CN104761449A - Antipyretic, analgesic and anti-inflammatory medicine compound and preparation method thereof - Google Patents
Antipyretic, analgesic and anti-inflammatory medicine compound and preparation method thereof Download PDFInfo
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- CN104761449A CN104761449A CN201510216063.5A CN201510216063A CN104761449A CN 104761449 A CN104761449 A CN 104761449A CN 201510216063 A CN201510216063 A CN 201510216063A CN 104761449 A CN104761449 A CN 104761449A
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- antipyretic
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- analgesia
- inflammatory drug
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- 238000002360 preparation method Methods 0.000 title claims abstract description 42
- 150000001875 compounds Chemical class 0.000 title claims abstract description 21
- 230000001754 anti-pyretic effect Effects 0.000 title claims abstract description 17
- 239000002221 antipyretic Substances 0.000 title claims abstract description 17
- 239000003814 drug Substances 0.000 title abstract description 19
- 230000000202 analgesic effect Effects 0.000 title abstract description 3
- 230000003110 anti-inflammatory effect Effects 0.000 title abstract 2
- 229960001138 acetylsalicylic acid Drugs 0.000 claims abstract description 83
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims abstract description 59
- -1 aspirin compound Chemical class 0.000 claims abstract description 34
- 230000000694 effects Effects 0.000 claims abstract description 12
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- 238000002156 mixing Methods 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 230000036592 analgesia Effects 0.000 claims description 14
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 14
- 229940124599 anti-inflammatory drug Drugs 0.000 claims description 13
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 12
- 239000012043 crude product Substances 0.000 claims description 6
- 238000001291 vacuum drying Methods 0.000 claims description 5
- 238000010792 warming Methods 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 abstract description 40
- 239000013078 crystal Substances 0.000 abstract description 24
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 abstract description 20
- 229960004889 salicylic acid Drugs 0.000 abstract description 20
- 239000002662 enteric coated tablet Substances 0.000 abstract description 13
- 238000003860 storage Methods 0.000 abstract description 4
- 230000002035 prolonged effect Effects 0.000 abstract description 3
- 238000002474 experimental method Methods 0.000 abstract description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract description 2
- 230000002411 adverse Effects 0.000 abstract 1
- 238000001228 spectrum Methods 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 238000000034 method Methods 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- 239000011248 coating agent Substances 0.000 description 8
- 238000000576 coating method Methods 0.000 description 8
- 239000013558 reference substance Substances 0.000 description 8
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 6
- 229920003081 Povidone K 30 Polymers 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- CUBCNYWQJHBXIY-UHFFFAOYSA-N benzoic acid;2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1O CUBCNYWQJHBXIY-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 229960004756 ethanol Drugs 0.000 description 6
- 238000005755 formation reaction Methods 0.000 description 6
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- 229960000583 acetic acid Drugs 0.000 description 5
- 239000012362 glacial acetic acid Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000004677 Nylon Substances 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 235000013339 cereals Nutrition 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000013016 damping Methods 0.000 description 4
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 229920001778 nylon Polymers 0.000 description 4
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- 235000019786 weight gain Nutrition 0.000 description 4
- 235000020985 whole grains Nutrition 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229960000935 dehydrated alcohol Drugs 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 229920003139 Eudragit® L 100 Polymers 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 2
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000002702 enteric coating Substances 0.000 description 2
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- 230000003179 granulation Effects 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229960003943 hypromellose Drugs 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
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- 238000001953 recrystallisation Methods 0.000 description 2
- 238000007493 shaping process Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000011122 softwood Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 239000001069 triethyl citrate Substances 0.000 description 2
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 2
- 235000013769 triethyl citrate Nutrition 0.000 description 2
- 208000012671 Gastrointestinal haemorrhages Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 description 1
- 108050003243 Prostaglandin G/H synthase 1 Proteins 0.000 description 1
- 206010039361 Sacroiliitis Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- ZCHPKWUIAASXPV-UHFFFAOYSA-N acetic acid;methanol Chemical compound OC.CC(O)=O ZCHPKWUIAASXPV-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
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- 238000011978 dissolution method Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 239000000413 hydrolysate Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000009862 primary prevention Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 239000011435 rock Substances 0.000 description 1
- 230000009863 secondary prevention Effects 0.000 description 1
- JZLOKWGVGHYBKD-UHFFFAOYSA-M sodium;2-acetyloxybenzoate Chemical compound [Na+].CC(=O)OC1=CC=CC=C1C([O-])=O JZLOKWGVGHYBKD-UHFFFAOYSA-M 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
Classifications
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- 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
-
- 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
-
- 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
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Crystallography & Structural Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicine, and relates to an antipyretic, analgesic and anti-inflammatory medicine compound and a preparation method thereof, in particular to a novel aspirin compound and a preparation method thereof. The aspirin compound has the X-ray powder diffraction spectrum shown in drawing 1. The aspirin compound is a novel crystal form aspirin compound which is different from aspirin reported in the prior art. Experiments show that compared with aspirin enteric coated tablets in the prior art, enteric coated tablets prepared through the novel crystal form aspirin compound have the low free salicylic acid concentration, the free salicylic acid concentration of the enteric coated tablets prepared through the novel crystal form aspirin compound is not obviously increased while the storage time is prolonged, and adverse gastrointestinal tract effects of medicine are greatly reduced.
