CN103804184B - The crystal formation of arginine ketoprofenate and preparation method - Google Patents
The crystal formation of arginine ketoprofenate and preparation method Download PDFInfo
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- CN103804184B CN103804184B CN201410051053.6A CN201410051053A CN103804184B CN 103804184 B CN103804184 B CN 103804184B CN 201410051053 A CN201410051053 A CN 201410051053A CN 103804184 B CN103804184 B CN 103804184B
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- arginine
- ketoprofenate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
- C07C59/84—Unsaturated compounds containing keto groups containing six membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
- C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
Abstract
The invention provides a kind of new crystal and preparation method of arginine ketoprofenate, specifically, provide a kind of arginine ketoprofenate crystal form A.Under nitrogen protection; successively Ketoprofen and arginine are joined in solvent; be heated to reaction solution clarification; stop heating; crystallization after slow cooling; namely leaching crystal obtains arginine ketoprofenate crystal form A, and wherein said solvent is made up of first alcohol and solvent B, and described solvent B to be selected from Virahol, ethylene glycol, ether, sherwood oil, hexanaphthene, methylene dichloride, trichloromethane, acetone, ethyl acetate and tetrahydrofuran (THF) one or more.Arginine ketoprofenate crystal form A of the present invention has good solubility and stability, is obviously better than existing arginine ketoprofenate solid.
Description
Technical field
The invention provides a kind of new crystal of arginine ketoprofenate, relate to pharmaceutical technology sectors.
Background technology
Arginine ketoprofenate is Ketoprofen arginic acid salt, has anti-inflammatory, analgesic activity.Arginine ketoprofenate not only maintains the drug effect of Ketoprofen, and change that it is water insoluble, make it have very outstanding water-soluble, it is made to make powder injection, improve drug effect, reduce dosage, reduce GI hormesis, add route of administration, expand the clinical application of Ketoprofen.
Disclosed in CN1376670A, the production technique of arginine ketoprofenate mainly adopts lyophilization, in reaction flask, add Ketoprofen successively, L-arginine and distilled water, stir to clarify, temperature-gradient method vacuum lyophilization from-40 degrees Celsius, obtains white solid arginine ketoprofenate.Its shortcoming is: 1, and the temperature of freeze-drying is too low, and vacuum level requirements is high, high to the requirement of equipment, increases production cost; 2, the product that lyophilization obtains, owing to not having purge process in production process, can make impurity pile up in the product, and product porous, and color is partially dark, has ferocious water absorbability; 3, batch output that lyophilization is produced is less, is not suitable for suitability for industrialized production.
CN101935293A discloses a kind of method preparing arginine ketoprofenate, is aseptically, is dissolved in by Ketoprofen in ethanolic soln, adds arginine powder after heating, reacts to solution clarification, obtains arginine ketoprofenate after decrease temperature crystalline.The method feeds intake complexity, adds arginine powder in a heated state, there is the possibility of unexpected bumping, have certain potential safety hazard.
The arginine ketoprofenate production technique of prior art, there is certain problem in obtained arginine ketoprofenate stability, is unfavorable for arginine ketoprofenate Clinical practice.Therefore a kind of method preparing stable arginine ketoprofenate is provided to be very necessary.
Summary of the invention
For solving the problems of the technologies described above, the invention provides a kind of method preparing stable arginine ketoprofenate, and obtain a kind of new arginine ketoprofenate crystal formation, described arginine ketoprofenate new crystal is called arginine ketoprofenate crystal form A, the present invention surprisingly this crystal form A except have good water-soluble except, also there is excellent stability.Present invention also offers the production technique of this stable arginine ketoprofenate new crystal.
Technical solution of the present invention is as follows:
The invention provides a kind of arginine ketoprofenate crystal form A, it is characterized in that, in the X-ray powder diffraction of described crystal form A, 2 θ characteristic peaks are 5.26 ± 0.1 °, 11.55 ± 0.1 °, 11.88 ± 0.1 °, 13.04 ± 0.1 °, 15.86 ± 0.1 °, 19.12 ± 0.1 °, 20.08 ± 0.1 °, 20.40 ± 0.1 °, 21.34 ± 0.1 °, 22.42 ± 0.1 °, 23.22 ± 0.1 °, 24.00 ± 0.1 °, 24.62 ± 0.1 °, 27.4 ± 0.1 °, 32.42 ± 0.1 °, 34.48 ± 0.1 °.
