CN113230221B - Aluminum magnesium pilin tablet (II) - Google Patents
Aluminum magnesium pilin tablet (II) Download PDFInfo
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- CN113230221B CN113230221B CN202110369709.9A CN202110369709A CN113230221B CN 113230221 B CN113230221 B CN 113230221B CN 202110369709 A CN202110369709 A CN 202110369709A CN 113230221 B CN113230221 B CN 113230221B
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- aspirin
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- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 108010000916 Fimbriae Proteins Proteins 0.000 title abstract description 9
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims abstract description 192
- 229960001138 acetylsalicylic acid Drugs 0.000 claims abstract description 191
- 239000011248 coating agent Substances 0.000 claims abstract description 55
- 238000002360 preparation method Methods 0.000 claims abstract description 54
- 238000000576 coating method Methods 0.000 claims abstract description 39
- 239000000203 mixture Substances 0.000 claims abstract description 39
- 239000002994 raw material Substances 0.000 claims abstract description 9
- 239000002245 particle Substances 0.000 claims description 60
- 239000008187 granular material Substances 0.000 claims description 37
- 239000000594 mannitol Substances 0.000 claims description 37
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 36
- 229930195725 Mannitol Natural products 0.000 claims description 36
- 235000010355 mannitol Nutrition 0.000 claims description 36
- 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 claims description 34
- 238000002156 mixing Methods 0.000 claims description 31
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- 239000000843 powder Substances 0.000 claims description 27
- 239000007931 coated granule Substances 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 23
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 21
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 21
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 19
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 18
- 238000007907 direct compression Methods 0.000 claims description 18
- 239000003086 colorant Substances 0.000 claims description 14
- 229910018134 Al-Mg Inorganic materials 0.000 claims description 13
- 229910018467 Al—Mg Inorganic materials 0.000 claims description 13
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 13
- 239000001095 magnesium carbonate Substances 0.000 claims description 13
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 13
- 235000005979 Citrus limon Nutrition 0.000 claims description 12
- 244000131522 Citrus pyriformis Species 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 11
- 239000000463 material Substances 0.000 claims description 11
- 229920002261 Corn starch Polymers 0.000 claims description 9
- 239000008120 corn starch Substances 0.000 claims description 9
- 239000004408 titanium dioxide Substances 0.000 claims description 9
- 238000005507 spraying Methods 0.000 claims description 8
- 239000000853 adhesive Substances 0.000 claims description 7
- 230000001070 adhesive effect Effects 0.000 claims description 7
- 238000000889 atomisation Methods 0.000 claims description 7
- QUVCFQAHXXKABX-UHFFFAOYSA-K C(CO)(=O)[O-].O[Al+]O Chemical compound C(CO)(=O)[O-].O[Al+]O QUVCFQAHXXKABX-UHFFFAOYSA-K 0.000 claims description 6
- 238000005550 wet granulation Methods 0.000 claims description 5
- BWZOPYPOZJBVLQ-UHFFFAOYSA-K aluminium glycinate Chemical compound O[Al+]O.NCC([O-])=O BWZOPYPOZJBVLQ-UHFFFAOYSA-K 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 238000007873 sieving Methods 0.000 claims description 4
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 3
- 229920002472 Starch Polymers 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 239000008107 starch Substances 0.000 claims description 3
- 235000019698 starch Nutrition 0.000 claims description 3
- 239000007921 spray Substances 0.000 claims description 2
- GANNOFFDYMSBSZ-UHFFFAOYSA-N [AlH3].[Mg] Chemical compound [AlH3].[Mg] GANNOFFDYMSBSZ-UHFFFAOYSA-N 0.000 claims 1
- 239000000454 talc Substances 0.000 claims 1
- 235000012222 talc Nutrition 0.000 claims 1
- 229910052623 talc Inorganic materials 0.000 claims 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 abstract description 36
- 238000012360 testing method Methods 0.000 abstract description 20
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 abstract description 18
- 229960004889 salicylic acid Drugs 0.000 abstract description 18
- 238000011835 investigation Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 18
- 230000000052 comparative effect Effects 0.000 description 15
- 238000004090 dissolution Methods 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 235000014380 magnesium carbonate Nutrition 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000012535 impurity Substances 0.000 description 8
- 239000004033 plastic Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 6
- 229910052782 aluminium Inorganic materials 0.000 description 6
- 238000007906 compression Methods 0.000 description 6
- 230000006835 compression Effects 0.000 description 6
- 238000004806 packaging method and process Methods 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000007858 starting material Substances 0.000 description 5
- 229920000858 Cyclodextrin Polymers 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000001116 FEMA 4028 Substances 0.000 description 4
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 4
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 4
- 229960004853 betadex Drugs 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000013112 stability test Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 3
- 241000282320 Panthera leo Species 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000013065 commercial product Substances 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 235000001258 Cinchona calisaya Nutrition 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 2
- 230000032798 delamination Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 2
- 229960000948 quinine Drugs 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- DEXFNLNNUZKHNO-UHFFFAOYSA-N 6-[3-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperidin-1-yl]-3-oxopropyl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1CCN(CC1)C(CCC1=CC2=C(NC(O2)=O)C=C1)=O DEXFNLNNUZKHNO-UHFFFAOYSA-N 0.000 description 1
- 208000011200 Kawasaki disease Diseases 0.000 description 1
- 206010061297 Mucosal erosion Diseases 0.000 description 1
- 241000121220 Tricholoma matsutake Species 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- GULNRVTWPJODDE-UHFFFAOYSA-K aluminum;2-(dihydroxyamino)acetate Chemical compound [Al+3].ON(O)CC([O-])=O.ON(O)CC([O-])=O.ON(O)CC([O-])=O GULNRVTWPJODDE-UHFFFAOYSA-K 0.000 description 1
- UTUUIUQHGDRVPU-UHFFFAOYSA-K aluminum;2-aminoacetate;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Al+3].NCC([O-])=O UTUUIUQHGDRVPU-UHFFFAOYSA-K 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229940057344 bufferin Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- RBNPZEHAODHBPZ-UHFFFAOYSA-M dihydroxyaluminium Chemical compound O.O.NCC(=O)O[Al] RBNPZEHAODHBPZ-UHFFFAOYSA-M 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000012154 double-distilled water Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000030136 gastric emptying Effects 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000011812 mixed powder Substances 0.000 description 1
- 208000001725 mucocutaneous lymph node syndrome Diseases 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000009475 tablet pressing Methods 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
Images
Classifications
-
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
- A61K33/10—Carbonates; Bicarbonates
-
- 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
- A61K9/2009—Inorganic compounds
-
- 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
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- 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
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
- A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
-
- 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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
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- Molecular Biology (AREA)
- Diabetes (AREA)
- Biophysics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides an aluminum magnesium Pilin tablet (II) and a preparation method thereof. The aluminum magnesium pirlind tablet (II) is a double-layer tablet consisting of an aspirin layer and a buffer layer, the raw materials comprise an aspirin layer composition and a buffer layer composition, and the mass ratio of the aspirin layer composition to the buffer layer composition is (0.8); wherein in the aspirin layer composition, 80% w/w aspirin is
Description
Technical Field
The invention belongs to the field of pharmaceutics and particularly relates to an aluminum magnesium pirlind tablet (II) and a preparation method thereof.
