CN111249241B - Solid preparation containing insoluble thienopyridine composition and preparation method thereof - Google Patents
Solid preparation containing insoluble thienopyridine composition and preparation method thereof Download PDFInfo
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- CN111249241B CN111249241B CN202010061857.XA CN202010061857A CN111249241B CN 111249241 B CN111249241 B CN 111249241B CN 202010061857 A CN202010061857 A CN 202010061857A CN 111249241 B CN111249241 B CN 111249241B
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- thienopyridine
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- compound
- mannitol
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- 239000000203 mixture Substances 0.000 title claims abstract description 282
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical compound C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 title claims abstract description 188
- 229940125670 thienopyridine Drugs 0.000 title claims abstract description 188
- 239000002175 thienopyridine Substances 0.000 title claims abstract description 188
- 238000002360 preparation method Methods 0.000 title claims abstract description 179
- 239000007787 solid Substances 0.000 title claims abstract description 77
- 150000001875 compounds Chemical class 0.000 claims abstract description 75
- 239000002994 raw material Substances 0.000 claims description 158
- 239000000463 material Substances 0.000 claims description 93
- 238000002156 mixing Methods 0.000 claims description 92
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 33
- 239000002245 particle Substances 0.000 claims description 26
- 238000009472 formulation Methods 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 238000009826 distribution Methods 0.000 claims description 6
- 239000000314 lubricant Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000007884 disintegrant Substances 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 17
- 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 description 112
- 229930195725 Mannitol Natural products 0.000 description 112
- 239000000594 mannitol Substances 0.000 description 112
- 235000010355 mannitol Nutrition 0.000 description 112
- 229960001855 mannitol Drugs 0.000 description 112
- 238000005303 weighing Methods 0.000 description 89
- 238000011049 filling Methods 0.000 description 48
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 43
- 239000008108 microcrystalline cellulose Substances 0.000 description 43
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 43
- 229940016286 microcrystalline cellulose Drugs 0.000 description 43
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 40
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 40
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 35
- 229920000881 Modified starch Polymers 0.000 description 33
- 239000003826 tablet Substances 0.000 description 28
- 239000002775 capsule Substances 0.000 description 25
- 238000004090 dissolution Methods 0.000 description 22
- 239000008187 granular material Substances 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 229920002472 Starch Polymers 0.000 description 11
- 239000003814 drug Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 239000008107 starch Substances 0.000 description 11
- 235000019698 starch Nutrition 0.000 description 11
- 229940032147 starch Drugs 0.000 description 11
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 10
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 10
- 239000008101 lactose Substances 0.000 description 10
- 229960001375 lactose Drugs 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 239000000843 powder Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical class C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 6
- 229960003009 clopidogrel Drugs 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 238000007865 diluting Methods 0.000 description 6
- 235000019359 magnesium stearate Nutrition 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 229920002785 Croscarmellose sodium Polymers 0.000 description 4
- 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 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 4
- 230000001133 acceleration Effects 0.000 description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 4
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 4
- 230000001276 controlling effect Effects 0.000 description 4
- 229960001681 croscarmellose sodium Drugs 0.000 description 4
- 229960000913 crospovidone Drugs 0.000 description 4
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 4
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 4
- 239000012488 sample solution Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 229920001353 Dextrin Polymers 0.000 description 3
- 239000004375 Dextrin Substances 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 235000019425 dextrin Nutrition 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 238000007922 dissolution test Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 238000000691 measurement method Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- 239000012088 reference solution Substances 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 102220042174 rs141655687 Human genes 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- KPCOLEDDUNYSQA-UHFFFAOYSA-N (3,5-dimethylphenyl)carbamic acid Chemical compound CC1=CC(C)=CC(NC(O)=O)=C1 KPCOLEDDUNYSQA-UHFFFAOYSA-N 0.000 description 1
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- -1 SMX compound Chemical group 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 235000002597 Solanum melongena Nutrition 0.000 description 1
- 244000061458 Solanum melongena Species 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 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 1
- 238000010828 elution Methods 0.000 description 1
- IEMGWBMVQLVHEY-UHFFFAOYSA-N ethyl 2-(3-amino-6,7-dihydro-5h-cyclopenta[b]pyridin-7-yl)acetate Chemical compound NC1=CN=C2C(CC(=O)OCC)CCC2=C1 IEMGWBMVQLVHEY-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000013022 formulation composition Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010572 single replacement reaction Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a solid preparation containing a poorly soluble thienopyridine composition and a preparation method thereof, wherein the preparation has low impurity content and can be rapidly dissolved out. The invention relates to a solid preparation containing a poorly soluble thienopyridine composition, which comprises a compound with a structure shown in a formula I and a compound with a structure shown in a formula II, wherein the mass ratio of the compound with the formula II to the compound with the formula I is less than or equal to 1:100;
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a solid preparation containing a poorly soluble thienopyridine composition and a preparation method thereof.