Description
Technical field
The invention belongs to medical art, relate to a kind of antipyretic, analgesia, anti-inflammatory drug compound and preparation method thereof, specifically, relate to a kind of acetylsalicylic acid novel cpd and preparation method thereof.
Background technology
Acetylsalicylic acid (aspirin), have another name called acetylsalicylic acid, one of three large classical medicines in history, as the time-honored antipyretic and analgesic of one, its effectiveness is obviously cheap, so far remain most widely used antipyretic-antalgic anti-inflammatory agent, and be the standard preparation comparing and evaluate other drug.Since the 60's of 20th century, pharmacological research shows, acetylsalicylic acid persistence deactivation COX-1 is active, suppress platelet function, without dosage dependent interaction, extremely low concentration (nmol/L) can reach restraining effect rapidly, namely has clear and definite blood coagulation resisting function, thus can as the medicine of pre-preventing thrombosis." Chinese Consensus of experts " suggestion acetylsalicylic acid prolonged application dosage in primary prevention is 75-100mg/ day, and is 75-150mg/ days at the prolonged application dosage of secondary prevention.
Mainly there is two problems in the Genprin of existing use: facile hydrolysis produces Whitfield's ointment and causes gastrointestinal hemorrhage.Whitfield's ointment is the hydrolysate of acetylsalicylic acid, is the principal element that acetylsalicylic acid causes digestive tube to stimulate simultaneously, and the height of its content is one of important indicator evaluating Genprin quality.In pharmacopeia, in regulation acetylsalicylic acid, salicylic content must not more than 1.5%.
The maximum toxic side effect of acetylsalicylic acid is exactly very easily cause rotten to the corn, hemorrhage and ulcer of gastrointestinal tract mucosa etc.Except analgesia, antipyretic except, all need Long-term taking medicine when acetylsalicylic acid is used for the treatment of the diseases such as rheumatic fever, sacroiliitis, antithrombotic, further increase the incidence of toxic side effect.Although people have carried out improving dosage form, as added suppository, avoid medicine and gi tract to touch, medication is extremely inconvenient; And for example make enteric coated preparation, although decrease the incidence of toxic side effect to a certain extent, have part slice, thin piece Seepage can occur under one's belt, stimulation can be caused to stomach like this, damage is caused to gastric mucosa; If the content of free salicylic acid is high in enteric coated tablet, salicylism can be caused to react, still 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, comparatively prior art is compared, this compound not only has lower free salicylic acid content, and along with period of storage its free salicylic acid content of prolongation increase not obvious, greatly reduce medicine gastrointestinal side effect.
The second object of the present invention is to provide the preparation method of described aspirin compound, and the method technique is simple, is suitable for industrialized production.
For realizing the first object of the present invention, the present invention adopts following technical scheme:
A kind of antipyretic, analgesia, anti-inflammatory drug compound, described compound has X-ray powder diffraction pattern as shown in Figure 1.
