CN106187772A - A kind of prepare antipyretic, analgesia, the method for anti-inflammatory drug aspirin crystal compound - Google Patents
A kind of prepare antipyretic, analgesia, the method for anti-inflammatory drug aspirin crystal compound Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
- C07C69/12—Acetic acid esters
- C07C69/14—Acetic acid esters of monohydroxylic compounds
- C07C69/145—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols
- C07C69/157—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols containing six-membered aromatic rings
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
- A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/52—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
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Abstract
The invention belongs to pharmaceutical technology field, relate to a kind of prepare antipyretic, analgesia, the method for anti-inflammatory drug aspirin crystal compound, described aspirin compound has the X-ray powder diffraction pattern shown in Fig. 1.Aspirin compound provided by the present invention is aspirin crystal compound, it it is a kind of aspirin being different from prior art report, find through test, enteric coatel tablets prepared by this aspirin crystal compound are compared compared with the Aspirin Enteric-coated Tablets of prior art, not only there is relatively low free salicylic acid content, and along with its free salicylic acid content of prolongation of period of storage increases inconspicuous, greatly reduce medicine gastrointestinal side effect.
Description
The application is that the application for a patent for invention that applicant Miao Yiwen proposes is (invention entitled: a kind of antipyretic, analgesia, antiinflammatory
Medical compounds and preparation method thereof, Application No.: 2015102160635, filing date: on April 30th, 2015) division Shen
Please.
Technical field
The invention belongs to pharmaceutical technology field, relate to a kind of prepare antipyretic, analgesia, the method for anti-inflammatory drug compound, tool
Say body, relate to a kind of method preparing aspirin new compound.
Background technology
Aspirin (aspirin), has another name called aspirin, is one of three big classical medicines in history, goes through as one
The antipyretic analgesic that history is long, its effectiveness is the most cheap, remains most widely used antipyretic-antalgic anti-inflammatory agent so far, and
And be the standard preparation comparing and evaluating other drug.Since the 60's of 20th century, pharmacological research shows, aspirin is lasting
Property inactivation COX-1 activity, suppress platelet function, without dosage dependent interaction, extremely low concentration (nmol/L) can be rapidly reached
Inhibitory action, i.e. has clear and definite blood coagulation resisting function, such that it is able to as the medicine of pre-preventing thrombosis." China's Consensus of experts " suggestion
In primary prevention, aspirin prolonged application dosage is 75-100mg/ day, and at the prolonged application dosage of secondary prevention is
75-150mg/ days.
The Genprin of existing use is primarily present two problems: facile hydrolysis produces salicylic acid and causes gastrointestinal to say
Blood.Salicylic acid is the hydrolyzate of aspirin, is the aspirin principal element that causes digestive tract to stimulate simultaneously, its content
Height be one of the important indicator evaluating Genprin quality.Pharmacopeia specifying, in aspirin, salicylic content is not
Must be more than 1.5%.
The maximum toxic and side effects of aspirin is exactly easily to cause gastrointestinal tract mucosa rotten to the corn, hemorrhage and ulcer etc..Except analgesia,
Outside antipyretic, aspirin is used for when treating the diseases such as rheumatic fever, arthritis, antithrombotic being required for Long-term taking medicine, further increases poison
The incidence rate of side effect.Although people have carried out improving dosage form, as added suppository, it is to avoid medicine touches with gastrointestinal tract, but medication
Extremely inconvenient；And for example make enteric coated preparation, although decrease the incidence rate of toxic and side effects to a certain extent, but have portion under one's belt
Burst can occur Seepage, so stomach can be caused stimulation, gastric mucosa is caused damage；If free salicylic acid in enteric coatel tablets
Content high, salicylism can be caused to react, the most do not tackle the problem at its root.
Therefore, reduce Free Salicylic Acid in Aspirin Enteric-coated Tablets to have very important significance.
Summary of the invention
The first object of the present invention is to provide a kind of aspirin compound, and compared with the prior art, this compound is not
Only there is relatively low free salicylic acid content, and along with its free salicylic acid content of prolongation of period of storage increases inconspicuous,
Greatly reduce medicine gastrointestinal side effect.