Background
Magadium matsutake (ii) was first developed by the japan Lion king (Lion) pharmaceutical company, approved for marketing as an antiplatelet inhibitor in japan at 9/19 of 2000, and increased in its indications for treating kawasaki disease at 11/2005. The commercial product is "バファリン fudge-FIG. A81" (BUFFERIN).
Each tablet of the aluminum magnesium pirlin tablet (II) contains 81mg of aspirin, 22mg of heavy magnesium carbonate and 11mg of dihydroxyaluminium glycolate. The alkaline components of heavy magnesium carbonate and dihydroxyaluminium glycinate can reduce the adverse stimulation of aspirin to stomach, obviously reduce the incidence rate of gastrointestinal mucosal erosion and ulcer, and increase the absorption rate of aspirin. In addition, the heavy magnesium carbonate and the dihydroxyaluminium aminoacetate can accelerate the gastric emptying, so that the aspirin can rapidly enter the small intestine which is the main absorption part. However, aspirin is unstable to moist heat, and when it is mixed with alkaline components, it is hydrolyzed easily to produce free salicylic acid, which affects the stability of the medicine. Therefore, in order to effectively isolate aspirin from alkaline components and increase product stability, the Almagainin tablet (II) is generally prepared into a double-layer tablet. However, in accelerated stability studies, the free salicylic acid content of the current commercial bilayer tablet is found to increase rapidly. Free salicylic acid is more irritating to the stomach than aspirin and therefore the levels need to be strictly controlled. The control limit of the related standard free salicylic acid of the Almagadium Picolina tablet (II) is not more than 1.5 percent. In order to ensure the medication safety of patients, the aluminum magnesium quinine tablet (II) should be strictly controlled and limited to free salicylic acid.
In order to improve the stability of the preparation, the Chinese invention patent application with the publication number CN 106727380A (2017, 5, 31) provides an aluminum magnesium pilin tablet (II). The aluminum magnesium pirlin tablet (II) is prepared from an aspirin layer and a buffer laminated tablet; the raw materials of the aspirin layer and the buffer layer are crushed and sieved by a sieve of 80 meshes, then gelatin is dissolved by 95% ethanol to prepare gelatin slurry, aspirin layer particles and buffer layer particles are respectively prepared by the gelatin slurry through wet granulation, and finally, a double-layer tablet press is adopted for tabletting to obtain the aluminum magnesium pilin tablet (II). In the preparation method, 95% ethanol is adopted, so that the cost is increased, and hidden danger is brought to safe production. In addition, the aspirin is crushed and sieved by a 80-mesh sieve, and the increase of the surface area is helpful for improving dissolution, but simultaneously increases the contact area with auxiliary materials, thereby bringing unstable factors. In addition, aspirin is poorly compressible, very prone to delamination when compressed into bilayer tablets, and not conducive to product control.
The invention patent application of publication number CN102961398A also discloses a preparation method of an almatypillin double-layer tablet, which adopts beta-cyclodextrin to respectively include active ingredients of an aspirin layer and a buffer layer; the preparation method of the aspirin layer granules comprises the following steps: firstly, coating aspirin with beta-cyclodextrin in the total prescription amount, and then mixing the aspirin with other auxiliary materials to prepare aspirin layer particles; the preparation method of the buffer layer particles comprises the following steps: the aluminum dihydroxyglycinate and the heavy magnesium carbonate with the prescription amount are firstly included by beta-cyclodextrin and then mixed with other auxiliary materials to obtain the buffer layer particles. The method has more working procedures and lower inclusion yield of the beta-cyclodextrin, and is not beneficial to controlling the manufacturing cost.
Disclosure of Invention
In order to overcome the defects of the prior art and strictly control the content of free salicylic acid, the invention provides a pharmaceutical composition for preparing an aluminum magnesium pirlind tablet (II), a method for preparing the aluminum magnesium pirlind tablet (II) based on the pharmaceutical composition and the aluminum magnesium pirlind tablet (II) prepared by the method.