The polymorphism of solid chemical is the spontaneous phenomenon that a kind of general material exists, this phenomenon refers to that a kind of solid chemical can exist 2 kinds or two or more crystal form state, be also called the polymorphic state of material, the polymorphic state of material is also referred to as " paramorphism " phenomenon.Although its chemical nature of allomorphous solid matter is identical, its physico-chemical property may be different.For " paramorphism medicine " that physico-chemical property is different, also can show the curative effect of different disease preventing and treating clinically, directly affect application and the clinical effectiveness of medicine.
Found by patent retrieval, in " preparation of stable sodium acetylsalicylate " that Chinese patent CN86102837A records Fred .P. Du Kateman invention, wherein relate to a kind of preparation method of plate crystal of sodium asprinin; Chinese patent CN101977888A records " the noncrystalline acetylsalicylic acid of room-temperature stable " of tod .F. Ao Wokaitaisi invention, relates to the armorphous solid existence and preparation method that find acetylsalicylic acid; Chinese patent CN103613500A records " preparation method of acetylsalicylic acid fine crystallization " of Shandong XinHua Pharmacy stock Co., Ltd's invention, relates to a kind of method preparing acetylsalicylic acid fine crystallization.
Further retrieval foreign language finds that relevant acetylsalicylic acid exists the data of 2 kinds of crystal formations, and the acetylsalicylic acid of Bayer is former to be ground involved by medicine and domestic acetylsalicylic acid bulk drug and preparation is all the crystal formation I that acetylsalicylic acid is known; At Science (1968,76:160) with J.PHarm.PHarmacol.Lett. (1969, two sections of articles 21:701-702) disclose acetylsalicylic acid the earliest and there is crystal form II, and by the Plasma Concentration in test healthy volunteer body, find that the medicinal than ever crystal formation I Plasma Concentration of crystal form II exceeds 70%.The crystal form II of scholars a large amount of subsequently to acetylsalicylic acid is studied, as Bundgaard, H.J.PHarm.PHarmacol., and 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 acetylsalicylic acid crystal form II characteristic information and disunity, and preparation method is loaded down with trivial details, stability of crystal form is bad, turns crystalline substance at normal temperatures very soon and becomes crystal formation I; Partha Pratim Bag in 2012 and C.Malla Reddy are published in one section of news flash (Cryst.Growth Des.2012 in " crystal growth and design ", 12,2740-2743) just clearly provide fusing point and the XRD information of crystal form II, preparation method is rapid evaporation method, recrystallisation solvent is ether or methylene dichloride, but the recrystallisation solvent toxicity involved by this method is very large, and be not suitable for suitability for industrialized production acetylsalicylic acid crystal form II, so the medicinal of crystal form II is very limited.
Chinese patent CN104151163A discloses a kind of crystal formation of acetylsalicylic acid
, have that release in vitro is quick, drug effect is high and the advantages characteristic that action time is lasting, but find this crystal formation after deliberation
free salicylic acid content higher, and free salicylic acid content increases very fast under acceleration conditions.
The present inventor obtains a kind of aspirin compound new crystal structure being different from prior art through a large amount of tests, and by test, show that this compound new crystal structure not only has lower free salicylic acid content, and along with period of storage its free salicylic acid content of prolongation increase not obvious, greatly reduce medicine gastrointestinal side effect.
For realizing the second object of the present invention, the present invention adopts following technical scheme:
A preparation method for aspirin compound, comprises the following steps:
(1) acetylsalicylic acid crude product is joined in the mixing solutions of dehydrated alcohol, ethyl acetate, hexanaphthene, heat up, be stirred to and dissolve completely;
(2) under the effect of sound field, the mixing solutions of ether, water is added while stirring;
(3) after the mixing solutions of ether, water adds, 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 mixing solutions of dehydrated alcohol, ethyl acetate, hexanaphthene described in step 1) is 5-7 times of acetylsalicylic acid weight.
In above-mentioned preparation method, described in step 1), the volume ratio of dehydrated alcohol, ethyl acetate, hexanaphthene is: 4.5:1.5:1.
In above-mentioned preparation method, heat up described in step 1) as being warming up to 35-45 DEG C.
In above-mentioned preparation method, step 2) described sound field frequency is 25-30KHz, output rating is 40-60W.
In above-mentioned preparation method, step 2) described ether, water mixed liquor volume be acetylsalicylic acid weight 10-15 doubly, the volume ratio of ether and water is 1:3.5.
