CN105503973B - A kind of glucoside-containing component and its extraction separation method - Google Patents
A kind of glucoside-containing component and its extraction separation method Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/22—Cyclohexane rings, substituted by nitrogen atoms
- C07H15/222—Cyclohexane rings substituted by at least two nitrogen atoms
- C07H15/226—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings
- C07H15/234—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to non-adjacent ring carbon atoms of the cyclohexane rings, e.g. kanamycins, tobramycin, nebramycin, gentamicin A2
- C07H15/236—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to non-adjacent ring carbon atoms of the cyclohexane rings, e.g. kanamycins, tobramycin, nebramycin, gentamicin A2 a saccharide radical being substituted by an alkylamino radical in position 3 and by two substituents different from hydrogen in position 4, e.g. gentamicin complex, sisomicin, verdamycin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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Abstract
The present invention relates to a kind of glucoside-containing component and its extraction separation method, which is isolated from Etimicin Sulfate crude product, is named as 6, and " N ethyl Gentamicin C1as, the invention further relates to the separation methods of the glucoside-containing component.
Description
Technical field
The present invention relates to medicinal chemistry art, more particularly to a kind of new glucoside-containing component and its extraction separation side
Method.
Background technology
Glucoside-containing component (Aminoglycosides) is to be formed by connecting by amino sugar with aminocyclitol by oxygen bridge
Glycoside.Have the native aminos glycosides such as streptomysin from streptomycete etc., gentamicin from micromonospora, also according to for
The rice semi-synthetic aminoglycoside of magnitude, belongs to broad-spectrum antibiotic.
Aminoglycoside antibiotics mainly inhibits bacteria the effect of bacterium the synthesis of protein, and position is in cell
The A positions of the 16SrRNA area decoders of 30S ribosomal subunits.Research shows that such drug can influence bacterio protein synthesis
Overall process interferes the synthesis of initial composite object, Induction of bacterial resultant fault albumen and the release for suppressing synthetic proteins, so as to
Lead to bacterial death.
Aminoglycoside antibiotics is mainly used for the general infection caused by sensitive aerobic gram negative bacilli.Although in recent years
There are many cephalosporins and quinolones drugs in wide clinical application, but since aminoglycoside antibiotics is to copper
The PAE longer of the Common Gram-negative Bacillis such as green pseudomonad, pneumobacillus, Escherichia coli, so, being still used for treatment needs
Severe infections caused by oxygen gram negative bacilli, such as meningitis, respiratory tract, the urinary tract, skin soft tissue, gastrointestinal tract, burn, wound
Injure bone joint infection etc..
Etimicin Sulfate (Etimicin sulfate) is that China scientific research personnel voluntarily develops, and possesses independent intellectual production
Efficient, less toxic, antimicrobial agent the semi-synthetic aminoglycoside antibiotics of a new generation of power is that unique first class national new drug that obtains is demonstrate,proved
The anti-infectives of book.
Etimicin Sulfate parenteral solution is suitable for its sensitive Escherichia coli, Klebsiella pneumoniae, sand Lei Shi bars
Pseudomonas, citrobacter, Enterobacter, acinetobacter, Proteus, bloodthirsty Bacillus influenzae, Pseudomonas aeruginosa and grape ball
Various infection caused by bacterium etc..Clinical studies show this product has a better effect following infection：Respiratory tract infection：Such as acute branch
Tracheitis, acute exacerbation of chronic bronchitis, community's pulmonary infection etc..Kidney and urogenital infections：Such as acute renal plevis
Ephritis, cystitis, chronic pyelonephritis or chronic cystitis acute attack etc..Skin soft tissue and other infection：Such as skin and
Soft tissue infection, wound, the infection of wound and postpartum of performing the operation and the infection of other sensitive bacterias.