Present invention also offers the method for arginine ketoprofenate crystal form A described above; it is characterized in that comprising the steps: under nitrogen protection; successively Ketoprofen and arginine are joined in solvent; be heated to reaction solution clarification; stop heating; crystallization after slow cooling; leaching crystal and get final product; wherein said solvent is made up of first alcohol and solvent B, and described solvent B to be selected from Virahol, ethylene glycol, ether, sherwood oil, hexanaphthene, methylene dichloride, trichloromethane, acetone, ethyl acetate and tetrahydrofuran (THF) one or more.
Wherein, method described above, wherein said solvent B is preferably Virahol, sherwood oil, methylene dichloride, acetone or ethyl acetate.
Preferably, the method that the present invention is described above, wherein said solvent is by first alcohol and solvent B 1:(1 ~ 3 by volume) form, particular methanol and solvent B 4:6 by volume.
Preferably, in the method that the present invention is described above, the consumption of wherein said solvent and Ketoprofen weight ratio are 2 ~ 6:1, are preferably 3:1.
Preferably, in the method that the present invention is described above, wherein Ketoprofen and arginine mol ratio are 1 ~ 1.1:1, are preferably 1:1.
Preferably, in the method that the present invention is described above, the temperature wherein heated is 40 ~ 80 degrees Celsius, is preferably 60 degrees Celsius.
Preferably, in the method that the present invention is described above, wherein recrystallization temperature keeps 0 to room temperature, is preferably room temperature.
Preferably, in the method that the present invention is described above, the time of wherein reacting heating is 0.5-3 hour, is preferably 1 hour.
Preferably, in the method that the present invention is described above, wherein temperature fall time is 2-4 hour, is preferably 4 hours.
Preferably, in the method that the present invention is described above, the crystal of the arginine ketoprofenate crystal form A of wherein separating out, after leaching, through vacuum-drying, preferred vacuum drying vacuum tightness is 400-1000Pa, and drying temperature is 40-50 degree Celsius, and time of drying is 5-7 hour.
Present invention also offers a kind of pharmaceutical composition, it is made up of arginine ketoprofenate crystal form A described above and pharmaceutically acceptable carrier, and this pharmaceutical composition contains the arginine ketoprofenate crystal form A of significant quantity, such as, containing arginine ketoprofenate crystal form A in unit formulation is 0.01 ~ 500 milligram, wherein preferably comprises 0.01,0.05,0.1,0.5,1.0,2.5,5.0,10.0,15.0,25.0,50.0,100,200,500 milligrams etc.Described carrier is not particularly limited, and can need the auxiliary material or the carrier that use pharmaceutics routine, wherein comprise lactose, starch, sucrose according to formulation, glucose, methylcellulose gum, Magnesium Stearate, Si Liaodengji dicalcium phosphate feed grade, calcium sulfate, N.F,USP MANNITOL, Sorbitol Powder, ethanol, glycerine, water etc.The formulation of pharmaceutical composition of the present invention is not particularly limited, such as, can be tablet, pill, capsule, powder, particle, sterile solution or suspension, metered aerosol or fluid spray agent, and drops, peace is cutd open, from injection or suppository etc.
The arginine ketoprofenate crystal form A that the present invention is described above, maintains the drug effect of Ketoprofen, has anti-inflammatory, analgesic activity, can be prepared into anti-inflammatory or analgesic.
In the method that the present invention is described above, wherein said Ketoprofen is left-handed Ketoprofen, dexketoprofen or racemic ketoprofen ibuprofen; Described arginine is L-arginine, D-Arg or DL-arginine.
The crystalline structure of arginine ketoprofenate crystal form A of the present invention is different from the obtained arginine ketoprofenate of CN1376670A.In X-ray powder diffraction, the arginine ketoprofenate crystal form A obtained by the present invention has obvious characteristic peak, and the arginine ketoprofenate obtained by CN1376670A is without characteristic peak, shows it for amorphous solid.
The crystalline structure of arginine ketoprofenate crystal form A of the present invention is also different from the obtained arginine ketoprofenate of CN101935293A.In X-ray powder diffraction, there is obvious difference in the two, and have diverse 2 θ characteristic peaks, both explanations are diverse crystal formations.
Arginine ketoprofenate crystal form A of the present invention very easily dissolves in water and methyl alcohol, suitable with the arginine ketoprofenate solvability obtained by CN1376670A and CN101935293A.