The second object of the present invention is to provide the preparation method of described aspirin compound, the letter of the method technique
Single, it is suitable for industrialized large-scaled production.
For realizing the first object of the present invention, the present invention adopts the following technical scheme that
A kind of antipyretic, analgesia, anti-inflammatory drug compound, described compound has X-ray powder diffraction figure as shown in Figure 1
Spectrum.
The polymorphism of solid chemical is the natural phenomena that a kind of universal material exists, and this phenomenon refers to one
Can there is 2 kinds or two or more crystal form state in solid chemical, be also called the polymorphic state of material, the polymorphic of material
State is also referred to as " allomorphism " phenomenon.Although its chemical nature of allomorphous solid matter is identical, but its physics and chemistry
Matter is probably different.For " allomorphism medicine " that physicochemical property is different, different preventing and treating can also be shown clinically
The curative effect of disease, directly affects application and the clinical effectiveness of medicine.
Found by patent retrieval, record Fred .P. Du Kateman invention at Chinese patent CN86102837A
" preparation of stable sodium acetylsalicylate ", is directed to the preparation method of the flaky crystal of a kind of sodium asprinin；In
State's patent CN101977888A records " the noncrystalline aspirin of room-temperature stable " of tod .F. Ao Wokaitaisi invention,
Relate to armorphous solid existence and the preparation method finding aspirin；Chinese patent CN103613500A records mountain
" preparation method of aspirin fine crystallization " of east Xinhua Pharmacy stock Co., Ltd invention, relating to one, to prepare aspirin thin
The method of crystallization.
Retrieval foreign language finds that relevant aspirin exists the data of 2 kinds of crystal formations further, and the aspirin of Bayer is former grinds medicine
And domestic aspirin crude drug and involved by preparation be all crystal formation I known to aspirin；Science (1968,
Two articles 76:160) and on J.PHarm.PHarmacol.Lett. (1969,21:701-702) disclose Ah Si the earliest
There is crystal formation II in woods, and by the blood drug level in test healthy volunteer's body, finds the most medicinal crystal formation of crystal formation II
I blood drug level exceeds 70%.The crystal formation II of aspirin is studied by the most substantial amounts of scholar, such as Bundgaard,
H.J.PHarm.PHarmacol.,1974,26,535-540；Braga,D；A.D.Bond,R.Boese and
G.R.Desiraju,Angew.Chem.,Int.Ed.,2007,46,615.；Grepioni,F.；Maini,
L.Chem.Commun., 2010,46,6232-6242 etc..But above-mentioned document provides aspirin crystal formation II characteristic information not
Unified, and preparation method is loaded down with trivial details, stability of crystal form is bad, the most quickly turns crystalline substance and becomes crystal formation I；Partha in 2012
Pratim Bag and C.Malla Reddy is published in a news flash (Cryst.Growth in " crystal growth and design "
Des.2012,12,2740-2743) the most clearly providing fusing point and the XRD information of crystal formation II, preparation method is rapid evaporation
Method, recrystallisation solvent is ether or dichloromethane, but the recrystallisation solvent toxicity involved by this method is very big, is not particularly suited for industrialization
Produce aspirin crystal formation II, so the medicinal of crystal formation II is very limited.
Chinese patent CN104151163A discloses a kind of crystal formation of aspirin, have release in vitro quickly, drug effect
High and that action time is lasting advantages characteristic, but it has been investigated that this crystal formationFree salicylic acid content higher, and accelerate
Under the conditions of free salicylic acid content increase very fast.
The present inventor has obtained a kind of aspirin compound novel crystal forms being different from prior art through substantial amounts of test
Structure, and by test, show that this compound novel crystal forms structure not only has relatively low free salicylic acid content, and along with storage
Its free salicylic acid content of prolongation depositing the time increases inconspicuous, greatly reduces medicine gastrointestinal side effect.
For realizing the second object of the present invention, the present invention adopts the following technical scheme that
The preparation method of a kind of aspirin compound, comprises the following steps:
(1) being joined by aspirin crude product in the mixed solution of dehydrated alcohol, ethyl acetate, hexamethylene, heat up, stirring is to complete
CL；
(2) under the effect of sound field, the mixed solution of ether, water is added while stirring；
(3) after ether, the mixed solution of water add, under the effect of sound field, to be cooled to 0-2 DEG C, growing the grain 3-6 hour, washing,
Vacuum drying, obtains aspirin compound.