The preparation method of Etimicin Sulfate is described in Chinese patent 93112412.3, is mainly comprised the following steps：Pass through hair
Ferment prepares Gentamicin C1a, further prepares 3,2,6 ,-three-N- acetyl group Gentamicin C1as (P1) and 3, and 2,6 ,-three-N-
Acetyl group -1-N ethyls Gentamicin C1a (P2) finally obtains 1-N-EthagentamycinC1a (Etimicin), due to the party
Method by ferment obtain Gentamicin C1a contain impurity, also contain in the Etimicin Sulfate being further prepared there are many
Impurity, at present to these impurity research it is few, the present invention relative substance is studied, be found surprisingly that it is a kind of activity and
Toxicity is better than a kind of new compound of Etimicin, is found through In vitro Bactericidal Experiments, which is under normal concentration
Escherichia coli, Klebsiella pneumoniae, Serratia category, Citrobacter Freundii, Enterobacter, non-lever can effectively be killed
The Gram-negative bacterias such as Pseudomonas, Proteus, haemophilus influenzae, pseudomonas aeruginosa and staphylococcus etc..
Invention content
The purpose of the present invention is to further investigate glucoside-containing component, sensitive to it with its searching MRSA,
The low new aminoglycoside antibiotics of ear renal toxicity.
The present invention provides a kind of 6 "-N- ethyl Gentamicin C1a compounds or its pharmaceutically acceptable salt.
Wherein, 6 "-N- ethyls Gentamicin C1a structural formula of compound is as follows：
Pharmaceutically acceptable salt of the present invention is 6 "-N- ethyl Gentamicin C1a compounds and the salt of acid formation,
Including with inorganic acid hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, trifluoroacetic acid, benzoic acid, fumaric acid, ascorbic acid, methanesulfonic acid, to first
The salt of the formation such as benzene sulfonic acid routinely can prepare these acid-addition salts by method for transformation.
Formula (I) compound of the present invention may be used following preparation method and prepare：
Etimicin crude product prepared by the method for taking 93112412.3 embodiment 1-3 of Chinese patent, is dissolved in water, loading
YPR-II type macroporous resin columns, with a concentration of 8%, 12%, 16%, 20% ethanol water gradient elution, (expansion is known in TLC inspections
Agent：Chloroform-methanol-ammonium hydroxide, 1 ﹕, 1 ﹕ 1, takes subnatant), merge fraction, obtain impurity enriched fraction.Respectively by impurity enriched
Fraction concentrates, and freeze-drying obtains 10 grams of solid mixtures, takes 300 grams of 100-200 mesh silica gel, with silica gel column chromatography separation (Lv Fang ﹕
First alcohol ﹕ ammonium hydroxide (3 ﹕, 1 ﹕ 1, take subnatant) and preparation liquid phase purifying, obtain formula (I) compound of the present invention.
Through Analysis of Nuclear Magnetic Resonance, the 1H of formula of the invention (I) compound, 13C-NMR data such as following table.
The 1H of 1 compound of table (I), 13C NMR datas
1In H-NMR spectrums, δH5.05 (1H, d, 3.6Hz), 5.76 (1H, d, 3.6Hz) are respectively the terminal hydrogen of sugar, are prompted
Sugar there are two containing in the compound.δH2.88 (3H, s) be amino on substituent methyl proton signal, δH1.31 (3H, s) are then
One methyl proton signal being connected on quaternary carbon.
13In C-NMR spectrums, δ is shownC101.4 (C-1 '), 95.4 (C-1 ") are the end group carbon signal of sugar, prompt compound
Sugar there are two containing in structure；With document[1]The carbon modal data of middle micronomicin (6-N- methyl gentamicin) compares, δC 101.4
(C-1 '), 66.3 (C-2 '), 63.5 (C-3 '), 69.9 (C-4 '), 68.0 (C-5 '), 34.55 (C-6 '), 21.0 (C-7 ') can return
Belong to for C ring gulosamine segment carbon signals, δC95.4 (C-1 "), 49.7 (C-2 "), 25.7 (C-3 "), 20.5 (C-4 "), 74.4
(C-5 "), 50.2 (C-6 ") can be attributed to the deep red brown sugar amine segment carbon signal of A rings, δC48.5 (C-1), 27.9 (C-1), 48.8 (C-
1), 77.2 (C-1), 65.8 (C-1), 83.8 (C-1) are then B ring carbon signals.Further it was found that having more one group of δC 43.9
(C-7 "), 10.4 (C-8 "), has lacked δC36.1, the methyl in micronomicin on original C-6 amino is prompted to become ethyl,
Remainder by trifluoroacetic acid according to may be influenced, with document ratio to High-Field displacement about -2.5ppm.