Moist test is drawn according to 2010 editions pharmacopeia, measure the obtained arginine ketoprofenate crystal form A of the embodiment of the present invention 1, arginine ketoprofenate that CN1376670A obtains and the arginine ketoprofenate that CN101935293A obtains draw moist, result arginine ketoprofenate of the present invention crystal form A draws wet weightening finish 0.9%, moist for slightly drawing, the arginine ketoprofenate being obviously better than CN101935293A obtained (draws wet weightening finish 4.1%, performance have draw moist) and CN1376670A obtained by arginine ketoprofenate (draw wet weightening finish 20%, show very easily draw moist).
Accompanying drawing explanation
Fig. 1: the X-ray powder diffraction figure of the arginine ketoprofenate crystal form A that embodiment 1 is obtained
The X-ray powder diffraction figure of Fig. 2: the CN1376670A arginine ketoprofenate obtained
The X-ray powder diffraction figure of Fig. 3: the CN101935293A arginine ketoprofenate obtained
Embodiment
Further illustrate the present invention below in conjunction with specific embodiment, but be not used for limiting the scope of the invention.Embodiment 1
Under nitrogen protection, successively by 25.43g Ketoprofen (0.1mol), 17.42g arginine joins (volume ratio is 4:6) in 76.2ml methanol/isopropanol solution; open and stir, be heated to 60 degrees Celsius, 1 as a child reaction solution change clarification; stop heating, be slow cooling to 24 degrees Celsius, temperature fall time is 4 hours; stirring and crystallizing 24 hours; filter, filter cake is at 50 degrees Celsius, and vacuum tightness is 400Pa; under condition, vacuum-drying 7 hours.Obtain arginine ketoprofenate solid 37.83g, yield is 88.28%.
Embodiment 2
Under nitrogen protection, successively by 25.43g Ketoprofen (0.1mol), 17.42g arginine joins (volume ratio is 4:6) in 76.2ml methyl alcohol/petroleum ether solution; open and stir, be heated to 60 degrees Celsius, 1 as a child reaction solution change clarification; stop heating, be slow cooling to 24 degrees Celsius, temperature fall time is 4 hours; stirring and crystallizing 24 hours; filter, filter cake is at 50 degrees Celsius, and vacuum tightness is 400Pa; under condition, vacuum-drying 7 hours.Obtain arginine ketoprofenate solid 34.55g, yield is 80.63%.
Embodiment 3
Under nitrogen protection, successively by 25.43g Ketoprofen (0.1mol), 17.42g arginine joins (volume ratio is 4:6) in 76.2ml methanol/dichloromethane solution; open and stir, be heated to 60 degrees Celsius, 1 as a child reaction solution change clarification; stop heating, be slow cooling to 24 degrees Celsius, temperature fall time is 4 hours; stirring and crystallizing 24 hours; filter, filter cake is at 50 degrees Celsius, and vacuum tightness is 400Pa; under condition, vacuum-drying 7 hours.Obtain arginine ketoprofenate solid 30.72g, yield is 71.69%.
Embodiment 4
Under nitrogen protection, successively by 25.43g Ketoprofen (0.1mol), 17.42g arginine joins (volume ratio is 4:6) in 76.2ml methanol/acetone solution; open and stir, be heated to 60 degrees Celsius, 1 as a child reaction solution change clarification; stop heating, be slow cooling to 24 degrees Celsius, temperature fall time is 4 hours; stirring and crystallizing 24 hours; filter, filter cake is at 50 degrees Celsius, and vacuum tightness is 400Pa; under condition, vacuum-drying 7 hours.Obtain arginine ketoprofenate solid 32.62g, yield is 76.13%.
Embodiment 5
Under nitrogen protection, successively by 25.43g Ketoprofen (0.1mol), 17.42g arginine joins (volume ratio is 4:6) in 76.2ml methanol/ethyl acetate solution; open and stir, be heated to 60 degrees Celsius, 1 as a child reaction solution change clarification; stop heating, be slow cooling to 24 degrees Celsius, temperature fall time is 4 hours; stirring and crystallizing 24 hours; filter, filter cake is at 50 degrees Celsius, and vacuum tightness is 400Pa; under condition, vacuum-drying 7 hours.Obtain arginine ketoprofenate solid 32.77g, yield is 76.48%.
Reference examples:
Under nitrogen protection, successively by 25.43g Ketoprofen (0.1mol), 17.42g arginine joins in 50.8ml methyl alcohol; open and stir, be heated to 60 degrees Celsius, 1 as a child reaction solution change clarification; stop heating, be slow cooling to 24 degrees Celsius, temperature fall time is 4 hours; add crystal seed, stirring and crystallizing 48 hours, filter; filter cake is at 50 degrees Celsius; vacuum tightness is 400Pa, under condition, and vacuum-drying 7 hours.Obtain arginine ketoprofenate solid 5.44g, yield is 12.70%.
