and the larger exothermic peak of last 240 ℃ of left and right is to show that it decomposes near this temperature.
the present invention also provides a kind of method of preparing the new crystal of described esomeprazole sodium compound, Esomeprazole sodium is soluble in water, second acid for adjusting pH, to 7-8, adds toluene extraction, standing, layering, get organic layer, to organic layer, add ethanol and the NaOH aqueous solution, stirring and crystallizing, filtration drying, obtains the aforesaid Esomeprazole sodium dihydrochloride dihydrate crystal of the present invention.
preferably, the preparation method of esomeprazole sodium novel crystal form described above is, 4g Esomeprazole sodium is dissolved in to 17mL purified water, add 27ml toluene, with separatory after acetic acid adjusting pH7-8,10ml saturated common salt water washing 1 time for organic layer, again by organic layer with filtering after anhydrous sodium sulfate drying, filtrate adds 2.4ml ethanol and the 1g 50%NaOH aqueous solution, and 10 ℃ of stirrings are spent the night, and obtain crystalline compounds.
the present invention also provides a kind of pharmaceutical composition, it is characterized in that, described composition comprises esomeprazole sodium novel crystal form of the present invention or makes with esomeprazole sodium compound new crystal of the present invention.
preferably, the dosage form of described composition can be enteric coated capsule, orally disintegrating tablet or injection.
according to the present invention, described composition also comprises pharmaceutically acceptable carrier.Pharmaceutically acceptable carrier normally those of ordinary skills can be according to concrete form of medication and concrete select.Available well known technology is manufactured pharmaceutical composition of the present invention as techniques such as conventional granulation, mixing, dissolving, formation capsule, freeze-drying.The present composition can be made to the form for various route of administration, for example, oral administration, intravenously etc.
esomeprazole sodium compound new crystal provided by the invention can be prepared into and be suitable for medicinal pharmaceutical composition according to prior art.Prior art is as commercially available injection Esomeprazole sodium (AstraZeneca pharmaceutical Co. Ltd, trade(brand)name: resistance to letter).
the invention provides a kind of pharmaceutical composition that contains above-mentioned Esomeprazole sodium crystalline compounds.Preferably, in described pharmaceutical composition, contain N.F,USP MANNITOL, Zonon D.More preferably, in described composition, the mass ratio of Esomeprazole sodium, N.F,USP MANNITOL and Zonon D is 2:(4 ~ 6): (0.1 ~ 0.2); Be most preferably 2:5:0.15.
aforementioned pharmaceutical compositions is preferably freeze-dried preparation, when pharmaceutical composition is freeze-dried preparation, in described pharmaceutical composition, also contain sodium hydroxide, the amount of described sodium hydroxide is for when described in use water dissolution during pharmaceutical composition, when esomeprazole na concn is 20mg/mL, pH value of solution is 10.0 ~ 12.0.
the present invention to the crystal formation of the esomeprazole sodium compound obtaining from drawing the investigation of the aspects such as moist and stability.According to 2010 editions two appendix XIX J of < < Chinese Pharmacopoeia > >, esomeprazole sodium compound new crystal provided by the invention draws and is moistly about 1%, moist for slightly drawing.Permanent stability and accelerated stability test show that described stable crystal form is effective, and moisture and active substance are without noticeable change, total assorted without significantly increasing.
the application of the crystal formation that the present invention also provides described esomeprazole sodium compound in preparing the medicine of proton pump inhibitor.Preferably, be mainly used in the treatment of stomach ulcer, duodenal ulcer, reflux esophagitis, Zollinger-Ellison Syndrome (Zollinger-Ellison syndrome), stoma ulcer.
the crystal formation of esomeprazole sodium compound provided by the invention all meets medicinal requirement at aspects such as drawing moist and stability.The stable preparation process of the crystal formation of esomeprazole sodium compound provided by the invention, favorable reproducibility, meets the requirement of industrialized production.
Accompanying drawing explanation
fig. 1: embodiment 1 makes the X-ray powder diffraction pattern of Esomeprazole sodium type.
fig. 2: embodiment 1 makes the DSC figure of Esomeprazole sodium type.
fig. 3: embodiment 1 makes the TG figure of Esomeprazole sodium type.