Background
The chemical name of the compound with the structure shown in the formula I is as follows: methyl (S) -2- (2-chlorophenyl) -2- ((S) -2-oxo-2, 6,7 a-tetrahydrothiophene [3,2-c ] pyridin-5 (4H) yl) acetate.
The compound of the formula I is a metabolite of clopidogrel in human bodies. Clopidogrel is a first-line drug for preventing and treating heart, brain and other arterial circulatory disorders caused by platelet high aggregation. However, there is a significant individual variability in the potency of clopidogrel, particularly in asians, i.e., clopidogrel Lei Dikang (CPGR). Recent studies indicate that the cause of CPGR is caused by the differentiation of CYP enzyme activity in the liver of an individual, and the CPGR is specifically characterized in that clopidogrel cannot be normally metabolized in the liver of a part of patients, and metabolic products with the structure of formula I and optical isomers thereof cannot be produced, so that the clopidogrel is blocked from being further metabolized into active ingredients subsequently, and the anticoagulation effect cannot be exerted. Thus, direct administration of the compound of formula I is effective in avoiding clopidogrel Lei Dikang (CPGR).
The compounds of formula I also produce impurity compounds of formula II:
other impurities may be generated during the placement of the compound of formula I, during the formulation and during the storage of the formulation, and during the exploratory study it was accidentally found that the compound of formula ii had a certain threshold value in the composition beyond which it may generate more impurities with other impurities, so that quality control of the compound of formula ii is very important and we have determined the optimum ratio of the composition through the inventive study. In addition, the compounds of formula I are very poorly soluble in whatever solvent they are soluble in, very slightly soluble in water, slightly soluble in ethanol, poorly soluble in methanol, practically insoluble in toluene and very slightly soluble in acetone. In the process of rapid disintegration and absorption, the speed limiting step of drug absorption of solid preparations is often the dissolution speed of drugs, and particularly for insoluble drugs, the slow dissolution speed can lead to the reduction of bioavailability. Therefore, the compound of the formula I is prepared into a preparation, not only the impurity content of the compound is required to be considered, but also the dissolution of the compound is required to be considered, so that the safety, the effectiveness and the stability of the medicine are ensured. In the prior art, the compound preparation is ensured to be dissolved out, impurities are controlled, and research reports on composition preparation ensuring drug property are not provided, so that how to ensure that the solid preparation of the compound of the formula I has low impurity content, can be quickly dissolved out, meets the requirement of medicine, and becomes a problem to be solved by the person skilled in the art.
Disclosure of Invention
The invention aims to provide a solid preparation containing a poorly soluble thienopyridine composition, which comprises a compound of formula I and an impurity compound of formula II generated in the preparation process of the compound of formula I, and the mass ratio of the compound of formula I to the compound of formula II is controlled to effectively control the impurity content of the preparation and improve the stability.
The second object of the present invention is to provide a method for producing the solid preparation.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
the invention relates to a solid preparation containing a poorly soluble thienopyridine composition, which comprises a compound with a structure shown in a formula I and a compound with a structure shown in a formula II:
further, the mass ratio of the compound of formula II to the compound of formula I is less than 1:100.
further, the mass ratio of the compound of formula II to the compound of formula I is less than 0.5:100.
further, the particle size distribution range of the composition is: d90 is less than or equal to 150 mu m.
Further, the particle size distribution range of the composition is: d90 is less than or equal to 100 mu m.
Further, the particle size distribution range of the composition is: d90 is less than or equal to 50 mu m.
Further, the tablet also comprises any one or more of a release agent, a disintegrating agent and a lubricant.
Further, the mass content of the solid preparation is 2% -30% based on 100%.
The mass content of the diluent is 30-96.9%, the mass content of the disintegrating agent is 1-30%, and the mass content of the lubricant is 0.1-10%.
Further, the mass content of the solid preparation is 4-20% based on 100%.
The mass content of the diluent is 40-80%, the mass content of the disintegrating agent is 2-20%, and the mass content of the lubricant is 0.5-5%.
The diluent comprises any one or more of mannitol, microcrystalline cellulose, lactose, starch, pregelatinized starch, powdered sugar, dextrin and inorganic salt.
The disintegrating agent comprises any one or more of low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, carboxymethyl starch sodium and dry starch.
The lubricant comprises any one or more of magnesium stearate, sodium stearyl fumarate, talcum powder, polyethylene glycol and hydrogenated vegetable oil.
The solid preparation provided by the invention is an oral solid preparation, and comprises tablets, capsules or granules.
The preparation method of the solid preparation provided by the invention comprises the following steps:
Step 1, crushing the raw materials of the composition to obtain crushed raw materials;
step 2, uniformly mixing the crushed raw materials and auxiliary materials to prepare a mixture;
and 3, tabletting, granulating or encapsulating the mixture prepared in the step 2.
The preparation method of the compound of the formula I is prepared by refining the compound according to the method of the example 2 disclosed by reference patent No. CN 104245707. The compound of formula II is prepared by synthesis.
The invention controls the proportion of the II compound and the formula I compound by refining the formula I compound.