The invention adopts the following technical scheme:
an aluminum magnesium pirlind tablet (II) is a double-layer tablet consisting of an aspirin layer and a buffer layer, the raw materials comprise an aspirin layer composition and a buffer layer composition, and the mass ratio of the aspirin layer composition to the buffer layer composition is 0.8; wherein in the aspirin layer composition, 80% w/w aspirin is
Coating with the premixed coating agent.
Preferably, the mass ratio of the aspirin layer composition to the buffer layer composition is 1:1.
Preferably, the composition of the aspirin layer composition is:
81 parts of aspirin,
2.5-5 parts of premixed coating agent, 6-10 parts of direct-compression mannitol, 2-4 parts of talcum powder, 3-5 parts of low-substituted hydroxypropyl cellulose, 0-2 parts of titanium dioxide and 0-1 part of coloring agent.
Further preferably, the composition of the aspirin layer composition is:
81 parts of aspirin,
2.5-4 parts of premixed coating agent, 7-8.5 parts of direct-compression mannitol, 2-4 parts of talcum powder, 3-5 parts of low-substituted hydroxypropyl cellulose, 0-2 parts of titanium dioxide and 0-1 part of coloring agent.
Preferably, the
The pre-mixed coating agent is selected from
IR White、
IR or
Protect。
Preferably, the mannitol is mannitol
100SD or Parteck TM M100。
Preferably, the colorant is a lemon yellow aluminum lake.
Preferably, the composition of the buffer layer composition is:
11 parts of dihydroxyaluminium glycolate, 22 parts of heavy magnesium carbonate, 40-50 parts of mannitol, 7-13 parts of corn starch, 3-5 parts of low-substituted hydroxypropyl cellulose, 0.05-0.3 part of lemon Huang Lvse starch, 0.5-2 parts of hydroxypropyl cellulose and 4-8 parts of talcum powder.
More preferably, the composition of the buffer layer composition is:
11 parts of dihydroxyaluminium glycolate, 22 parts of heavy magnesium carbonate, 46 parts of mannitol, 10 parts of corn starch, 4 parts of low-substituted hydroxypropyl cellulose, 0.1 part of lemon Huang Lv lake, 0.8 part of hydroxypropyl cellulose and 6 parts of talcum powder.
Preferably, the hydroxypropylcellulose is selected from the group consisting of ashitabaKlucel of blue (Ashland) TM Hydroxypropylcellulose EF or CENLY of Japan Caoda TM Hydroxypropylcellulose SL.
The invention also aims to provide a preparation method of the aluminum magnesium Pirine tablet (II), which takes the pharmaceutical composition as a raw material and comprises the following steps:
I. preparation of aspirin layer total mixed granules
I-1, preparing all components of the aspirin layer according to parts by weight;
i-2 preparation of Aspirin coated granule
Mixing the components in parts by weight
Premixing coating agent, 40-50% of talcum powder, titanium dioxide, colorant and water to prepare aspirin powder coating liquid with solid content of 10-30%; coating 80% of aspirin in parts by weight with the aspirin powder coating solution to obtain aspirin coated particles with the water content of less than or equal to 0.5%;
i-3 preparation of Aspirin layer Total particles
Uniformly mixing the aspirin coated particles prepared in the step I-2 with the rest of aspirin, the part by weight of the direct compression mannitol and the part by weight of the low-substituted hydroxypropyl cellulose, then adding the rest part by weight of the talcum powder, and uniformly mixing to obtain aspirin layer total particles;
preparation of buffer layer Total Mixed particles
II-1, preparing the components of the buffer layer according to parts by weight;
II-2, sieving the mannitol in parts by weight with a 50-mesh sieve for later use;
II-3, dissolving the hydroxypropyl cellulose in parts by weight in water to prepare an adhesive solution with the mass percentage concentration of 4%;
II-4, mixing the dihydroxyaluminum glycinate, the heavy magnesium carbonate, the corn starch, the low-substituted hydroxypropyl cellulose, the lemon Huang Lv lake and the screened mannitol obtained in the step II-2 in parts by weight, adding the adhesive solution prepared in the step II-2 for wet granulation, drying at 50-70 ℃ until the water content of the granules is less than or equal to 3.0%, granulating, adding the talcum powder in parts by weight, and uniformly mixing to obtain the total mixed granules of the buffer layer;
III double layer tabletting
And (3) tabletting the aspirin total mixed particles prepared in the step (I) and the buffer layer total mixed particles prepared in the step (II) in a double-layer tabletting machine according to the mass ratio of 0.8.
Preferably, in the step I, the particle size of the aspirin is 40-150 meshes.
Preferably, in the step I-2, the coating is carried out in a fluidized bed bottom spray coating machine.
Further preferably, in the step I-2, the process parameters of coating by using the fluidized bed bottom spraying coating machine are as follows:
the frequency of a fan is 19-23Hz, the air inlet temperature is 35-40 ℃, the material temperature is 28-30 ℃, the liquid supply rotating speed is 7-13rpm, and the atomization pressure is 0.15Mpa.
Preferably, in the step III, the mass ratio of the aspirin layer total mixed particles to the buffer layer total mixed particles is 1:1.
The third purpose of the invention is to provide the aluminum magnesium pilar tablet (II) obtained by the preparation method.
In the present specification, "parts by weight" of each raw material is not a unit of mass, but is a weight (mass) ratio relationship of each raw material. As the case may be, 1 part by weight may be 1g, 10g, 500g, 1kg, or any other mass.
In the present specification, unless otherwise specified, the "water" is purified water and is selected from distilled water, double distilled water, deionized water, and the like.
Through an accelerated 6-month stability investigation test (40 +/-2 ℃ and RH75 +/-5%), the content of free salicylic acid in the aluminum magnesium quinine tablet (II) provided by the invention is below 0.41%, which is far lower than that of a commercially available preparation of the same variety, so that the medication safety of patients is better ensured. Moreover, during the stability test, the tablet of the present invention showed no delamination or the like, indicating good stability.