In above-mentioned preparation method, the volume of the mixed solution of dehydrated alcohol, ethyl acetate, hexamethylene described in step 1) be Ah
5-7 times of department's woods weight.
In above-mentioned preparation method, described in step 1), dehydrated alcohol, ethyl acetate, the volume ratio of hexamethylene are: 4.5:1.5:
1。
In above-mentioned preparation method, heat up as being warming up to 35-45 DEG C described in step 1).
In above-mentioned preparation method, step 2) described sound field frequency is 25-30KHz, output is 40-60W.
In above-mentioned preparation method, step 2) described ether, the mixed liquor volume of water be aspirin weight 10-15 times,
Ether is 1:3.5 with the volume ratio of water.
In above-mentioned preparation method, step 2) described mixing speed is 150-260 rev/min, adding speed is 80-120 milli
Liter/min.
In above-mentioned preparation method sound field frequency described in step 3) be 15-20KHz, output be 10-20W.
In above-mentioned preparation method, cooling rate described in step 3) is 2-4 DEG C/h.
In the present invention, described aspirin crude product can use the method for prior art to prepare, it is also possible to buys city
The aspirin crude drug sold.
Compared with prior art, present invention have the advantage that
Aspirin compound provided by the present invention is aspirin crystal compound, is that one is different from prior art report
The aspirin in road, finds through test, this aspirin crystal compound is compared compared with the aspirin of prior art, not only has
There is relatively low free salicylic acid content, and along with its free salicylic acid content of prolongation of period of storage increases inconspicuous, significantly
Reduce medicine gastrointestinal side effect.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction spectrum of the aspirin compound that the embodiment of the present invention 1 prepares.
Detailed description of the invention
Be below the detailed description of the invention of the present invention, described embodiment be in order to further describe the present invention rather than
Limit the present invention.
The preparation of embodiment 1 aspirin compound
(1) aspirin crude product is joined 5 times that volume is aspirin weight dehydrated alcohol, ethyl acetate, hexamethylene
Mixed solution in, dehydrated alcohol, ethyl acetate, the volume ratio of hexamethylene be: 4.5:1.5:1, is warming up to 35 DEG C, and stirring is to the completeest
CL；
(2) frequency be 25KHz, output be 40W sound field under, while stirring add volume be aspirin weight 10 times
Ether, the mixed solution of water, the volume ratio of ether and water is 1:3.5, and mixing speed is 150 revs/min, and adding speed is 80
Ml/min；
(3) after ether, the mixed solution of water add, frequency be 15KHz, output be 10W sound field under, with 2 DEG C/h
It is cooled to 0-2 DEG C, growing the grain 3 hours, washing, vacuum drying, obtain aspirin compound.
The aspirin compound of gained uses powder X-ray diffraction algoscopy to measure, and obtains in range of error
The X-ray powder diffraction pattern consistent with embodiment 1.
The preparation of embodiment 2 aspirin compound
(1) aspirin crude product is joined 6 times that volume is aspirin weight dehydrated alcohol, ethyl acetate, hexamethylene
Mixed solution in, dehydrated alcohol, ethyl acetate, the volume ratio of hexamethylene be: 4.5:1.5:1, is warming up to 40 DEG C, and stirring is to the completeest
CL；
(2) frequency be 27.5KHz, output be 50W sound field under, while stirring add volume be aspirin weight
The ether of 12.5 times, the mixed solution of water, ether is 1:3.5 with the volume ratio of water, and mixing speed is 205 revs/min, adds speed
Degree is 100 ml/min；
(3) after ether, the mixed solution of water add, frequency be 17.5KHz, output be 15W sound field under, with 3 DEG C/little
Time be cooled to 0-2 DEG C, growing the grain 4.5 hours, washing, vacuum drying, obtain aspirin compound.
The aspirin compound of gained uses powder X-ray diffraction algoscopy to measure, and obtains in range of error
The X-ray powder diffraction pattern consistent with embodiment 1.