Compared with the prior art, the invention has the following beneficial effects:
the invention creatively combines the compound of the formula I and the compound of the formula II into the composition, and can achieve the unexpected effects of controlling the impurity content in the solid preparation and improving the stability by controlling the mass ratio of the compound of the formula I and the compound of the formula II.
The invention effectively improves the dissolution rate of the solid preparation by controlling the particle size of the bulk drug, so that the solid preparation meets the preparation requirement. And experiments prove that the solid preparation can still have the dissolution rate of 92% under the condition of accelerating for 6 months. The invention has good dissolution and stability.
The invention has simple preparation process, can directly tablet by adopting powder, has low production cost and is suitable for industrial production.
The specific embodiment is as follows:
the present invention is further illustrated in detail by the following examples and experimental examples. These examples and experimental examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Single replacement or improvement and the like belong to the technical scheme protected by the invention.
In embodiments of the invention, compounds of formula II: the compounds of formula I are all referred to as mass ratios.
Example 1
The embodiment discloses a preparation method of a compound of a formula II, which comprises the following steps:
synthesis of methyl N-oxo- (S) -2- (2-chlorophenyl) -2- ((S) -2-oxo-2, 6,7 a-tetrahydrothiophene [3,2-c ] naphthyridin-5 (4H) -yl) acetate
Step 1 resolution of the racemic product
After our synthesis of the structure SMX compound structure with reference to patent CN104245707A, 4.6g of the obtained racemization product is resolved by preparing a chiral column to obtain two purer corresponding chiral isomers SMX-1 and SMX-2, 1.24g and 1.51g respectively. (yield 59.8%) LC-MS (ESI) [ M+H ] + ] + ＝338.8(M+H + ) Is consistent with the structure.
Step 2 preparation of a compound of formula II:
will be at room temperatureSMX-1.51 g,10mL glacial acetic acid are put into a 50mL three-mouth bottle, 1mL hydrogen peroxide is dripped under ice bath, the temperature is raised to 80 ℃ for 2H after the dripping is completed, TLC monitoring reaction (developing agent: ethyl acetate/petroleum ether=1/3, color development under a 254nm ultraviolet lamp) is carried out, the raw materials are reacted completely, the acetic acid is concentrated under reduced pressure, saturated sodium carbonate is used for regulating pH value to be 8-9, dichloromethane is used for extracting 10mL, anhydrous sodium sulfate is used for drying, filtering, and the solution is concentrated under reduced pressure at 30 ℃ to be dried, thus obtaining 0.74g of target product, the yield is 46.9%, LC-MS (ESI) [ M+H ] + ] + ＝354.8(M+H + ) 1H-NMR (400 MHz, CDCl 3) 7.5 (m, 1H), 7.39 (m, 1H), 7.27 (m, 1H), 7.27 (m, 1H), 5.98 (s, 1H), 4.88 (s, 1H), 4.15 (d, 1H), 3.23-3.89 (d, 2H), 3.69 (s, 3H), 2.58-2.99 (d, 2H), 1.82-2.32 (m, 2H) are consistent with the structure.
Example 2: investigation of the different ratios of Compounds of formula II to Compounds of formula I
The pure products of the compound of the formula I and the compound of the formula II in the thienopyridine compositions with different proportions are added for research, and the quality stability of the pure products is examined. The method comprises the following steps: the thienopyridine composition and auxiliary materials with the same dosage are adopted, only the proportion of the compound of the formula II is different from that of the compound of the formula I, and the tablet is prepared by adopting the same preparation method. The relevant substance content was measured on the tablets at 0 day and 6 months acceleration. The prescription composition is 1000 tablets, as shown in Table 1:
table 1 prescription composition table 1
The preparation method comprises the following steps:
1. weighing the compound of the formula I and the pure compound of the formula II respectively; after being uniformly mixed, the mixture is crushed to obtain thienopyridine composition powder;
2. weighing auxiliary materials, premixing thienopyridine composition powder with 30% of mannitol in total, uniformly mixing the mixture of the thienopyridine composition and mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate for uniform mixing;
3. Tabletting the uniformly mixed materials by a tablet press to obtain tablets.
Raw materials and auxiliary materials were prepared according to the prescription composition of table 1, tablets of numbers A1 to a10 were prepared by the preparation method of this example, and each sample was subjected to related substance detection at 0 day, and the results are shown in table 2:
the detection method of the related substances comprises the following steps:
taking a proper amount of fine powder (about 10 mg) of the product, putting the fine powder into a10 ml measuring flask, adding acetonitrile for dissolving and diluting to a scale, shaking uniformly, filtering, and taking the subsequent filtrate as a sample solution; precisely measuring 1.0ml of the sample solution, placing in a 100ml measuring flask, adding acetonitrile to dilute to scale, shaking uniformly, and taking as a control solution. Taking 10 mu l of control solution, injecting into a liquid chromatograph, adjusting the detection sensitivity to ensure that the peak height of a main component chromatographic peak is about 20% of the full scale range, precisely measuring 10 mu l of each of the sample solution and the control solution, injecting into the liquid chromatograph respectively, and recording the chromatograms.