The discovery of hydrogen modal data, δ are analyzed againH 4.20(1H,dd,11.0,3.8Hz),3.43(1H,d,10.7Hz),3.96
(1H, d, 12.8Hz, H-5 ' a), 3.58 (1H, d, 12.8Hz, H-5 ' b) be respectively garamine the positions of H-2 ', 3 ' and 5 ' proton
Signal, further analyzes its coupling constant, and the coupling constant of 3 ' position hydrogen of C rings is 10.7Hz, therefore the hydrogen of 2 ' and 3 ' positions is all in axial bond,
The coupling constant of 1 ' and 2 ' positions is 3.6,3.8Hz, therefore 1 ' position hydrogen is in horizontal key.On B rings the coupling constant of 4,5,6 hydrogen for 8.8,
10th, 8.8Hz illustrates the hydrogen of 1,3,4,5,6 on axial bond, consistent with the relative configuration of Gentamicin C1a[1].And it celebrates big
Mycin C1a is the initial feed for synthesizing Etimicin, and structure mutation in the reaction, impurity source is clear and definite.
Interpretation of mass spectra (ESI-MS)：
ESI-MSnDetermination data and analysis result：
ESI-MS：m/z 478.4[M+H]+；
ESI-MS2(478.4)：M/z 461,350,322,163.
The MS fragment pathways of compound (I)
Conclusion：Ion source is electrospray ionization mass spectrum, and the molecular ion that positive ion mode mainly provides sample adds hydrogen peak.Cation
The lytic pathway for the second order ms that pattern provides is shown in above formula.More than ESI-MS2Information, it was demonstrated that sample is with inferring that structure is consistent.
In summary NMR and ESI-MSnParsing, related compound identification are 6, and "-N- ethyl Gentamicin C1as are one new
Compound, compound (I) NMR and ESI-MSn spectrograms are shown in attached drawing.
Therefore, the compound of the present invention (I) is named as：6 "-N- ethyls Gentamicin C1a.
English name：6″-N-Ethylgentamicin C1a
Molecular formula：C21H43N5O7
Molecular weight：477
The present invention also provides contain salt medicine as active component acceptable in the compound of the present invention or its pharmacodynamics
Compositions.The weight ratio of the compounds of this invention that pharmaceutical composition contains in the composition is 0.01-99.9%, and drug can connect
The weight ratio of the carrier received in the composition is 0.01-99.9%.Pharmaceutical composition exists with suitable medicinal dosage form.Medicine
Preparation is tablet, sugar coated tablet, film coated tablet, enteric coated tablet, sustained-release tablet, capsule, hard capsule, soft capsule
Agent, Duracaps, oral liquid, mixture, mouth containing agent, granule, electuary, pill, powder, paste, sublimed preparation, suspension, solution
Agent, injection, powder-injection, freeze drying powder injection, suppository, ointment, emplastrum, creme, spray, aerosol, drops, patch.
The pharmaceutical composition of the present invention, as dosage form, the effective quantity of invention compound contained in every dose is
0.1mg-1000mg, described every dose refers to each preparation unit, such as every of tablet, every of capsule, also can refer to each taking
With dosage, such as each taking 100mg.
The pharmaceutical composition of the present invention is being prepared into pulvis, tablet, dispersible pulvis, capsule, cachet, suppository and ointment
During the solid or semisolid pharmaceutical preparation of form, solid carrier can be used.Workable solid carrier be preferably selected from diluent,
One or more substances in flavoring agent, solubilizer, lubricant, suspending agent, adhesive, swelling agent etc. can be encapsulating substance.