In above-mentioned preparation method, step 2) described stirring velocity is 150-260 rev/min, adding speed is 80-120 ml/min.
In above-mentioned preparation method, sound field frequency described in step 3) is 15-20KHz, output rating is 10-20W.
In above-mentioned preparation method, cooling rate described in step 3) is 2-4 DEG C/h.
In the present invention, described acetylsalicylic acid crude product can adopt the method for prior art to prepare, and also can buy commercially available acetylsalicylic acid bulk drug.
Compared with prior art, tool of the present invention has the following advantages:
Aspirin compound provided by the present invention is acetylsalicylic acid crystal compound, it is a kind of acetylsalicylic acid being different from prior art report, find through test, this acetylsalicylic acid crystal compound is compared compared with the acetylsalicylic acid of prior art, not only there is lower free salicylic acid content, and along with period of storage its free salicylic acid content of prolongation increase not obvious, greatly reduce medicine gastrointestinal side effect.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction of the aspirin compound that the embodiment of the present invention 1 obtains.
Embodiment
Be below the specific embodiment of the present invention, described embodiment is to further describe the present invention, instead of restriction the present invention.
The preparation of embodiment 1 aspirin compound
(1) acetylsalicylic acid crude product is joined in the mixing solutions of dehydrated alcohol that volume is 5 times of acetylsalicylic acid weight, ethyl acetate, hexanaphthene, the volume ratio of dehydrated alcohol, ethyl acetate, hexanaphthene is: 4.5:1.5:1, be warming up to 35 DEG C, be stirred to and dissolve completely;
(2) frequency be 25KHz, under output rating is the sound field of 40W, adding volume is while stirring the ether of acetylsalicylic acid weight 10 times, the mixing solutions of water, the volume ratio of ether and water is 1:3.5, and stirring velocity is 150 revs/min, and adding speed is 80 ml/min;
(3) after the mixing solutions of ether, water adds, frequency be 15KHz, under output rating is the sound field of 10W, be cooled to 0-2 DEG C with 2 DEG C/h, growing the grain 3 hours, washing, vacuum-drying, obtains aspirin compound.
The aspirin compound of gained uses powder X-ray diffraction assay method to measure, and obtains X-ray powder diffraction pattern consistent with embodiment 1 in limit of error.
The preparation of embodiment 2 aspirin compound
(1) acetylsalicylic acid crude product is joined in the mixing solutions of dehydrated alcohol that volume is 6 times of acetylsalicylic acid weight, ethyl acetate, hexanaphthene, the volume ratio of dehydrated alcohol, ethyl acetate, hexanaphthene is: 4.5:1.5:1, be warming up to 40 DEG C, be stirred to and dissolve completely;
(2) frequency be 27.5KHz, under output rating is the sound field of 50W, adding volume is while stirring the ether of acetylsalicylic acid weight 12.5 times, the mixing solutions of water, the volume ratio of ether and water is 1:3.5, and stirring velocity is 205 revs/min, and adding speed is 100 ml/min;
(3) after the mixing solutions of ether, water adds, frequency be 17.5KHz, under output rating is the sound field of 15W, be cooled to 0-2 DEG C with 3 DEG C/h, growing the grain 4.5 hours, washing, vacuum-drying, obtains aspirin compound.
The aspirin compound of gained uses powder X-ray diffraction assay method to measure, and obtains X-ray powder diffraction pattern consistent with embodiment 1 in limit of error.
The preparation of embodiment 3 aspirin compound
(1) acetylsalicylic acid crude product is joined in the mixing solutions of dehydrated alcohol that volume is 7 times of acetylsalicylic acid weight, ethyl acetate, hexanaphthene, the volume ratio of dehydrated alcohol, ethyl acetate, hexanaphthene is: 4.5:1.5:1, be warming up to 45 DEG C, be stirred to and dissolve completely;
(2) frequency be 30KHz, under output rating is the sound field of 60W, adding volume is while stirring the ether of acetylsalicylic acid weight 15 times, the mixing solutions of water, the volume ratio of ether and water is 1:3.5, and stirring velocity is 260 revs/min, and adding speed is 120 ml/min;
(3) after the mixing solutions of ether, water adds, frequency be 20KHz, under output rating is the sound field of 20W, be cooled to 0-2 DEG C with 4 DEG C/h, growing the grain 6 hours, washing, vacuum-drying, obtains aspirin compound.