Table 20 days related substance detection results
| Numbering device | A1 | A2 | A3 | A4 | A5 | A6 | A7 | A8 | A9 | A10 |
| Single impurity (%) | 0.01 | 0.03 | 0.03 | 0.03 | 0.05 | 0.06 | 0.06 | 0.09 | 0.10 | 0.11 |
| Total impurity (%) | 0.07 | 0.08 | 0.11 | 0.12 | 0.13 | 0.14 | 0.21 | 0.25 | 0.29 | 0.38 |
Each sample of tablets numbered A1-a10 was stored at 40 ℃ ± 2 ℃ and 75% ± 5% RH for 6 months, after which the relevant substances were tested and the results are shown in table 3:
TABLE 3 results of 6 month acceleration of related substances
| Numbering device | A1 | A2 | A3 | A4 | A5 | A6 | A7 | A8 | A9 | A10 |
| Single impurity (%) | 0.01 | 0.02 | 0.04 | 0.05 | 0.06 | 0.06 | 0.13 | 0.13 | 0.15 | 0.17 |
| Total impurity (%) | 0.12 | 0.13 | 0.14 | 0.15 | 0.19 | 0.19 | 1.01 | 1.10 | 1.15 | 1.26 |
From the results of the detection of the related substances in Table 2 and Table 3, the sample stability of the numbers A1 to A6 is better than the sample stability of the numbers A7 to A10, namely, the mass ratio of the compound of formula II to the compound of formula I in the composition is less than or equal to 1: at 100, the solid preparation has good stability; the mass ratio of the compound of the formula II to the compound of the formula I is less than or equal to 0.5: at 100, the stability of the solid formulation is best. Especially after 6 months of storage at 40 ℃ +/-2 ℃ and 75% +/-5% RH, the stability advantage is more remarkable, which indicates that the compound of the formula II has a certain critical value in the composition, and above the critical value, the compound of the formula II possibly generates more impurities with other impurities, so that the quality control of the compound of the formula II is very important, and the optimal proportion of the composition is determined through creative research.
Example 3: process for preparing refined products by controlling the ratio of compounds of formula II to compounds of formula I
Preparing a compound crude product (containing a II compound) synthesized as shown in I and placed for a period of time according to an example 2 method disclosed in CN 104245707, adding 1.0g of the compound crude product shown in the formula I into a 50mL eggplant type bottle, adding 30mL of tetrahydrofuran, heating to 60 ℃ for stirring and dissolving, basically dissolving, filtering while the solution is hot, placing the filtrate in a 50mL beaker for stirring, slowly cooling to room temperature, stirring overnight for crystallization, and drying to obtain 0.50g of a compound finished product, wherein the mass ratio of the II compound to the compound shown in the formula I in the finished product is less than or equal to 0.5:100, and can be repeatedly refined, thereby further reducing the mass ratio of the compound II to the compound of the formula I.
The content determination method of the compound of the formula II and the compound of the formula I is as follows:
amylose-tris (3, 5-xylylcarbamate) was used as a filler, n-hexane-isopropanol-absolute ethanol (90:4:6) was used as a mobile phase, and the detection wavelength was 220nm and the column temperature was 30 ℃. The theoretical plate number is not lower than 2000 based on the compound of formula I, and the separation degree of the compound of formula I and the compound of formula II is not lower than 2.0.
Taking a proper amount of the product, adding absolute ethyl alcohol for dissolution and quantitatively diluting to prepare a solution which contains about 1mg of the product per 1ml and is used as a test sample solution;
and (3) taking a compound reference substance of the formula I (a calibrated compound of the formula I provided by Chengdu Shi Beikang biological medicine technology Co., ltd.), precisely weighing, dissolving in acetonitrile in a 10ml volumetric flask, diluting to a scale, precisely weighing 1ml, placing in a 100ml volumetric flask, diluting to the scale with absolute ethyl alcohol, and shaking uniformly to obtain a compound reference solution of the formula I.
And (3) taking a compound reference substance of the formula II (a calibrated compound of the formula II provided by Chengdu Shi Beikang biological medicine technology Co., ltd.), precisely weighing, dissolving in ethanol in a 10ml volumetric flask, diluting to a scale, precisely weighing 1ml, placing in a 100ml volumetric flask, diluting to the scale with absolute ethanol, and shaking uniformly to obtain a compound reference solution of the formula II.
According to the rule 0512 of the fourth edition of the Chinese pharmacopoeia 2015 of high performance liquid chromatography, precisely measuring 10 μl of each of the test solution and the control solution, respectively injecting into a liquid chromatograph, and recording the chromatograms.