Drawings
The invention will be further described with reference to the accompanying drawings.
FIG. 1 is a graph showing the dissolution profile measured in test example 2.
Detailed Description
The invention is illustrated below with reference to specific examples. It will be understood by those skilled in the art that these examples are merely illustrative of the present invention and do not limit the scope of the present invention in any way.
The experimental procedures in the following examples are all conventional ones unless otherwise specified. The raw materials and auxiliary materials used in the following examples are all commercially available products unless otherwise specified. Wherein,
from basf; the mannitol is derived from Rogat
100SD or Merck Parteck TM M100; the hydroxypropylcellulose is selected from Klucel of Ashland (Ashland) TM Hydroxypropylcellulose EF or CENLY of Japan Caoda TM Hydroxypropylcellulose SL.
In the equipment used in the following examples, the fluidized bed bottom spray coater was from pioneer science and technology; the bi-layer tablet press is from shanghai tianfeng pharmaceutical facilities limited.
The invention provides an aluminum magnesium pirlind tablet (II), which is a double-layer tablet consisting of an aspirin layer and a buffer layer, and comprises raw materials of an aspirin layer composition and a buffer layer composition, wherein the mass ratio of the aspirin layer composition to the buffer layer composition is 0.8; wherein in the aspirin layer composition, 80% w/w of aspirin is
Coating with pre-mixed coating agent.
In practice, in order to facilitate production, aspirin coated particles can be prepared separately, aspirin layer total mixed particles are prepared according to a proportion, and finally the aspirin layer total mixed particles and the buffer layer total mixed particles are tabletted to prepare the aluminum magnesium pirlind tablet (II).
In the following examples and comparative examples, the preparation process of the aluminum magnesium pirlind sheet (ii) is not strictly described according to the preparation method described in the summary of the invention, but the method and process are within the scope of the present invention.
In the following examples and comparative examples, 1 part by weight =10g.
Example 1 an Al-Mg Pilin tablet (II)
The Al-Mg-Pilin tablet (II) described in this example was a two-layer tablet composed of an aspirin layer and a buffer layer, in the aspirin layer, 80% w/w of aspirin was dissolved
Coating with the premixed coating agent.
The almag pin sheet (ii) of this example was prepared by the following method:
I. preparation of aspirin layer Total granule
(1) Preparation of aspirin coated granule
200 parts of aspirin (40-150 meshes)
Purified water 48 parts by weight
Taking the prescribed amount of water, adding
White, stirring and dissolving to obtain the aspirin powder coating liquid. And (3) putting the aspirin powder into a fluidized bed bottom spray coating machine for coating until the coating solution is completely coated to obtain the aspirin coated granules. The operating parameters are as follows: the frequency of the fan is 19-23Hz; air inlet temperature: 35-40 ℃; the material temperature is 28-30 ℃; the liquid supply rotating speed is 7-13rpm; the atomization pressure is 0.15Mpa.
(2) Preparation of aspirin layer total mixed granule
68.9 parts by weight of aspirin-coated particles (prepared in step I-1, which contain 65 parts by weight of aspirin);
16 parts of aspirin (40-150 meshes)
8.1 parts by weight of direct-compression mannitol
4 parts of low-substituted hydroxypropyl cellulose
3 parts of talcum powder
Uniformly mixing the aspirin coated granules, aspirin, direct-compression mannitol and low-substituted hydroxypropyl cellulose, and then adding talcum powder and mixing for 4 minutes to obtain the aspirin layer total mixed granules.
Preparation of buffer layer Total Mixed particles
11 parts of dihydroxyaluminum glycolate
22 parts by weight of heavy magnesium carbonate
Mannitol 46 parts by weight
10 parts of corn starch
4 parts of low-substituted hydroxypropyl cellulose
0.1 part by weight of lemon Huang Lv lake
Hydroxypropyl cellulose 0.8 part by weight
6 parts by weight of talcum powder
Sieving mannitol with 50 mesh sieve; dissolving hydroxypropyl cellulose EF in water to prepare a 4 mass percent adhesive solution for later use; adding dihydroxyaluminum glycinate, heavy magnesium carbonate, mannitol, corn starch, low-substituted hydroxypropyl cellulose and lemon Huang Lvse starch into a wet mixing granulator, and stirring and premixing for 3 minutes; adding a binder solution for wet granulation; drying at 50-70 deg.C until the water content of the granule is less than or equal to 3.0% to obtain dried granule; granulating the dried granules by using a conical granulator to obtain granulated granules; and adding talcum powder into the whole granules to obtain the buffer layer total mixed granules.
III, double layer tablet compression
100 parts by weight of aspirin total mixed particles prepared in step I
Step II of preparing buffer layer Total Mixed particles 100 parts by weight
And tabletting the aspirin total mixed particles and the buffer layer total mixed particles in a double-layer tabletting machine, wherein each tablet is 0.2g, and packaging by aluminum plastic.
Example 2 an Al-Mg Pilin tablet (II)
The Al-Mg-Pilin tablet (II) described in this example was a two-layer tablet composed of an aspirin layer and a buffer layer, in the aspirin layer, 80% w/w of aspirin was dissolved
Coating with the premixed coating agent.
The almag pin sheet (ii) of this example was prepared by the following method:
I. preparation of aspirin layer Total granule
(1) Preparation of aspirin coated granule
200 parts of aspirin (40-150 meshes)
2.5 parts of talcum powder
Titanium dioxide 2 parts by weight
Colorant 1 part by weight
Purified water 83.5 parts by weight
Taking the prescribed amount of water and adding
IR, talcum powder, titanium dioxide and colorant are uniformly stirred and dispersed to be used as aspirin powder coating liquid. And (3) putting the aspirin powder into a fluidized bed bottom spray coating machine for coating until the coating solution is completely coated to obtain the aspirin coated granules. The operating parameters are as follows: the frequency of the fan is 19-23Hz; air inlet temperature: 35-40 ℃; the material temperature is 28-30 ℃; the liquid supply rotating speed is 7-13rpm; the atomization pressure is 0.15Mpa.