In powderous preparations, in the carrier containing 5% to 70% micronised active ingredient.Suitable solid carrier include magnesium carbonate,
Magnesium stearate, talcum powder, sucrose, lactose, pectin, dextrin, starch, gelatin, methylcellulose, sodium carboxymethylcellulose, low boiling
Point wax, cocoa butter etc..Since they are easy to be administered, tablet, pulvis, cachet and the best oral administration solid system of Capsules representative
Agent.
The liquid preparation of the present invention includes solution, suspension and lotion.For example, the ejection preparation of parenteral administration can be water
Or water-propylene glycol solution form, adjusting its isotonic degree, pH etc. makes the physiological condition for being suitable for live body.Liquid preparation may also be fabricated which
Solution form in polyethylene glycol, aqueous solution.Suitable colorant, tune can be added by the way that active constituent is dissolved in water
Taste agent, stabilizer and thickener, to prepare oral aqueous solution.It is for example natural the active constituent of micronized can be dispersed in stickum
It is suitable for oral aqueous suspensions with being prepared in rubber polymer, methylcellulose, sodium carboxymethylcellulose and other known suspending agent.
It is uniform for ease of administration and dosage, said medicine preparation is configured to dosage unit form and is particularly advantageous.
The dosage unit form of preparation refers to the physical separation unit for being suitable for single dose, and each unit, which contains, generates desired control
The active constituent of the predetermined amount calculated of therapeutic effect.This dosage unit form can be packaged form, such as tablet, capsule or dress
Pulvis in the tubule or bottle or ointment in pipe or bottle, gel or creme.
Although the amount of contained active constituent can change in dosage unit form, generally according to selected active constituent
Effect is adjusted in the range of 1-800mg.
When formula (I) compound of the present invention is used as the drug for the treatment of bacterium infection, dosage can be with the need of patient
Seriousness, selected compounds of the infection, to be treated etc. and change.Those skilled in the art can determine to be suitable for according to a conventional method
The preferred dose of certain situation.Generally, the amount for starting treatment is less than the optimal dose of active constituent, is then gradually increased to medicament
Amount, until reaching optimum therapeuticing effect.For convenience, total daily dose can be divided into several parts, score time administration.
Illustrate beneficial effects of the present invention below by way of experimental data.
1st, antibacterial activity test：
Formula (I) compound of the present invention and the antibacterial activity result of the test of Etimicin are as follows：
2nd, toxicity test：
Mouse and rat muscle injection LD50
It is compared with Etimicin Sulfate, the stronger toxicity of activity of the invention is lower.
3rd, in addition other glucoside-containing components similar with structure therewith have carried out antibacterial experiment comparison, and experiment is such as
Under：
Description of the drawings：
Fig. 1：The ESI-MS collection of illustrative plates of compound (I)
Fig. 2：Compound (I)1H-NMR amplifies collection of illustrative plates
Fig. 3：Compound (I)13C NMR amplify collection of illustrative plates
Specific embodiment：
It further illustrates the present invention by the following examples, but not as limitation of the present invention.
Embodiment 1
20 grams of the Etimicin crude product of prior art production is taken, 40ml is added to purify water dissolution, by aqueous solution along pillar
Wall slowly flows down, and loading YPR-II type macroporous resin columns are washed with a concentration of 8%, 12%, 16%, 20% ethanol water gradient
De-, (solvent is known in TLC inspections：Chloroform-methanol-ammonium hydroxide, 1 ﹕, 1 ﹕ 1, takes subnatant), merge fraction, obtain impurity enriched fraction.
Impurity enriched fraction is concentrated respectively, is lyophilized, is obtained 10 grams of solid mixtures, take 300 grams of 100-200 mesh silica gel, use silicagel column
Chromatography (imitate ﹕ first alcohol ﹕ ammonium hydroxide (3 ﹕, 1 ﹕ 1, take subnatant) and prepare liquid phase purifying, by the stream containing target compound by chlorine
Divide concentration, freeze-drying obtains 50mg faint yellow solid powdery products, and mass spectrum and nuclear-magnetism, which combine, determines target compound structure.