Example 4: investigation of the Effect of thienopyridine compositions of different particle sizes on the dissolution of formulations
In this example, the effect of thienopyridine compositions of different particle sizes on the dissolution rate of the preparation was examined. The preparation is prepared by adopting thienopyridine compositions with different particle sizes, and the dissolution rate is measured. The formulation composition of the thienopyridine composition formulations of different particle sizes is shown in table 4:
TABLE 4 formulation of thienopyridine compositions of different particle sizes
The preparation method comprises the following steps:
1. the compound of formula II in the composition is 0.5:100, crushing the raw materials of the composition for different times to obtain the raw materials with different particle diameters.
2. Weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% mannitol of the total amount, uniformly mixing the thienopyridine composition, mannitol mixture, the rest mannitol, microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate for uniform mixing.
3. Tabletting the uniformly mixed materials by a tabletting machine.
Raw materials and auxiliary materials were prepared according to the prescription composition of table 4, tablets of numbers 1 to 6 were prepared by the preparation method of this example, and the dissolution rates of the respective samples were measured.
The dissolution rate measurement method is specifically as follows:
taking a sample, taking the sample according to a dissolution and release degree measurement method (Chinese pharmacopoeia, 2015 edition, four parts, general rule 0931 second method), taking 900ml of hydrochloric acid solution with pH of 1.2 as a dissolution medium, rotating at 50 revolutions per minute, operating according to the law, taking the solution after 30 minutes, filtering, and taking a proper amount of subsequent filtrate; the reference substance (the calibrated compound of formula I provided by Chengdu Shi Beikang biomedical technology Co., ltd.) is taken and precisely weighed into a 10ml volumetric flask, acetonitrile is added to dissolve and dilute to scale, 1ml is precisely measured, the flask is placed into a 100ml volumetric flask, and a dissolution medium is added to dilute and prepare a solution containing about 10 mug of the compound of formula I per 1 ml. The two solutions were taken and absorbance was measured at 220nm by ultraviolet-visible spectrophotometry (general rule 0401), and the elution amount of each tablet was calculated. The limit is 80% of the indicated amount, which should be in compliance with the regulations.
The results are shown in Table 5.
TABLE 5 dissolution test results Table
| Numbering device | B1 | B2 | B3 | B4 | B5 | B6 |
| Measurement results | 96％ | 91％ | 88％ | 86％ | 72％ | 61％ |
The measurement results are shown in Table 5, and it is clear from the dissolution rate measurement results that the particle size of the crude drug is controlled to be D90 to 150 μm or less, and the dissolution rate can be 80% or more.
Example 5
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making 1000 tablets.
The preparation process comprises the following steps:
1. the compound of formula II in the composition is 0.2:100, crushing the composition raw materials to obtain a thienopyridine composition raw material with d90= 30.737 mu m, and weighing the raw materials according to a formula.
2. Weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% of mannitol in total, uniformly mixing the thienopyridine composition with mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate for uniform mixing.
3. Tabletting the uniformly mixed materials by a tabletting machine.
Example 6
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making 1000 tablets.
The preparation process comprises the following steps:
1. the compound of formula II in the composition is 0.1:100, crushing the composition raw materials to obtain a thienopyridine composition raw material with d90= 35.147 mu m, and weighing the raw materials according to a formula.
2. Weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% of mannitol in total, uniformly mixing the thienopyridine composition with mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate for uniform mixing.
3. Tabletting the uniformly mixed materials by a tabletting machine.
Example 7
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making 1000 tablets.
The preparation process comprises the following steps:
1. the compound of formula II in the composition is 0.5:100, crushing the composition raw materials to obtain a thienopyridine composition raw material with d90= 45.247 mu m, and weighing the raw materials according to a formula.
2. Weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% of mannitol in total, uniformly mixing the thienopyridine composition with mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate for uniform mixing.
3. Tabletting the uniformly mixed materials by a tabletting machine.
Example 8
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making 1000 tablets.
The preparation process comprises the following steps:
1. the compound of formula II in the composition is 0.5:100, crushing the raw materials to obtain a raw material of the thienopyridine composition with d90= 54.235 μm, and weighing the raw materials according to a formula.
2. Weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% of mannitol in total, uniformly mixing the thienopyridine composition with mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate for uniform mixing.
3. Tabletting the uniformly mixed materials by a tabletting machine.
Example 9
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making 1000 tablets.
The preparation process comprises the following steps:
1. the compound of formula II in the composition is 0.5:100, crushing the composition raw materials to obtain a thienopyridine composition raw material with d90= 76.613 mu m, and weighing the raw materials according to a formula.
2. Weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% of mannitol in total, uniformly mixing the thienopyridine composition with mannitol, the rest mannitol, microcrystalline cellulose and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate for uniform mixing.
3. Tabletting the uniformly mixed materials by a tabletting machine.
Example 10
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making 1000 tablets.
The preparation process comprises the following steps:
1. the compound of formula II in the composition is 0.5:100, crushing the composition raw materials to obtain a thienopyridine composition raw material with d90= 92.340 mu m, and weighing the raw materials according to a formula.
2. Weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% of mannitol in total, uniformly mixing the thienopyridine composition with mannitol, the rest mannitol, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate for uniform mixing.