The preparation of embodiment 3 aspirin compound
(1) aspirin crude product is joined 7 times that volume is aspirin weight dehydrated alcohol, ethyl acetate, hexamethylene
Mixed solution in, dehydrated alcohol, ethyl acetate, the volume ratio of hexamethylene be: 4.5:1.5:1, is warming up to 45 DEG C, and stirring is to the completeest
CL；
(2) frequency be 30KHz, output be 60W sound field under, while stirring add volume be aspirin weight 15 times
Ether, the mixed solution of water, the volume ratio of ether and water is 1:3.5, and mixing speed is 260 revs/min, adds speed and is
120 ml/min；
(3) after ether, the mixed solution of water add, frequency be 20KHz, output be 20W sound field under, with 4 DEG C/h
It is cooled to 0-2 DEG C, growing the grain 6 hours, washing, vacuum drying, obtain aspirin compound.
The aspirin compound of gained uses powder X-ray diffraction algoscopy to measure, and obtains in range of error
The X-ray powder diffraction pattern consistent with embodiment 1.
The preparation of embodiment 4 Aspirin Enteric-coated Tablets
Prescription: in parts by weight
Preparation technology:
1, weigh according to prescription；
2, prepare 5% PVP K30 ethanol: be placed in stainless steel cask by 3.80kg95% ethanol, add 0.20kg while stirring
PVP K30, stirs to all dissolving standby；
3, mixing granulation: be added in wet mixing pelletizer by the interior supplementary material that adds, opens stirring motor and is dry mixed 10 minutes；Add
The 5% PVP K30 solution 4kg prepared；Wet mixing 90-120 second soft material, 24 mesh nylon wires are arranged in oscillating granulator
Pelletize；
4, it is dried: arranging boiling drier inlet temperature is 60 DEG C, is dried to moisture 1.0-2.0%, dried selection 20 mesh nylon
Net is arranged on granulate in oscillating granulator；
5, always mix: the dry granule after granulate and additional adjuvant Pulvis Talci are joined in mixer, motor rotation frequency is set
200r/min, opens mixer and mixes 15 minutes；
6, selecting high speed tablet press tabletting, regulation pressure makes slice, thin piece energy molding and hardness at 4-6kgf；
7, insulating liquid coating: hypromellose is dissolved in purified water and is configured to insulating liquid, coating pan inlet temperature is set
It is 60 DEG C, coating weight gain 1.5-2.0%；
8, enteric coating: Eudragit L 100, triethyl citrate, Pulvis Talci are joined 95% ethanol, stirs.
Arranging coating pan inlet temperature is 60 DEG C, coating weight gain 5.0-5.5%.
The preparation of comparative example 1 Aspirin Enteric-coated Tablets
Prescription: in parts by weight
Preparation technology:
1, weigh according to prescription；
2, prepare 5% PVP K30 ethanol: be placed in stainless steel cask by 3.80kg95% ethanol, add 0.20kg while stirring
PVP K30, stirs to all dissolving standby；
3, mixing granulation: be added in wet mixing pelletizer by the interior supplementary material that adds, opens stirring motor and is dry mixed 10 minutes；Add
The 5% PVP K30 solution 4kg prepared；Wet mixing 90-120 second soft material, 24 mesh nylon wires are arranged in oscillating granulator
Pelletize；
4, it is dried: arranging boiling drier inlet temperature is 60 DEG C, is dried to moisture 1.0-2.0%, dried selection 20 mesh nylon
Net is arranged on granulate in oscillating granulator；
5, always mix: the dry granule after granulate and additional adjuvant Pulvis Talci are joined in mixer, motor rotation frequency is set
200r/min, opens mixer and mixes 15 minutes；
6, selecting high speed tablet press tabletting, regulation pressure makes slice, thin piece energy molding and hardness at 4-6kgf；
7, insulating liquid coating: hypromellose is dissolved in purified water and is configured to insulating liquid, coating pan inlet temperature is set
It is 60 DEG C, coating weight gain 1.5-2.0%；
8, enteric coating: Eudragit L 100, triethyl citrate, Pulvis Talci are joined 95% ethanol, stirs.