The aspirin compound of gained uses powder X-ray diffraction assay method to measure, and obtains X-ray powder diffraction pattern consistent with embodiment 1 in limit of error.
The preparation of embodiment 4 Aspirin Enteric-coated Tablets
Prescription: with parts by weight
Preparation technology:
1, weigh according to prescription;
2, prepare 5% PVP K30 ethanol: 3.80kg95% ethanol is placed in stainless steel cask, add 0.20kg PVP K30 while stirring, be stirred to all dissolvings for subsequent use;
3, mixing granulation: be added in Wetmixinggranulator by the interior supplementary material that adds, opens agitator motor and is dry mixed 10 minutes; Add the 5% PVP K30 solution 4kg prepared; Wet mixing 90-120 softwood second, 24 order nylon wires are arranged in Pendulargranulator granulates;
4, dry: arranging boiling drier inlet temperature is 60 DEG C, is dried to moisture 1.0-2.0%, select 20 order nylon wires to be arranged on whole grain in Pendulargranulator after dry;
5, always mix: the dry particle after whole grain and additional auxiliary material talcum powder are joined in mixing machine, motor rotation frequency 200r/min is set, open mixing machine and mix 15 minutes;
6, select high speed tablet press compressing tablet, regulate pressure make slice, thin piece can shaping and hardness at 4-6kgf;
7, spacer pad dressing: hypromellose is dissolved in purified water and is mixed with spacer pad, arranging coating pan inlet temperature is 60 DEG C, coating weight gain 1.5-2.0%;
8, enteric coating: Eudragit L 100, triethyl citrate, talcum powder 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: with parts by weight
Preparation technology:
1, weigh according to prescription;
2, prepare 5% PVP K30 ethanol: 3.80kg95% ethanol is placed in stainless steel cask, add 0.20kg PVP K30 while stirring, be stirred to all dissolvings for subsequent use;
3, mixing granulation: be added in Wetmixinggranulator by the interior supplementary material that adds, opens agitator motor and is dry mixed 10 minutes; Add the 5% PVP K30 solution 4kg prepared; Wet mixing 90-120 softwood second, 24 order nylon wires are arranged in Pendulargranulator granulates;
4, dry: arranging boiling drier inlet temperature is 60 DEG C, is dried to moisture 1.0-2.0%, select 20 order nylon wires to be arranged on whole grain in Pendulargranulator after dry;
5, always mix: the dry particle after whole grain and additional auxiliary material talcum powder are joined in mixing machine, motor rotation frequency 200r/min is set, open mixing machine and mix 15 minutes;
6, select high speed tablet press compressing tablet, regulate pressure make slice, thin piece can shaping and hardness at 4-6kgf;
7, spacer pad dressing: hypromellose is dissolved in purified water and is mixed with spacer pad, arranging coating pan inlet temperature is 60 DEG C, coating weight gain 1.5-2.0%;
8, enteric coating: Eudragit L 100, triethyl citrate, talcum powder are joined 95% ethanol, stirs.Arranging coating pan inlet temperature is 60 DEG C, coating weight gain 5.0-5.5%.
test exampleaspirin Enteric-coated Tablets release and the experiment of free salicylic acid assay
1 burst size
Burst size in acid: the enteric coated tablet sample prepared of Example and comparative example respectively, according to drug release determination method (annex I D second method method 1), adopt dissolution method first method device, with the hydrochloric acid soln 600ml of 0.lmol/L for dissolution medium, rotating speed is per minute 100 turns, operates in accordance with the law, constantly little through 2, get solution 10ml, filter, get subsequent filtrate as need testing solution; Get acetylsalicylic acid reference substance, accurately weighed, acetate methanol solubilize on the rocks also dilutes the solution made containing 4.25 μ g in every lml, product solution in contrast.Measure according to the method under assay item.The burst size of acetylsalicylic acid in the every sheet of meter grate, limit should be less than 10% of acetylsalicylic acid labelled amount.