3. Tabletting the uniformly mixed materials by a tabletting machine.
Example 11
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making 1000 tablets.
The preparation process comprises the following steps:
1. the compound of formula II in the composition is 0.5:100, crushing the composition raw materials to obtain a thienopyridine composition raw material with d90= 105.127 mu m, and weighing the raw materials according to a formula.
2. Weighing raw materials and auxiliary materials, premixing a thienopyridine composition and part of microcrystalline cellulose, uniformly mixing the mixture of the thienopyridine composition and the microcrystalline cellulose, the rest microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate for uniform mixing.
3. Tabletting the uniformly mixed materials by a tabletting machine.
Example 12
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making 1000 tablets.
The preparation process comprises the following steps:
1. the compound of formula II in the composition is 0.5:100, crushing the composition raw materials to obtain a thienopyridine composition raw material with d90= 122.350 mu m, and weighing the raw materials according to a formula.
2. Weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% mannitol in total, uniformly mixing the mixture of the thienopyridine composition and mannitol, the residual mannitol and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate for uniform mixing.
3. Tabletting the uniformly mixed materials by a tabletting machine.
Example 13
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making 1000 tablets.
The preparation process comprises the following steps:
1. the compound of formula II in the composition is 0.4:100, crushing the composition raw materials to obtain a thienopyridine composition raw material with d90= 130.156 mu m, and weighing the raw materials according to a formula.
2. Weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% of mannitol in total, uniformly mixing the thienopyridine composition with mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and crospovidone, and then adding sodium stearyl fumarate for uniform mixing.
3. Tabletting the uniformly mixed materials by a tabletting machine.
Example 14
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
Prescription:
making 1000 tablets.
The preparation process comprises the following steps:
1. the compound of formula II in the composition is 0.5:100, crushing the composition raw materials to obtain a thienopyridine composition raw material with d90= 135.020 mu m, and weighing the raw materials according to a formula.
2. Weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% of mannitol in total, uniformly mixing the thienopyridine composition with mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and croscarmellose sodium, and then adding sodium stearyl fumarate for uniform mixing.
3. Tabletting the uniformly mixed materials by a tabletting machine.
Example 15
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making 1000 tablets.
The preparation process comprises the following steps:
1. the compound of formula II in the composition is 0.5:100, crushing the composition raw materials to obtain a thienopyridine composition raw material with d90= 145.234 mu m, and weighing the raw materials according to a formula.
2. Weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% of mannitol in total, uniformly mixing the thienopyridine composition with mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and carboxymethyl starch sodium, and then adding sodium stearyl fumarate for uniform mixing.
3. Tabletting the uniformly mixed materials by a tabletting machine.
Example 16
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making 1000 tablets.
The preparation process comprises the following steps:
1. the compound of formula II in the composition is 0.5:100, crushing the composition raw materials to obtain a thienopyridine composition raw material with d90= 149.710 mu m, and weighing the raw materials according to a formula.
2. Weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% of mannitol in total, uniformly mixing the thienopyridine composition with mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding magnesium stearate for uniform mixing.
3. Tabletting the uniformly mixed materials by a tabletting machine.
Example 17
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making 1000 tablets.
The preparation process comprises the following steps:
1. taking the thienopyridine composition raw material in example 16 as a raw material, and weighing according to the formula amount of the example;
2. weighing raw materials and auxiliary materials, premixing a thienopyridine composition and part of lactose, uniformly mixing the thienopyridine composition with lactose mixture, residual lactose, microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate for uniform mixing.
3. Tabletting the uniformly mixed materials by a tabletting machine.
Example 18
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making 1000 tablets.
The preparation process comprises the following steps:
1. taking the thienopyridine composition raw material in example 16 as a raw material, and weighing according to the formula amount of the example;
2. weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% of mannitol in total, uniformly mixing the thienopyridine composition with mannitol, the rest mannitol, microcrystalline cellulose, starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate for uniform mixing.
3. Tabletting the uniformly mixed materials by a tabletting machine.
Example 19
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making 1000 tablets.
The preparation process comprises the following steps:
1. taking the thienopyridine composition raw material in example 16 as a raw material, and weighing according to the formula amount of the example;
2. weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% of mannitol in total, uniformly mixing the thienopyridine composition with mannitol, the rest mannitol, microcrystalline cellulose, dextrin and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate for uniform mixing.
3. Tabletting the uniformly mixed materials by a tabletting machine.
Example 20
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making 1000 tablets.
The preparation process comprises the following steps:
1. taking the thienopyridine composition raw material in example 16 as a raw material, and weighing according to the formula amount of the example;
2. weighing raw materials and auxiliary materials, premixing the thienopyridine composition and part of sugar powder, uniformly mixing the mixture of the thienopyridine composition and the sugar powder, the rest sugar powder, starch, dextrin and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate for uniform mixing.
3. Tabletting the uniformly mixed materials by a tabletting machine.
Example 21
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making into 1000 granule.