Embodiment 2, the preparation of hydrochloride：
20 grams of the Etimicin crude product of prior art production is taken, 40ml is added to purify water dissolution, by aqueous solution along pillar
Wall slowly flows down, and loading YPR-II type macroporous resin columns are washed with a concentration of 8%, 12%, 16%, 20% ethanol water gradient
De-, (solvent is known in TLC inspections：Chloroform-methanol-ammonium hydroxide, 1 ﹕, 1 ﹕ 1, takes subnatant), merge fraction, obtain impurity enriched fraction.
Impurity enriched fraction is concentrated respectively, is lyophilized, is obtained 10 grams of solid mixtures, take 300 grams of 100-200 mesh silica gel, use silicagel column
Chromatography (imitate ﹕ first alcohol ﹕ ammonium hydroxide (3 ﹕, 1 ﹕ 1, take subnatant) and prepare liquid phase purifying, by the stream containing target compound by chlorine
Divide concentration, freeze-drying obtains 50mg faint yellow solid powdery products, and mass spectrum and nuclear-magnetism, which combine, determines target compound structure.It takes
10ml purified water dissolved solid samples adjust PH to 4.0-5.0 with the hydrochloric acid of 10mol/L, add the activated carbon of 2%-5%,
60-80 DEG C of stirring is decolourized 30 minutes, and the HCl, solid to get the substance is lyophilized in filtering, filtrate.
Embodiment 3, the preparation of sulfate：
20 grams of the Etimicin crude product of prior art production is taken, 40ml is added to purify water dissolution, by aqueous solution along pillar
Wall slowly flows down, and loading YPR-II type macroporous resin columns are washed with a concentration of 8%, 12%, 16%, 20% ethanol water gradient
De-, (solvent is known in TLC inspections：Chloroform-methanol-ammonium hydroxide, 1 ﹕, 1 ﹕ 1, takes subnatant), merge fraction, obtain impurity enriched fraction.
Impurity enriched fraction is concentrated respectively, is lyophilized, is obtained 10 grams of solid mixtures, take 300 grams of 100-200 mesh silica gel, use silicagel column
Chromatography (imitate ﹕ first alcohol ﹕ ammonium hydroxide (3 ﹕, 1 ﹕ 1, take subnatant) and prepare liquid phase purifying, by the stream containing target compound by chlorine
Divide concentration, freeze-drying obtains 50mg faint yellow solid powdery products, and mass spectrum and nuclear-magnetism, which combine, determines target compound structure.It takes
10ml purified water dissolved solid samples adjust PH to 4.0-5.0 with the hydrochloric acid of 10mol/L, add the activated carbon of 2%-5%,
60-80 DEG C of stirring is decolourized 30 minutes, and the sulfate solid to get the substance is lyophilized in filtering, filtrate.
Embodiment 4, the preparation of tablet：
Take 5 to 20 parts of the sulfate solid of the substance or HCl, solid, add in 5 to 10 parts talcum powder or other, add
Enter 5 to 10 parts of sodium carboxymethylcelluloses, powder granulation, tabletting to obtain the final product.
Embodiment 5, the preparation of injection：
The sulfate solid or HCl, solid of the substance are taken, the 10-25 times of water for injection measured is added in, adds a ten thousandth extremely
5/1000ths activated carbon, stirring half an hour, filtering, with the embedding of 1ml, 2ml, 5ml or 10ml ampoule bottle, sterilizing, thus obtaining the product.
Claims (3)
1.6 "-N- ethyls Gentamicin C1a compound or the preparation method of its pharmaceutically acceptable salt, which is characterized in that warp
Cross following steps：Etimicin crude product is taken, with water dissolution, upper YPR-II types macroporous resin column, respectively with ethanol water gradient
Elution, TLC inspection know, merge fraction, obtain impurity enriched fraction, impurity enriched fraction detached with silica gel column chromatography, then with make
Standby liquid phase separation purifies, and obtains 6, and " compound and respective acids are prepared into salt by-N- ethyl Gentamicin C1as as needed.