Burst size in damping fluid: the solution for continuous in acid under burst size check item adds the 0.2mol/L sodium radio-phosphate,P-32 solution of 37 DEG C, mixing, with pH value to 6.8 ± 0.05 of 2mol/L hydrochloric acid soln or 2mol/L sodium hydroxide solution regulator solution, continue stripping 15 minutes, get solution 10ml, filter, get subsequent filtrate as need testing solution; It is appropriate that another precision takes acetylsalicylic acid reference substance, accurately weighed, also dilutes the solution made containing 22 μ g in every 1ml, as acetylsalicylic acid reference substance solution with Glacial acetic acid dissolve with methanol solution; Separately get Whitfield's ointment reference substance, accurately weighed, add 1% Glacial acetic acid dissolve with methanol solution and dilute the solution made containing 1.7 μ g in every lml, as Whitfield's ointment reference substance solution.According to the chromatographic condition under assay item, precision measures each 10 μ l Fen Do of need testing solution, acetylsalicylic acid reference substance solution and Whitfield's ointment reference substance solution and notes people's liquid chromatograph, record color atlas, acetylsalicylic acid and salicylic content in every sheet is calculated by external standard method, after salicylic acid content is multiplied by 1.304, is added with aspirin content and obtains burst size in every sheet damping fluid.Limit is 70% of labelled amount, should conform with the regulations.
free salicylic acid content
The enteric coated tablet sample prepared of Example and comparative example appropriate (being about equivalent to acetylsalicylic acid 0.lg) respectively, wear into fine powder, accurately weighed, put in 100ml measuring bottle, the methanol solution jolting adding 1% Glacial acetic acid makes acetylsalicylic acid dissolve, and is diluted to scale, shakes up, filter membrane filters, and gets subsequent filtrate as need testing solution (facing by brand-new); Get Whitfield's ointment reference substance and be about 15mg, accurately weighed, put in 50ml measuring bottle, add the dissolve with methanol solution of 1% Glacial acetic acid and be diluted to scale, shake up, precision measures 5ml, puts in 100ml measuring bottle, be diluted to scale with the methanol solution of 1% Glacial acetic acid, shake up, in contrast product solution.Measure according to the method under acetylsalicylic acid free salicylic acid item, by external standard method with calculated by peak area, 0.5% of labelled amount must not be crossed.
The measurement result (0 day) of table 1 Aspirin Enteric-coated Tablets release, free salicylic acid
Release after table 2 accelerated test, free salicylic acid measurement result (6 months, 40 DEG C of 75%RH)
As can be seen from the test-results of table 1 and table 2, the Aspirin Enteric-coated Tablets prepared of the embodiment of the present invention 4 before acceleration after in acid burst size be 0 substantially, discharge completely in damping fluid, free salicylic acid is substantially constant; And in acid, burst size will much larger than embodiment 4 in comparative example 1 and commercially available enteric coated tablet, in damping fluid, burst size is much smaller than embodiment 4, and free salicylic acid increases obviously.
Also carried out above-mentioned test to the aspirin compound prepared by other embodiment of the present invention, its result obtained is similar.
Claims (10)
1. antipyretic, analgesia, an anti-inflammatory drug compound, it is characterized in that: described compound has the X-ray powder diffraction pattern shown in Fig. 1.
2. according to claim 1 antipyretic, analgesia, anti-inflammatory drug compound a preparation method, it is characterized in that, described preparation method comprises the following steps:
(1) acetylsalicylic acid crude product is joined in the mixing solutions of dehydrated alcohol, ethyl acetate, hexanaphthene, heat up, be stirred to and dissolve completely;
(2) under the effect of sound field, the mixing solutions of ether, water is added while stirring;
(3) after the mixing solutions of ether, water adds, 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.
3. the preparation method of antipyretic, analgesia according to claim 2, anti-inflammatory drug compound, is characterized in that: in described step 1), the volume of the mixing solutions of described dehydrated alcohol, ethyl acetate, hexanaphthene be the 5-7 of acetylsalicylic acid weight doubly.
4. according to claim 2 antipyretic, analgesia, anti-inflammatory drug compound preparation method, it is characterized in that: in described step 1), the volume ratio of described dehydrated alcohol, ethyl acetate, hexanaphthene is: 4.5:1.5:1.