The preparation process comprises the following steps:
1. taking the thienopyridine composition raw material in example 15 as a raw material, and weighing according to the formula amount of the example;
2. weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% of mannitol in total, uniformly mixing the thienopyridine composition with mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate for uniform mixing.
3. And filling the uniformly mixed materials into capsules by a capsule filling machine.
Example 22
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making into 1000 granule.
The preparation process comprises the following steps:
1. the compound of formula II in the composition is 0.4:100 the raw materials of the composition are crushed to obtain the raw materials of the thienopyridine composition with D90= 149.230 mu m, and the raw materials are weighed according to a formula.
2. Weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% of mannitol in total, uniformly mixing the thienopyridine composition with mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate for uniform mixing.
3. And filling the uniformly mixed materials into capsules by a capsule filling machine.
Example 23
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making into 1000 granule.
The preparation process comprises the following steps:
1. taking the thienopyridine composition raw material in example 16 as a raw material, and weighing according to the formula amount of the example;
2. weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% of mannitol in total, uniformly mixing the thienopyridine composition with mannitol mixture, residual mannitol, microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate for uniform mixing.
3. And filling the uniformly mixed materials into capsules by a capsule filling machine.
Example 24
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making into 1000 granule.
The preparation process comprises the following steps:
1. the compound of formula II in the composition is 0.5:100, crushing the composition raw materials to obtain a thienopyridine composition raw material with d90= 142.360 mu m, and weighing the raw materials according to a formula.
2. Weighing raw materials and auxiliary materials, mixing the thienopyridine composition with 30% of mannitol, uniformly mixing the thienopyridine composition with mannitol, the rest mannitol, pregelatinized starch and substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate for uniform mixing.
3. And filling the uniformly mixed materials into capsules by a capsule filling machine.
Example 25
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making into 1000 granule.
The preparation process comprises the following steps:
1. taking the thienopyridine composition raw material in example 16 as a raw material, and weighing according to the formula amount of the example;
2. weighing raw materials and auxiliary materials, premixing a thienopyridine composition and part of lactose, uniformly mixing the thienopyridine composition with the mixture of lactose, the rest lactose, microcrystalline cellulose, starch and low-substituted hydroxypropyl cellulose, and then adding magnesium stearate for uniform mixing.
3. And filling the uniformly mixed materials into capsules by a capsule filling machine.
Example 26
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making into 1000 granule.
The preparation process comprises the following steps:
1. the compound of formula II in the composition is 0.4:100 the raw materials of the composition are crushed to obtain the raw materials of the thienopyridine composition with D90= 147.340 mu m, and the raw materials are weighed according to a formula.
2. Weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% of mannitol in total, uniformly mixing the thienopyridine composition with mannitol, the rest mannitol, microcrystalline cellulose and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate for uniform mixing.
3. And filling the uniformly mixed materials into capsules by a capsule filling machine.
Example 27
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making into 1000 granule.
The preparation process comprises the following steps:
1. the compound of formula II in the composition is 0.1:100, crushing the composition raw materials to obtain a thienopyridine composition raw material with d90= 147.431 mu m, and weighing the raw materials according to a formula.
2. Weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% of mannitol in total, uniformly mixing the mixture of the thienopyridine composition and mannitol, the rest mannitol, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate for uniform mixing.
3. And filling the uniformly mixed materials into capsules by a capsule filling machine.
Example 28
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making into 1000 granule.
The preparation process comprises the following steps:
1. taking the thienopyridine composition raw material in example 16 as a raw material, and weighing according to the formula amount of the example;
2. weighing raw materials and auxiliary materials, premixing a thienopyridine composition and part of microcrystalline cellulose, uniformly mixing the mixture of the thienopyridine composition and the microcrystalline cellulose, the rest microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate for uniform mixing.
3. And filling the uniformly mixed materials into capsules by a capsule filling machine.
Example 29
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
Prescription:
making into 1000 granule.
The preparation process comprises the following steps:
1. taking the thienopyridine composition raw material in example 16 as a raw material, and weighing according to the formula amount of the example;
2. weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% mannitol in total, uniformly mixing the mixture of the thienopyridine composition and mannitol, the residual mannitol and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate for uniform mixing.
3. And filling the uniformly mixed materials into capsules by a capsule filling machine.
Example 30
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making into 1000 granule.
The preparation process comprises the following steps:
1. taking the thienopyridine composition raw material in example 16 as a raw material, and weighing according to the formula amount of the example;
2. weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% of mannitol in total, uniformly mixing the mixture of the thienopyridine composition and mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and crospovidone, and then adding sodium stearyl fumarate for uniform mixing.
3. And filling the uniformly mixed materials into capsules by a capsule filling machine.
Example 31
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making into 1000 granule.
The preparation process comprises the following steps:
1. taking the thienopyridine composition raw material in example 16 as a raw material, and weighing according to the formula amount of the example;
2. weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% of mannitol in total, uniformly mixing the thienopyridine composition with mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and croscarmellose sodium, and then adding sodium stearyl fumarate for uniform mixing.