(2) Preparation of aspirin layer total mixed granule
70 parts by weight of aspirin-coated granule (prepared in step I-1, containing 65 parts by weight of aspirin)
16 parts of aspirin (40-150 meshes)
Direct compression mannitol 7 weight parts
4 parts of low-substituted hydroxypropyl cellulose
3 parts of talcum powder
Mixing the aspirin coated granule, aspirin, direct-compression mannitol, and low-substituted hydroxypropyl cellulose, adding pulvis Talci, and mixing for 4 min to obtain aspirin layer total mixed granule.
Preparation of buffer layer Total Mixed particles
The starting materials and preparation were the same as in step II of example 1.
III, double layer tablet compression
100 parts by weight of aspirin total mixed particles prepared in step I
Step II of preparing buffer layer Total Mixed particles 100 parts by weight
Tabletting the aspirin total mixed particles and the buffer layer total mixed particles in a double-layer tabletting machine, wherein each tablet is 0.2g, and packaging by aluminum plastic.
EXAMPLE 3 an Al-Mg Pilin tablet (II)
The Al-Mg-Pilin tablet (II) described in this example was a two-layer tablet composed of an aspirin layer and a buffer layer, in the aspirin layer, 80% w/w of aspirin was dissolved
Coating with pre-mixed coating agent.
The almag pin sheet (ii) of this example was prepared by the following method:
I. preparation of aspirin layer Total granule
(1) Preparation of aspirin coated granule
200 parts of aspirin (40-150 meshes)
3 parts of talcum powder
Colorant 1 part by weight
86 parts by weight of purified water
Taking the prescribed amount of water, adding
Protect, talcum powder and colorant are evenly stirred and dispersed to be used as the coating liquid of aspirin powder. And (3) putting the aspirin powder into a fluidized bed bottom spray coating machine for coating until the coating solution is completely coated to obtain the aspirin coated granules. The operating parameters are as follows: the frequency of the fan is 19-23Hz; air inlet temperature: 35-40 ℃; the material temperature is 28-30 ℃; the liquid supply rotating speed is 7-13rpm; the atomization pressure is 0.15Mpa.
(2) Preparation of aspirin layer total mixed granule
69.6 parts by weight of aspirin-coated granule (prepared in step I-1, containing 65 parts by weight of aspirin)
16 parts of aspirin (40-150 meshes)
7.4 parts by weight of direct-compression mannitol
4 parts of low-substituted hydroxypropyl cellulose
3 parts of talcum powder
Mixing the aspirin coated granule, aspirin, direct-compression mannitol, and low-substituted hydroxypropyl cellulose, adding pulvis Talci, and mixing for 4 min to obtain aspirin layer total mixed granule.
Preparation of buffer layer Total Mixed particles
The starting materials and preparation were the same as in step II of example 1.
III. Double layer tablet compression
100 parts by weight of aspirin total mixed particles prepared in step I
100 parts by weight of the aluminum-magnesium layer total mixed particle prepared in the step II
And tabletting the aspirin total mixed particles and the buffer layer total mixed particles in a double-layer tabletting machine, wherein each tablet is 0.2g, and packaging by aluminum plastic.
COMPARATIVE EXAMPLE 1 an Al-Mg Pilin tablet (II)
The aluminum magnesium pilin tablet (ii) of this comparative example was prepared by the following method:
I. preparation of aspirin layer total mixed powder
81 parts by weight of aspirin powder (40-150 meshes)
12 parts by weight of direct-compression mannitol
4 parts of low-substituted hydroxypropyl cellulose
3 parts of talcum powder
Mixing aspirin powder, direct-pressure mannitol, and low-substituted hydroxypropyl cellulose, adding pulvis Talci, and mixing for 4 min.
Preparation of buffer layer Total Mixed particles
The starting materials and preparation were the same as in step II of example 1.
III. Double layer tablet compression
100 parts by weight of aspirin total mixed particles prepared in step I
100 parts by weight of buffer layer total mixed particles prepared in step II
Tabletting the aspirin total mixed particles and the buffer layer total mixed particles in a double-layer tabletting machine, wherein each tablet is 0.2g, and packaging by aluminum plastic.
COMPARATIVE EXAMPLE 2 an Al-Mg Pilin tablet (II)
The aluminum magnesium pilin tablet (ii) of this comparative example was prepared by the following method:
I. preparation of aspirin layer Total granule
(1) Preparation of aspirin coated granule
200 parts of aspirin (40-150 meshes)
Purified water 48 parts by weight
Taking the prescribed amount of water, adding
And IR White, stirring and dissolving to obtain the aspirin powder coating solution. And (3) putting the aspirin powder into a fluidized bed bottom spray coating machine for coating until the coating solution is completely coated to obtain the aspirin coated granules. The operating parameters are: the frequency of the fan is 19-23Hz; air inlet temperature: 35-40 ℃; the material temperature is 28-30 ℃; the liquid supply rotating speed is 7-13rpm; the atomization pressure is 0.15Mpa.
(2) Preparation of aspirin layer total mixed granule
Aspirin coated granule 42.4 parts by weight (prepared in step I-1, containing aspirin 41 parts by weight)
41 parts of aspirin (40-150 meshes)
Direct compression mannitol 9.6 weight parts
4 parts of low-substituted hydroxypropyl cellulose
3 parts of talcum powder
Mixing the aspirin coated granule, aspirin, direct-compression mannitol, and low-substituted hydroxypropyl cellulose, adding pulvis Talci, and mixing for 4 min to obtain aspirin layer total mixed granule.