5. according to claim 2 antipyretic, analgesia, anti-inflammatory drug compound preparation method, it is characterized in that: in described step 1), described intensification is for being warming up to 35-45 DEG C.
6. according to claim 2 antipyretic, analgesia, anti-inflammatory drug compound preparation method, it is characterized in that: described step 2) in, described sound field frequency is 25-30KHz, output rating is 40-60W.
7. the preparation method of antipyretic, analgesia according to claim 2, anti-inflammatory drug compound, is characterized in that: described step 2) in, the mixed liquor volume of described ether, water be acetylsalicylic acid weight 10-15 doubly, the volume ratio of ether and water is 1:3.5.
8. according to claim 2 antipyretic, analgesia, anti-inflammatory drug compound preparation method, it is characterized in that: described step 2) in, described stirring velocity is 150-260 rev/min, and adding speed is 80-120 ml/min.
9. according to claim 2 antipyretic, analgesia, anti-inflammatory drug compound preparation method, it is characterized in that: in described step 3), described sound field frequency is 15-20KHz, output rating is 10-20W.
10. according to claim 2 antipyretic, analgesia, anti-inflammatory drug compound preparation method, it is characterized in that: in described step 3), described cooling rate is 2-4 DEG C/h.
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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 |
| CN201610612986.7A CN106220505A (en) | 2015-04-30 | 2015-04-30 | A kind of prepare antipyretic, analgesia, the method for anti-inflammatory drug compound |
| CN201610612992.2A CN106220506A (en) | 2015-04-30 | 2015-04-30 | A kind of prepare antipyretic, analgesia, the method for anti-inflammatory drug compound |
| CN201510216063.5A CN104761449B (en) | 2015-04-30 | 2015-04-30 | A kind of antipyretic, analgesia, anti-inflammatory drug compound and preparation method thereof |
| CN201610620572.9A CN106038504A (en) | 2015-04-30 | 2015-04-30 | Antipyretic analgesic and anti-inflammatory medicine of aspirin enteric-coated tablet |
| CN201610613004.6A CN105997919A (en) | 2015-04-30 | 2015-04-30 | Method for preparing aspirin enteric-coated tablet for removing fever, easing pain and resisting inflammation |
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| CN201610620573.3A Division CN106187772A (en) | 2015-04-30 | 2015-04-30 | A kind of prepare antipyretic, analgesia, the method for anti-inflammatory drug aspirin crystal compound |
| CN201610613004.6A Division CN105997919A (en) | 2015-04-30 | 2015-04-30 | Method for preparing aspirin enteric-coated tablet for removing fever, easing pain and resisting inflammation |
| CN201610620572.9A Division CN106038504A (en) | 2015-04-30 | 2015-04-30 | Antipyretic analgesic and anti-inflammatory medicine of aspirin enteric-coated tablet |
| CN201610612992.2A Division CN106220506A (en) | 2015-04-30 | 2015-04-30 | A kind of prepare antipyretic, analgesia, the method for anti-inflammatory drug compound |
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| CN201610612986.7A Withdrawn CN106220505A (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 |
| CN201510216063.5A Active CN104761449B (en) | 2015-04-30 | 2015-04-30 | A kind of antipyretic, analgesia, anti-inflammatory drug compound and preparation method thereof |
| CN201610620573.3A Withdrawn CN106187772A (en) | 2015-04-30 | 2015-04-30 | A kind of prepare antipyretic, analgesia, the method for anti-inflammatory drug aspirin crystal compound |
| CN201610612992.2A Withdrawn CN106220506A (en) | 2015-04-30 | 2015-04-30 | A kind of prepare antipyretic, analgesia, the method for anti-inflammatory drug compound |
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| CN201610612986.7A Withdrawn CN106220505A (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 |