The arginine ketoprofenate solid phase prod that above embodiment 2-5 and reference examples obtain, X-ray powder diffraction after measured, all has 2 θ characteristic peaks in X-ray powder diffraction as identical in embodiment 1, is obtained for identical arginine ketoprofenate crystal form A.
Claims (12)
1. an arginine ketoprofenate crystal form A, is characterized in that, in the X-ray powder diffraction of described crystal form A, 2 θ characteristic peaks are 5.26 ± 0.1 °, 11.55 ± 0.1 °, 11.88 ± 0.1 °, 13.04 ± 0.1 °, 15.86 ± 0.1 °, 19.12 ± 0.1 °, 20.08 ± 0.1 °, 20.40 ± 0.1 °, 21.34 ± 0.1 °, 22.42 ± 0.1 °, 23.22 ± 0.1 °, 24.00 ± 0.1 °, 24.62 ± 0.1 °, 27.4 ± 0.1 °, 32.42 ± 0.1 °, 34.48 ± 0.1 °.
2. prepare the method for arginine ketoprofenate crystal form A according to claim 1 for one kind; it is characterized in that comprising the steps: under nitrogen protection; successively Ketoprofen and arginine are joined in solvent; be heated to reaction solution clarification; stop heating; crystallization after slow cooling; leaching crystal and get final product; wherein said solvent is made up of first alcohol and solvent B, and described solvent B to be selected from Virahol, ethylene glycol, ether, sherwood oil, hexanaphthene, methylene dichloride, trichloromethane, acetone, ethyl acetate and tetrahydrofuran (THF) one or more.
3. method according to claim 2, wherein said solvent B is Virahol, sherwood oil, methylene dichloride, acetone or ethyl acetate.
4. method according to claim 2, wherein said solvent is by first alcohol and solvent B 1:(1 ~ 3 by volume) form.
5. method according to claim 4, wherein said solvent by first alcohol and solvent B by volume 4:6 form.
6. the method according to any one of claim 2-5, the consumption of wherein said solvent and Ketoprofen weight ratio are 2 ~ 6:1.
7. the method according to any one of claim 2-5, wherein Ketoprofen and arginine mol ratio are 1 ~ 1.1:1.
8. the method according to any one of claim 2-5, the temperature wherein heated is 40 ~ 80 degrees Celsius.
9. the method according to any one of claim 2-5, wherein recrystallization temperature keeps 0 DEG C to room temperature.
10. method according to claim 9, wherein recrystallization temperature keeps room temperature.
11. 1 kinds of pharmaceutical compositions, it is made up of arginine ketoprofenate crystal form A according to claim 1 and pharmaceutically acceptable carrier.
12. arginine ketoprofenate crystal form As according to claim 1 are preparing the application in anti-inflammatory or analgesic.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5665384A (en) * | 1990-04-06 | 1997-09-09 | Rhone-Poulenc Rorer S.A. | Oily capsules of ketoprofen |
| CN1376670A (en) * | 2002-04-10 | 2002-10-30 | 成都圣诺科技发展有限公司 | Arginine-ketoprofen with antalgic and inflammation relieving actions and its preparing process |
| CN1767824A (en) * | 2003-03-18 | 2006-05-03 | 德国柏林开米艾克泰尼盖塞尔查福特联合股份公司 | Photostabilized topical formulations of KETOPROFEN |
| CN101935293A (en) * | 2010-09-03 | 2011-01-05 | 蚌埠丰原涂山制药有限公司 | Method for preparing arginine ketoprofenate |
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- 2014-02-14 CN CN201410051053.6A patent/CN103804184B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5665384A (en) * | 1990-04-06 | 1997-09-09 | Rhone-Poulenc Rorer S.A. | Oily capsules of ketoprofen |
| CN1376670A (en) * | 2002-04-10 | 2002-10-30 | 成都圣诺科技发展有限公司 | Arginine-ketoprofen with antalgic and inflammation relieving actions and its preparing process |
| CN1767824A (en) * | 2003-03-18 | 2006-05-03 | 德国柏林开米艾克泰尼盖塞尔查福特联合股份公司 | Photostabilized topical formulations of KETOPROFEN |
| CN101935293A (en) * | 2010-09-03 | 2011-01-05 | 蚌埠丰原涂山制药有限公司 | Method for preparing arginine ketoprofenate |
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