Arranging coating pan inlet temperature is 60 DEG C, coating weight gain 5.0-5.5%.
Test example Aspirin Enteric-coated Tablets release and the experiment of free salicylic acid assay
1 burst size
Burst size in acid: the enteric coatel tablets sample that respectively prepared by Example and comparative example, according to drug release determination method (annex I
D the second method method 1), use dissolution method the first subtraction unit, be situated between for dissolution with the hydrochloric acid solution 600ml of 0.lmol/L
Matter, rotating speed is 100 turns per minute, operates in accordance with the law, little takes solution 10ml constantly through 2, filters, takes subsequent filtrate as test sample
Solution；Taking aspirin reference substance, accurately weighed, acetate methanol solution on the rocks dissolves and dilutes to be made in every lml containing 4.25 μ g
Solution, as reference substance solution.Measure according to the method under assay item.The burst size of the meter middle aspirin of grate every tablet, limit
Degree should be less than the 10% of aspirin labelled amount.
Burst size in buffer: continuously add the 0.2mol/L phosphorus of 37 DEG C in acid in the solution under burst size check item
Acid sodium solution, mixing, with 2mol/L hydrochloric acid solution or 2mol/L sodium hydroxide solution regulate the pH value of solution to 6.8 ±
0.05, continue dissolution 15 minutes, take solution 10ml, filter, take subsequent filtrate as need testing solution；Another precision weighs Ah Si
Woods reference substance is appropriate, accurately weighed, dissolves with glacial acetic acid methanol solution and dilutes and make the solution containing 22 μ g in every 1ml, makees
For aspirin reference substance solution；Separately take salicylic acid reference substance, accurately weighed, add 1% glacial acetic acid methanol solution and dissolve and dilute
Make the solution containing 1.7 μ g in every lml, as salicylic acid reference substance solution.According to the chromatographic condition under assay item, accurate
Measure need testing solution, aspirin reference substance solution and each 10 μ l of salicylic acid reference substance solution, dispensing people's chromatograph of liquid,
Record chromatogram, calculates every tablet of middle aspirin and salicylic content by external standard method, salicylic acid content is multiplied by 1.304
After, it is added with aspirin content and i.e. obtains burst size in every buffer.Limit is the 70% of labelled amount, should meet regulation.
Free salicylic acid content
The enteric coatel tablets sample that respectively prepared by Example and comparative example is appropriate (being approximately equivalent to aspirin 0.lg), wears into thin
Powder, accurately weighed, to put in 100ml measuring bottle, the methanol solution shaking adding 1% glacial acetic acid makes aspirin dissolve, and is diluted to carve
Degree, shakes up, and filter membrane filters, and takes subsequent filtrate as need testing solution (facing by brand-new)；Take salicylic acid reference substance about 15mg, accurate title
Fixed, to put in 50ml measuring bottle, the methanol solution adding 1% glacial acetic acid dissolves and is diluted to scale, shakes up, and precision measures 5ml, puts
In 100ml measuring bottle, it is diluted to scale with the methanol solution of 1% glacial acetic acid, shakes up, as reference substance solution.Swim according to aspirin
Method under salicylic acid item measures, and by external standard method with calculated by peak area, must not cross the 0.5% of labelled amount.
Table 1 Aspirin Enteric-coated Tablets release, the measurement result (0 day) of free salicylic acid
Release after table 2 accelerated test, free salicylic acid measurement result (6 months, 40 DEG C of 75%RH)
From the result of the test of table 1 and table 2 it can be seen that the embodiment of the present invention 4 preparation Aspirin Enteric-coated Tablets before acceleration
In rear acid, burst size is essentially 0, discharges completely in buffer, and free salicylic acid is basically unchanged；And comparative example 1 and commercially available enteric
In sheet, in acid, burst size is significantly larger than embodiment 4, and in buffer, burst size is much smaller than embodiment 4, and free salicylic acid increases substantially.
Aspirin compound prepared by other embodiments of the present invention is also carried out above-mentioned test, its result obtained
Similar.