Preparation of buffer layer Total Mixed particles
The starting materials and preparation were the same as in step II of example 1.
III. Double layer tablet compression
100 parts by weight of aspirin total mixed particles prepared in step I
Step II of preparing buffer layer Total Mixed particles 100 parts by weight
And tabletting the aspirin total mixed particles and the buffer layer total mixed particles in a double-layer tabletting machine, wherein each tablet is 0.2g, and packaging by aluminum plastic.
COMPARATIVE EXAMPLE 3 an Al-Mg Pilin tablet (II)
The aluminum magnesium pilin tablet (ii) of this comparative example was prepared by the following method:
I. preparation of aspirin layer Total granules
(1) Preparation of aspirin coated granule
200 parts of aspirin (40-150 meshes)
Purified water 48 parts by weight
Taking the prescribed amount of water, adding
And IR, stirring and dissolving to obtain the aspirin powder coating solution. And (3) putting the aspirin powder into a fluidized bed bottom spray coating machine for coating until the coating solution is completely coated to obtain the aspirin coated granules. The operating parameters are: the frequency of the fan is 19-23Hz; air inlet temperature: 35-40 ℃; the material temperature is 28-30 ℃; the liquid supply rotating speed is 7-13rpm; the atomization pressure is 0.15Mpa.
(2) Preparation of aspirin layer total mixed granule
85.9 parts by weight of aspirin-coated granule (prepared in step I-1, containing 81 parts by weight of aspirin)
Direct compression mannitol 7.1 weight parts
4 parts of low-substituted hydroxypropyl cellulose
3 parts of talcum powder
Mixing the aspirin coated granule, direct-pressure mannitol, and low-substituted hydroxypropyl cellulose, adding pulvis Talci, and mixing for 4 min.
Preparation of buffer layer Total Mixed particles
The starting materials and preparation were the same as in step II of example 1.
III, double layer tablet compression
100 parts by weight of aspirin total mixed particles prepared in step I
Step II of preparing buffer layer Total Mixed particles 100 parts by weight
And tabletting the aspirin total mixed particles and the buffer layer total mixed particles in a double-layer tabletting machine, wherein each tablet is 0.2g, and packaging by aluminum plastic.
Test example 1. Evaluation of stability test:
the Al-Mg Pilin tablets (II) (aluminum-plastic packages) obtained in examples 1 to 3 and comparative examples 1 to 3 and test examples 1 to 2 were subjected to an accelerated 6-month stability test (40. + -. 2 ℃ C., RH 75. + -. 5%). And (4) inspecting whether the tablet is layered or not, and determining the content of aspirin and the content of salicylic acid serving as an impurity by adopting a high performance liquid chromatography.
(1) The aspirin content determination method comprises the following steps: measuring by high performance liquid chromatography (China pharmacopoeia 2020 edition four-part general regulation 0512).
Solvent: 1% glacial acetic acid in methanol.
Test solution: taking 10 samples to be tested, precisely weighing, grinding, precisely weighing an appropriate amount of fine powder (containing 80mg of aspirin), placing in a 100ml measuring flask, adding an appropriate amount of solvent, shaking to dissolve the fine powder, diluting with the solvent to scale, shaking uniformly, filtering, and taking a subsequent filtrate.
Control solution: taking a proper amount of aspirin reference substance, precisely weighing, adding a solvent to dissolve, and quantitatively diluting to prepare a solution containing about 0.8mg in each 1 ml.
Chromatographic conditions and system applicability test using octadecylsilane chemically bonded silica as a filler, acetonitrile-tetrahydrofuran-glacial acetic acid-water (volume ratio 20; the detection wavelength is 276nm; the injection volume was 10. Mu.l.
(2) The method for measuring the content of salicylic acid impurities comprises the following steps: measuring by high performance liquid chromatography (China pharmacopoeia 2020 edition four-part general regulation 0512).
Solvent: 1% glacial acetic acid in methanol.
Test solution: is used newly. Taking about 0.lg of sample fine powder to be measured, accurately weighing, placing in a 10ml measuring flask, adding a proper amount of methanol solution of 1% glacial acetic acid, shaking to dissolve, diluting to scale, and shaking uniformly to obtain the product.
Control solution: an appropriate amount of salicylic acid control was weighed precisely, dissolved in a solvent and diluted to make a solution containing about 600. Mu.g per 1 ml.
Chromatographic conditions and system applicability test using octadecylsilane chemically bonded silica as a filler, acetonitrile-tetrahydrofuran-glacial acetic acid-water (volume ratio 20; the detection wavelength is 303nm; the injection volume was 10. Mu.l.
The results are shown in Table 1.
TABLE 1 two-layer tablet accelerated test (40. + -. 2 ℃ C., RH 75. + -. 5%) stability test results
Note that: test example 1 is a commercial product of Japanese lion Wang Lvmei Ping tablet (II); test example 2 is a commercial product of Al-Mg Pilin tablet (II) produced in a certain country
The results in table 1 show that the aluminum magnesium pirlind tablet prepared by the technology has no layering phenomenon, stable aspirin and low content of impurity salicylic acid.
Comparative example 1 the aspirin layer was powder pressed directly: the product is layered in 6 months; and the content of the impurity salicylic acid is more than 1.0 percent. The reason for this analysis is probably that due to the powder direct compression process, the aspirin and the aluminum magnesium layer are still partially contacted, and in the presence of a small amount of moisture, alkaline substances continuously permeate into the aspirin layer, so that aspirin is continuously degraded into salicylic acid.