Embodiment
mode below by embodiment further illustrates the present invention, but following embodiment is not limiting the scope of the invention, and the improvement that those skilled in the art make on basis of the present invention and polishing should be within protection scope of the present invention.
embodiment 1
under room temperature, get Esomeprazole sodium 4g, add purified water 17mL to dissolve, add toluene 27ml, with acetic acid, regulate after pH7-8, standing, layering, gets organic layer.Saturated aqueous common salt for organic layer (10ml) washing 1 time, again by organic layer with filtering after anhydrous sodium sulfate drying, filtrate adds 2.4ml ethanol and the 1g 50%NaOH aqueous solution, 10-20 ℃ of stirring and crystallizing, filter, 30 ℃ of vacuum-drying 2-4h obtain 2.5g crystalline compounds.X-ray powder diffraction, DSC collection of illustrative plates, TG collection of illustrative plates are respectively as shown in accompanying drawing 1, Fig. 2, Fig. 3.
embodiment 2
according to the method for embodiment 1, obtain crystal formation, its water content of sampling and measuring, and draw moist experiment.
water content detection method, with reference to K-F method, is drawn moist detection with reference to 2010 editions two appendix XIX J of < < Chinese Pharmacopoeia > >.
detected result is as follows:
water content: 8.95%, be equivalent to 2 crystal water.
draw moist: 1%.
embodiment 3
according to the method for embodiment 1, prepare esomeprazole sodium crystal, sampling, at 30 ℃, RH(relative humidity) under 60% environment, and 2 ~ 8 ℃, under the natural environmental condition of RH25%, carry out respectively accelerated test and test of long duration, stability is investigated, test-results respectively in Table 2, table 3.
table 2 accelerated test (30
o
c, RH 60%)
| The setting-out time | Outward appearance | Total assorted % | Content % |
| 0M | White powder | 0.08 | 99.9 |
| 1M | White powder | 0.11 | 99.9 |
| 2M | White powder | 0.14 | 99.9 |
| 3M | White powder | 0.16 | 99.8 |
| 6M | Off-white powder | 0.20 | 99.8 |
table 3 test of long duration (2 ~ 8
o
c)
| The setting-out time | Outward appearance | Total assorted % | Content % |
| 0M | White powder | 0.08 | 99.9 |
| 3M | White powder | 0.11 | 99.9 |
| 6M | White powder | 0.16 | 99.8 |
| 9M | White powder | 0.21 | 99.8 |
| 12M | White powder | 0.24 | 99.8 |
from study on the stability result, the stable crystal form that the present invention obtains is effective, is applicable to pharmaceutical applications.
Claims (10)
1. an esomeprazole sodium compound, its structural formula is suc as formula shown in I,
Formula I
It is characterized in that, the crystalline form that described esomeprazole sodium compound is dihydrate, it is 21.2314 dusts that its X-ray powder diffraction pattern comprises spacing, diffraction angle is the First Characteristic peak of 4.16 degree.
2. esomeprazole sodium compound according to claim 1, is characterized in that, in the X-ray powder diffraction pattern of described compound crystal, also comprising spacing is 10.6660 dusts, and diffraction angle is the Second Characteristic peak of 8.28 degree; And spacing is 2.8147 dusts, diffraction angle is the 3rd characteristic peak of 31.77 degree.
3. Esomeprazole according to claim 2 is received compound, it is characterized in that, in the X-ray powder diffraction pattern of described compound crystal, also comprising spacing is 16.4208 dusts, diffraction angle is the 4th characteristic peak of 5.38 degree, spacing is 4.8873 dusts, diffraction angle is the 5th characteristic peak of 18.14 degree, and spacing is 3.5675 dusts, and diffraction angle is the 6th characteristic peak of 24.94 degree.
4. esomeprazole sodium compound according to claim 3, it is characterized in that, it is 12.5748 dusts that the X-ray powder diffraction pattern of described compound crystal also comprises spacing, diffraction angle is the 7th characteristic peak of 7.02 degree, spacing is 10.0222 dusts, diffraction angle is the 8th characteristic peak of 8.82 degree, spacing is 9.4844 dusts, diffraction angle is the 9th characteristic peak of 9.32 degree, spacing is 8.2439 dusts, diffraction angle is the tenth characteristic peak of 10.72 degree, spacing is 7.1027 dusts, diffraction angle is the 11 characteristic peak of 12.45 degree, spacing is 5.6412 dusts, diffraction angle is the 12 characteristic peak of 15.70 degree, spacing is 3.8015 dusts, diffraction angle is the 13 characteristic peak of 23.38 degree, spacing is 3.7417, diffraction angle is the 14 characteristic peak of 23.76 degree, spacing is 3.5006, diffraction angle is the 15 characteristic peak of 25.42 degree, spacing is 3.0120 dusts, diffraction angle is the 16 characteristic peak of 29.64 degree.