2. preparation method as described in claim 1, which is characterized in that by following steps, take prior art production according to
For 20 grams of rice star crude product, 40ml is added to purify water dissolution, aqueous solution is slowly flowed down along pillar inner wall, loading YPR-II type macropore trees
Fat column, with a concentration of 8%, 12%, 16%, 20% ethanol water gradient elution, TLC inspections are known, solvent：Chloroform-methanol-ammonia
Water, 1 ﹕, 1 ﹕ 1 take subnatant, merge fraction, obtain impurity enriched fraction, respectively concentrate impurity enriched fraction, are lyophilized, obtain
To 10 grams of solid mixtures, 300 grams of 100-200 mesh silica gel is taken, is detached with silica gel column chromatography, Lv Fang ﹕ Jia Chun ﹕ ammonium hydroxide=3 ﹕, 1 ﹕ 1,
Subnatant is taken, liquid phase purifying is prepared, the fraction containing target compound is concentrated, freeze-drying obtains 200mg faint yellow solids
Powdery product, mass spectrum and nuclear-magnetism, which combine, determines structure, 200mg products is dissolved in 10ml purified waters, with the salt of 12mol/L
Acid for adjusting pH adds the activated carbon of 2%-5% to 4.0-5.0,60-80 DEG C of stirring decoloration 30 minutes, filtering, filtrate freeze-drying,
Up to the HCl, solid of the substance.
3. preparation method as described in claim 1, which is characterized in that the pharmaceutically acceptable salt is selected from and hydrochloric acid, hydrogen
The salt that bromic acid, phosphoric acid, sulfuric acid, trifluoroacetic acid, benzoic acid, fumaric acid, ascorbic acid, methanesulfonic acid, p-methyl benzenesulfonic acid are formed.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1100467A (en) * | 1993-04-23 | 1995-03-22 | 江苏省微生物研究所 | 1-N-ethyl gentamicin derivative and its preparing method |
| CN1557958A (en) * | 2004-02-12 | 2004-12-29 | 窦德献 | Gentamicin, preparation method and uses thereof |
| CN102443026A (en) * | 2011-10-26 | 2012-05-09 | 无锡济民可信山禾药业股份有限公司 | Aminoglycoside compounds and extraction and separation method therefor |
-
2015
- 2015-12-25 CN CN201510991925.1A patent/CN105503973B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1100467A (en) * | 1993-04-23 | 1995-03-22 | 江苏省微生物研究所 | 1-N-ethyl gentamicin derivative and its preparing method |
| CN1557958A (en) * | 2004-02-12 | 2004-12-29 | 窦德献 | Gentamicin, preparation method and uses thereof |
| CN102443026A (en) * | 2011-10-26 | 2012-05-09 | 无锡济民可信山禾药业股份有限公司 | Aminoglycoside compounds and extraction and separation method therefor |
Non-Patent Citations (2)
| Title |
|---|
| Isolation and structure characterization of related impurities in etimicin sulfate by LC/ESIMS and NMR.;Hao Wang, et al.,;《Journal of Pharmaceutical and Biomedical Analysis》;20110308;第55卷;第902–907页. * |
| 高效液相色谱-电喷雾-离子阱质谱法推定硫酸依替米星中有关物质的结构.;袁耀佐等，;《分析化学研究报告》;20100630;第38卷(第6期);第817-822页. * |
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| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB03 | Change of inventor or designer information | ||
| CB03 | Change of inventor or designer information |
Inventor after: Qiang Guangcan Inventor after: Mao Juhong Inventor before: Qiang Guangcan |
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| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CP03 | Change of name, title or address | ||
| CP03 | Change of name, title or address |
Address after: 214028 Changjiang South Road, new Wu District, Wuxi, Jiangsu Province, No. 12 Co-patentee after: Jiangxi Jinshuibao Pharmaceutical Co.,Ltd. Patentee after: Wuxi Jiyu Shanhe Pharmaceutical Co., Ltd Address before: 214028 No. 12 Changjiang South Road, New District, Jiangsu, Wuxi Co-patentee before: JIANGXI JIMINKEXIN JINSHUIBAO PHARMACEUTICAL Co.,Ltd. Patentee before: WUXI JIMIN KEXIN SHANHE PHARMACEUTICAL Co.,Ltd. |