Comparative example 2 the aspirin layer was coated with 50% aspirin powder, and the 50% powder was directly pressed: the content of impurity salicylic acid is accelerated to be less than 1.0 percent in 6 months; but the product appeared to delaminate.
Comparative example 3 aspirin was all coated and then compressed with the buffer layer granules into a bi-layer tablet: the product did not delaminate at 6 months of acceleration and the impurity salicylic acid content was < 1.0%, but the dissolution results showed a slightly slower dissolution, see table 2 and figure 1.
The test example 1 and the test example 2 are commercial products, and the content of the impurity salicylic acid exceeds 1.0% in the accelerated 6 months.
And (4) conclusion: the invention adopts aspirin powder coating and double-layer tablet pressing, reduces contact between aspirin and aluminum magnesium layer to the maximum extent, and accelerates the content of stable impurity salicylic acid not to be obviously increased within 6 months.
Test example 2 dissolution curve determination:
the dissolution rate measuring method comprises the steps of taking the aluminum magnesium pilin tablets of the examples 1-3, the comparative example 3 and the test examples 1-2, measuring according to a second method paddle method for measuring the dissolution rate of Chinese pharmacopoeia, taking 900ml of hydrochloric acid solution with the pH value of 1.2 as a dissolution medium, rotating at the speed of 50rpm, and measuring by adopting a high performance liquid chromatography. The results are shown in Table 2 and FIG. 1.
TABLE 2 determination of dissolution Profile in pH1.2 medium (unit:%)
| Time (min) | Example 1 | Example 2 | Example 3 | Comparative example 3 | Test example 1 | Test example 2 |
| 5 | 28.9 | 30.0 | 26.6 | 16.1 | 29.1 | 39.8 |
| 10 | 44.0 | 42.9 | 38.7 | 23.9 | 42.6 | 59.6 |
| 15 | 53.2 | 51.6 | 47.2 | 31.2 | 51.7 | 72.9 |
| 30 | 68.6 | 66.0 | 62.3 | 48.2 | 67.0 | 93.0 |
| 45 | 78.6 | 75.3 | 71.6 | 60.5 | 76.6 | 98.2 |
| 60 | 85.3 | 82.2 | 79.3 | 70.2 | 83.4 | 100.7 |
| 90 | 93.2 | 91.4 | 88.9 | 83.5 | 92.5 | 101.2 |
| 120 | 99.1 | 96.7 | 95.6 | 91.1 | 98.1 | 102.3 |
Both table 2 and fig. 1 show that the dissolution curves of examples 1 to 3 and test example 1 are close; the dissolution of comparative example 3 was slower than that of examples 1 to 3 and test example 1; the dissolution of test example 2 was faster than that of test example 1. Therefore, the results show that the invention improves the stability of the product and simultaneously the dissolution behavior is not affected.
Claims (18)
1. An aluminum magnesium sprilin tablet (II) is a double-layer tablet consisting of an aspirin layer and a buffer layer, the raw materials comprise an aspirin layer composition and a buffer layer composition, and the mass ratio of the aspirin layer composition to the buffer layer composition is 0.8; wherein in the aspirin layer composition, 80% w/w of aspirin is Kollicoat ® Coating with a pre-mixed coating agent;
the composition of the aspirin layer is as follows:
81 parts by weight of aspirin and Kollicoat ® 2.5-5 parts of premixed coating agent, 6-10 parts of direct-compression mannitol, 2-4 parts of talcum powder, 3-5 parts of low-substituted hydroxypropyl cellulose, 0-2 parts of titanium dioxide and 0-1 part of coloring agent;
the composition of the buffer layer composition is as follows:
11 parts of dihydroxyaluminium glycolate, 22 parts of heavy magnesium carbonate, 40-50 parts of mannitol, 7-13 parts of corn starch, 3-5 parts of low-substituted hydroxypropyl cellulose, 0.05-0.3 part of lemon Huang Lvse starch, 0.5-2 parts of hydroxypropyl cellulose and 4-8 parts of talcum powder;
the aluminum magnesium sprilin tablet (II) is prepared by the following steps:
I. preparation of aspirin layer total mixed granules
I-1, preparing all components of the aspirin layer according to parts by weight;
i-2 preparation of Aspirin coated granules
Mixing the said parts by weight of Kollicoat ® Mixing 40-50% of a pre-mixed coating agent, 40-50% of talcum powder, titanium dioxide, a colorant and water to prepare an aspirin powder coating solution with a solid content of 10-30%; coating 80% of aspirin in parts by weight with the aspirin powder coating solution to obtain the aspirin powder with the water content less than or equal to0.5% of aspirin coated granules;
i-3 preparation of Aspirin layer Total granules
Uniformly mixing the aspirin coated particles prepared in the step I-2 with the rest of aspirin, the part by weight of the direct compression mannitol and the part by weight of the low-substituted hydroxypropyl cellulose, then adding the rest part by weight of the talcum powder, and uniformly mixing to obtain aspirin layer total particles;
preparation of buffer layer Total Mixed particles
II-1, preparing the components of the buffer layer according to parts by weight;
II-2, sieving the mannitol in parts by weight with a 50-mesh sieve for later use;
II-3, dissolving the hydroxypropyl cellulose in parts by weight in water to prepare an adhesive solution with the mass percentage concentration of 4%;
II-4, mixing the dihydroxyaluminum glycinate, the heavy magnesium carbonate, the corn starch, the low-substituted hydroxypropyl cellulose, the lemon Huang Lv lake and the screened mannitol obtained in the step II-2 in parts by weight, adding the adhesive solution prepared in the step II-3 for wet granulation, drying at 50-70 ℃ until the water content of the granules is less than or equal to 3.0%, granulating, adding the talcum powder in parts by weight, and uniformly mixing to obtain the total mixed granules of the buffer layer;
III double layer tabletting
And (3) tabletting the aspirin total mixed granules prepared in the step I and the buffer layer total mixed granules prepared in the step II in a double-layer tablet machine according to the mass ratio of 0.8.