Claims (1)
1. one kind prepare antipyretic, analgesia, the method for anti-inflammatory drug aspirin crystal compound, it is characterised in that include following
Step:
(1) aspirin crude product is joined 7 times that volume is aspirin weight dehydrated alcohol, ethyl acetate, hexamethylene
Mixed solution in, dehydrated alcohol, ethyl acetate, the volume ratio of hexamethylene be: 4.5:1.5:1, is warming up to 45 DEG C, and stirring is to the completeest
CL；
(2) frequency be 30KHz, output be 60W sound field under, while stirring add volume be aspirin weight 15 times
Ether, the mixed solution of water, the volume ratio of ether and water is 1:3.5, and mixing speed is 260 revs/min, adds speed and is
120 ml/min；
(3) after ether, the mixed solution of water add, frequency be 20KHz, output be 20W sound field under, with 4 DEG C/h
It is cooled to 0-2 DEG C, growing the grain 6 hours, washing, vacuum drying, obtain aspirin compound；
Described aspirin compound uses powder X-ray diffraction algoscopy to measure, and has the x-ray powder shown in Fig. 1
Diffracting spectrum.
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| CN201610620573.3A CN106187772A (en) | 2015-04-30 | 2015-04-30 | A kind of prepare antipyretic, analgesia, the method for anti-inflammatory drug aspirin crystal compound |
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| CN201510216063.5A CN104761449B (en) | 2015-04-30 | 2015-04-30 | A kind of antipyretic, analgesia, anti-inflammatory drug compound and preparation method thereof |
| CN201610620573.3A CN106187772A (en) | 2015-04-30 | 2015-04-30 | A kind of prepare antipyretic, analgesia, the method for anti-inflammatory drug aspirin crystal compound |
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| CN201610613004.6A Withdrawn CN105997919A (en) | 2015-04-30 | 2015-04-30 | Method for preparing aspirin enteric-coated tablet for removing fever, easing pain and resisting inflammation |
| CN201610612992.2A Withdrawn CN106220506A (en) | 2015-04-30 | 2015-04-30 | A kind of prepare antipyretic, analgesia, the method for anti-inflammatory drug compound |
| CN201610620572.9A Withdrawn CN106038504A (en) | 2015-04-30 | 2015-04-30 | Antipyretic analgesic and anti-inflammatory medicine of aspirin enteric-coated tablet |
| CN201610612986.7A Withdrawn CN106220505A (en) | 2015-04-30 | 2015-04-30 | A kind of prepare antipyretic, analgesia, the method for anti-inflammatory drug compound |
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| CN201610613004.6A Withdrawn CN105997919A (en) | 2015-04-30 | 2015-04-30 | Method for preparing aspirin enteric-coated tablet for removing fever, easing pain and resisting inflammation |
| CN201610612992.2A Withdrawn CN106220506A (en) | 2015-04-30 | 2015-04-30 | A kind of prepare antipyretic, analgesia, the method for anti-inflammatory drug compound |
| CN201610620572.9A Withdrawn CN106038504A (en) | 2015-04-30 | 2015-04-30 | Antipyretic analgesic and anti-inflammatory medicine of aspirin enteric-coated tablet |
| CN201610612986.7A Withdrawn CN106220505A (en) | 2015-04-30 | 2015-04-30 | A kind of prepare antipyretic, analgesia, the method for anti-inflammatory drug compound |
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| CN105106128A (en) * | 2015-08-18 | 2015-12-02 | 青岛蓝盛洋医药生物科技有限责任公司 | Antipyretic, analgesic and anti-inflammatory aspirin composite dry suspension |
| CN105232484A (en) * | 2015-09-24 | 2016-01-13 | 青岛华之草医药科技有限公司 | Antipyretic analgesic anti-inflammatory aspirin composition tablet |
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| Publication number | Publication date |
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| CN106220505A (en) | 2016-12-14 |
| CN104761449B (en) | 2016-08-31 |
| CN106220506A (en) | 2016-12-14 |
| CN104761449A (en) | 2015-07-08 |
| CN105997919A (en) | 2016-10-12 |
| CN106038504A (en) | 2016-10-26 |
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Inventor after: Zheng Dequan Inventor after: Yu Meili Inventor before: Yu Meili |
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Application publication date: 20161207 |