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| CN201610612992.2A Withdrawn CN106220506A (en) | 2015-04-30 | 2015-04-30 | A kind of prepare antipyretic, analgesia, the method for anti-inflammatory drug compound |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080319068A1 (en) * | 2005-04-27 | 2008-12-25 | Transform Pharmaceuticals, Inc. | Novel Polymorph of Acetylsalicylic Acid, and Methods of Making and Using the Same |
| US20090082592A1 (en) * | 2007-09-21 | 2009-03-26 | Council Of Scientific And Industrial Research. | Green catalytic process for the synthesis of acetyl salicylic acid |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4555399A (en) * | 1983-11-18 | 1985-11-26 | Key Pharmaceuticals, Inc. | Aspirin tablet |
| JP3174818B2 (en) * | 1992-03-05 | 2001-06-11 | 規夫 真崎 | Method for producing crystal with improved dissolution rate |
| WO2004078161A1 (en) * | 2003-02-28 | 2004-09-16 | Transform Pharmaceuticals, Inc. | Pharmaceutical co-crystal compositions of drugs such as carbamazeptine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide, acetaminophen, aspirin, flurbiprofen, phenytoin and ibuprofen |
| CN1442145A (en) * | 2003-01-10 | 2003-09-17 | 郑州市协和制药厂 | Aspilrin slow release tablet |
| CN101486644B (en) * | 2009-02-24 | 2012-07-25 | 合肥工业大学 | Preparation of arginine acetylsalicylate |
| CN101973876B (en) * | 2010-10-12 | 2013-02-20 | 扬州大学 | Synthesis method of acetylsalicylic acid |
| CN103142531B (en) * | 2013-03-27 | 2015-01-14 | 郑州市协和制药厂 | Aspirin slow release tablet and preparation method thereof |
| CN103524533B (en) * | 2013-10-10 | 2016-01-27 | 珠海金鸿药业股份有限公司 | A kind of cefprozil compound, its dispersible tablet, dry suspensoid and preparation method |
| CN103613500B (en) * | 2013-12-13 | 2015-12-09 | 山东新华制药股份有限公司 | The preparation method of acetylsalicylic acid fine crystallization |
| CN104086418A (en) * | 2014-07-14 | 2014-10-08 | 山东省泰和水处理有限公司 | Method for preparing acetyl salicylic acid |
| CN104151163B (en) * | 2014-07-14 | 2016-08-24 | 西安交通大学 | A kind of crystal formation of aspirin and its preparation method and application |
-
2015
- 2015-04-30 CN CN201610613004.6A patent/CN105997919A/en not_active Withdrawn
- 2015-04-30 CN CN201610612986.7A patent/CN106220505A/en not_active Withdrawn
- 2015-04-30 CN CN201610620572.9A patent/CN106038504A/en not_active Withdrawn
- 2015-04-30 CN CN201510216063.5A patent/CN104761449B/en active Active
- 2015-04-30 CN CN201610620573.3A patent/CN106187772A/en not_active Withdrawn
- 2015-04-30 CN CN201610612992.2A patent/CN106220506A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080319068A1 (en) * | 2005-04-27 | 2008-12-25 | Transform Pharmaceuticals, Inc. | Novel Polymorph of Acetylsalicylic Acid, and Methods of Making and Using the Same |
| US20090082592A1 (en) * | 2007-09-21 | 2009-03-26 | Council Of Scientific And Industrial Research. | Green catalytic process for the synthesis of acetyl salicylic acid |
Non-Patent Citations (1)
| Title |
|---|
| 雷春华等: "乙醚在阿司匹林重结晶中的作用", 《化学工程师》, no. 2, 2010 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Also Published As
| Publication number | Publication date |
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| CN105997919A (en) | 2016-10-12 |
| CN106187772A (en) | 2016-12-07 |
| CN106220505A (en) | 2016-12-14 |
| CN106038504A (en) | 2016-10-26 |
| CN106220506A (en) | 2016-12-14 |
| CN104761449B (en) | 2016-08-31 |
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| CB03 | Change of inventor or designer information | ||
| CB03 | Change of inventor or designer information |
Inventor after: Xiang Zhiqiang Inventor after: Ji Rifeng Inventor after: Zheng Fang Inventor after: Yu Meili Inventor after: Jiang Wei Inventor after: Wang Ping Inventor after: Bao Huailai Inventor after: Liu Changsheng Inventor after: Bao Tongwen Inventor after: Zheng Dequan Inventor after: Wu Shaoqin Inventor before: Xiang Zhiqiang Inventor before: Yu Meili Inventor before: Jiang Wei Inventor before: Wang Ping Inventor before: Bao Huailai Inventor before: Liu Changsheng Inventor before: Bao Tongwen |