2. The aluminum magnesium pirlind tablet (ii) according to claim 1, wherein the mass ratio of the aspirin layer composition to the buffer layer composition is 1:1.
3. The almatmagine tablet (ii) according to claim 1 or 2, characterized in that the composition of the aspirin layer composition is:
81 parts by weight of aspirin and Kollicoat ® 2.5-4 parts of premixed coating agent, 7-8.5 parts of direct-compression mannitol and 2-4 parts of talcum powder3-5 parts of low-substituted hydroxypropyl cellulose, 0-2 parts of titanium dioxide and 0-1 part of colorant.
4. The Al-Mg Pilin sheet (II) according to claim 1, wherein said Kollicoat is ® The pre-mixed coating agent is selected from Kollicoat ® IR White、Kollicoat ® IR or Kollicoat ® Protect。
5. The Al-Mg Pilin sheet (II) according to claim 3, wherein said Kollicoat is ® The pre-mixed coating agent is selected from Kollicoat ® IR White、Kollicoat ® IR or Kollicoat ® Protect。
6. The Al-Mg Pilin tablet (II) according to claim 1, wherein said mannitol is PEARLITOL ® 100SD or Parteck. TM.M 100.
7. The Al-Mg Pilin tablet (II) according to claim 3, wherein the mannitol is PEARLITOL ® 100SD or Partech. TM.M 100.
8. The aluminum magnesium pirlind sheet (ii) according to claim 1, wherein the colorant is lemon yellow aluminum lake.
9. The aluminum magnesium pirlind sheet (ii) according to claim 3, wherein the colorant is lemon yellow aluminum lake.
10. The aluminum magnesium pirlind sheet (ii) according to claim 1 or 2, wherein the composition of the buffer layer composition is:
11 parts of dihydroxyaluminium glycolate, 22 parts of heavy magnesium carbonate, 46 parts of mannitol, 10 parts of corn starch, 4 parts of low-substituted hydroxypropyl cellulose, 0.1 part of lemon Huang Lv lake, 0.8 part of hydroxypropyl cellulose and 6 parts of talcum powder.
11. The aluminium magnesium piece (II) of claim 1, wherein the hydroxypropylcellulose is selected from the group consisting of Klucel ™ hydroxypropyl cellulose EF of Ashland Asia or CENLY ™ hydroxypropyl cellulose SL of Japanese Caoda.
12. The Al-Mg Piclin tablet (II) of claim 7, wherein the hydroxypropylcellulose is selected from Klucel-hydroxypropyl cellulose EF of Askalada or CENLY-hydroxypropyl cellulose SL of Japan Caoda.
13. Process for the preparation of an almag pint (ii) according to any one of claims 1 to 12, comprising the steps of:
I. preparation of aspirin layer total mixed granule
I-1, preparing the components of the aspirin layer according to parts by weight;
i-2 preparation of Aspirin coated granules
Mixing the said parts by weight of Kollicoat ® Mixing 40-50% of a pre-mixed coating agent, 40-50% of talcum powder, titanium dioxide, a colorant and water to prepare an aspirin powder coating solution with a solid content of 10-30%; coating 80% of aspirin in parts by weight with the aspirin powder coating solution to obtain aspirin coated particles with the water content of less than or equal to 0.5%;
i-3 preparation of Aspirin layer Total granules
Uniformly mixing the aspirin coated particles prepared in the step I-2 with the rest of aspirin, the part by weight of the direct compression mannitol and the part by weight of the low-substituted hydroxypropyl cellulose, then adding the rest part by weight of the talcum powder, and uniformly mixing to obtain aspirin layer total particles;
preparation of buffer layer Total Mixed particles
II-1, preparing the components of the buffer layer according to parts by weight;
II-2, sieving the mannitol in parts by weight with a 50-mesh sieve for later use;
II-3, dissolving the hydroxypropyl cellulose in parts by weight in water to prepare an adhesive solution with the mass percentage concentration of 4%;
II-4, mixing the dihydroxyaluminum glycinate, the heavy magnesium carbonate, the corn starch, the low-substituted hydroxypropyl cellulose, the lemon Huang Lv lake and the screened mannitol obtained in the step II-2 in parts by weight, adding the adhesive solution prepared in the step II-3 for wet granulation, drying at 50-70 ℃ until the water content of the granules is less than or equal to 3.0%, granulating, adding the talcum powder in parts by weight, and uniformly mixing to obtain the total mixed granules of the buffer layer;
III double layer tabletting
And (3) tabletting the aspirin total mixed granules prepared in the step I and the buffer layer total mixed granules prepared in the step II in a double-layer tablet machine according to the mass ratio of 0.8 to 1.2 to 1.8.
14. The process according to claim 13, wherein in step I, the particle size of aspirin is 40 to 150 mesh.
15. The method according to claim 13, wherein the coating is performed in step I-2 in a fluidized bed bottom spray coater.
16. The preparation method according to claim 15, wherein in the step I-2, the coating process parameters of the fluidized bed bottom spraying coating machine are as follows:
the frequency of a fan is 19-23Hz, the air inlet temperature is 35-40 ℃, the material temperature is 28-30 ℃, the liquid supply rotating speed is 7-13rpm, and the atomization pressure is 0.15Mpa.
17. The preparation method according to claim 13, wherein in the step III, the mass ratio of the aspirin layer total mixed particles to the buffer layer total mixed particles is 1:1.
18. An almatmagelin tablet (ii) obtainable by the process according to any one of claims 13 to 17.
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