5. according to the esomeprazole sodium compound described in any one in claim 1-4, it is characterized in that, described compound is the crystalline form of Esomeprazole sodium dihydrate, prepares by the following method:
Esomeprazole sodium is soluble in water, and second acid for adjusting pH, to 7-8, adds toluene extraction, standing, layering; Get organic layer, to organic layer, add ethanol and the NaOH aqueous solution, after stirring and crystallizing, filtration drying.
6. a pharmaceutical composition that contains the esomeprazole sodium compound described in any one in claim 1 ~ 5.
7. pharmaceutical composition according to claim 6, is characterized in that, described pharmaceutical composition is containing esomeprazole sodium compound, N.F,USP MANNITOL and Zonon D;
Wherein the mass ratio of esomeprazole sodium compound, N.F,USP MANNITOL and Zonon D is 2:(4 ~ 6): (0.1 ~ 0.2), is preferably 2:5:0.15.
8. pharmaceutical composition according to claim 7, is characterized in that, described pharmaceutical composition is freeze-dried preparation.
9. pharmaceutical composition according to claim 8, it is characterized in that, also contain sodium hydroxide in described composition, the amount of described sodium hydroxide is for when described in use water dissolution during freeze-dried preparation, when Esomeprazole sodium is when in the aqueous solution, concentration is 20mg/mL, pH value of solution is 11.5 ~ 12.0.
10. the application in preparing proton pump inhibitor medicine according to the esomeprazole sodium compound described in any one in claim 1 ~ 5.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105669648A (en) * | 2014-11-21 | 2016-06-15 | 北大方正集团有限公司 | Preparation method of high-purity esomeprazole sodium |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070259921A1 (en) * | 2006-05-04 | 2007-11-08 | Vijayabhaskar Bolugoddu | Polymorphic forms of esomeprazole sodium |
| CN102321071A (en) * | 2011-07-20 | 2012-01-18 | 江苏奥赛康药业股份有限公司 | Industrial production method of high-purity esomeprazole sodium |
| CN102746272A (en) * | 2012-04-11 | 2012-10-24 | 江苏奥赛康药业股份有限公司 | Esomeprazole sodium polymorph, preparation method and application thereof |
| CN103121992A (en) * | 2004-06-24 | 2013-05-29 | 阿斯利康(瑞典)有限公司 | New process for the preparation of crystal modifications for use in the preparation of esomeprazole sodium salt |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103121992A (en) * | 2004-06-24 | 2013-05-29 | 阿斯利康(瑞典)有限公司 | New process for the preparation of crystal modifications for use in the preparation of esomeprazole sodium salt |
| US20070259921A1 (en) * | 2006-05-04 | 2007-11-08 | Vijayabhaskar Bolugoddu | Polymorphic forms of esomeprazole sodium |
| CN102321071A (en) * | 2011-07-20 | 2012-01-18 | 江苏奥赛康药业股份有限公司 | Industrial production method of high-purity esomeprazole sodium |
| CN102746272A (en) * | 2012-04-11 | 2012-10-24 | 江苏奥赛康药业股份有限公司 | Esomeprazole sodium polymorph, preparation method and application thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105669648A (en) * | 2014-11-21 | 2016-06-15 | 北大方正集团有限公司 | Preparation method of high-purity esomeprazole sodium |
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Application publication date: 20140910 Assignee: Nanjing Hairun Pharmaceutical Co. Ltd. Assignor: Jiangsu Aosaikang Pharmaceutical Co., Ltd. Contract record no.: 2017320000132 Denomination of invention: Esomeprazole sodium compound and medicine composition thereof Granted publication date: 20160427 License type: Exclusive License Record date: 20170522 |
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Address after: 211112 Jiangsu Province, Nanjing City, Jiangning Science Park Road No. 699 Patentee after: Jiangsu Aosaikang Pharmaceutical Co., Ltd. Address before: 211112 Jiangsu Province, Nanjing City, Jiangning Science Park Road No. 699 Patentee before: Jiangsu Aosaikang Pharmaceutical Co., Ltd. |