3. Tabletting the uniformly mixed materials by a tabletting machine.
Example 32
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making into 1000 granule.
The preparation process comprises the following steps:
1. taking the thienopyridine composition raw material in example 16 as a raw material, and weighing according to the formula amount of the example;
2. weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% of mannitol in total, uniformly mixing the thienopyridine composition with mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and carboxymethyl starch sodium, and then adding sodium stearyl fumarate for uniform mixing.
3. And filling the uniformly mixed materials into capsules by a capsule filling machine.
Example 33
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making into 1000 granule.
The preparation process comprises the following steps:
1. the compound of formula II in the composition is 0.3:100, crushing the composition raw materials to obtain a thienopyridine composition raw material with d90= 145.722 mu m, and weighing the raw materials according to a formula.
2. Weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% of mannitol in total, uniformly mixing the thienopyridine composition with mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding magnesium stearate for uniform mixing.
3. And filling the uniformly mixed materials into capsules by a capsule filling machine.
Example 34
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making 1000 bags.
The preparation process comprises the following steps:
1. the compound of formula II in the composition is 0.2:100, crushing the composition raw materials to obtain a thienopyridine composition raw material with d90= 149.377 mu m, and weighing the raw materials according to a formula.
2. Weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% of mannitol in total, uniformly mixing the thienopyridine composition with mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate for uniform mixing.
3. And filling the uniformly mixed materials into bags by a particle filling machine.
Example 35
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making 1000 bags.
The preparation process comprises the following steps:
1. the compound of formula II in the composition is 0.4:100, crushing the composition raw materials to obtain a thienopyridine composition raw material with d90= 148.720 mu m, and weighing the raw materials according to a formula.
2. Weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% mannitol in total, uniformly mixing the mixture of the thienopyridine composition and mannitol, and adding sodium stearyl fumarate to uniformly mix after the rest mannitol, microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose are uniformly mixed.
And 3, filling the uniformly mixed materials into bags by a particle filling machine.
Example 36
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
Prescription:
making 1000 bags.
The preparation process comprises the following steps:
1. taking the thienopyridine composition raw material in example 16 as a raw material, and weighing according to the formula amount of the example;
2. weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% of mannitol in total, uniformly mixing the thienopyridine composition with mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate for uniform mixing.
3. And filling the uniformly mixed materials into bags by a particle filling machine.
Example 37
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making 1000 bags.
The preparation process comprises the following steps:
1. taking the thienopyridine composition raw material in example 16 as a raw material, and weighing according to the formula amount of the example;
2. weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% of mannitol in total, uniformly mixing the thienopyridine composition with mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate for uniform mixing.
3. And filling the uniformly mixed materials into bags by a particle filling machine.
Example 38
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making 1000 bags.
The preparation process comprises the following steps:
1. taking the thienopyridine composition raw material in example 16 as a raw material, and weighing according to the formula amount of the example;
2. weighing raw materials and auxiliary materials, premixing a thienopyridine composition and part of lactose, uniformly mixing the thienopyridine composition with the mixture of lactose, the rest lactose, microcrystalline cellulose, starch and low-substituted hydroxypropyl cellulose, and then adding magnesium stearate for uniform mixing.
3. And filling the uniformly mixed materials into bags by a particle filling machine.
Example 39
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making 1000 bags.
The preparation process comprises the following steps:
1. taking the thienopyridine composition raw material in example 24 as a raw material, and weighing according to the formula amount of the example;
2. weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% of mannitol in total, uniformly mixing the mixture of the thienopyridine composition and mannitol, the rest mannitol, microcrystalline cellulose and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate for uniform mixing.
3. And filling the uniformly mixed materials into bags by a particle filling machine.
Example 40
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making 1000 bags.
The preparation process comprises the following steps:
1. a compound of formula ii: the compound of formula I is 0.4:100, crushing the composition raw materials to obtain a thienopyridine composition raw material with d90= 145.430 mu m, and weighing the raw materials according to a formula.
2. Weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% of mannitol in total, mixing the thienopyridine composition with mannitol, uniformly mixing the rest mannitol, gelatinized starch and low-substituted hydroxypropyl cellulose, and adding sodium stearyl fumarate for uniform mixing.
3. And filling the uniformly mixed materials into bags by a particle filling machine.
Example 41
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making 1000 bags.
The preparation process comprises the following steps:
1. taking the thienopyridine composition raw material in example 33 as a raw material, and weighing according to the formula amount of the example;
2. weighing raw materials and auxiliary materials, premixing a thienopyridine composition and part of microcrystalline cellulose, uniformly mixing the mixture of the thienopyridine composition and the microcrystalline cellulose, the rest microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate for uniform mixing.
3. And filling the uniformly mixed materials into bags by a particle filling machine.
Example 42
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making 1000 bags.
The preparation process comprises the following steps:
1. taking the thienopyridine composition raw material in example 16 as a raw material, and weighing according to the formula amount of the example;
2. weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% mannitol in total, mixing the thienopyridine composition with mannitol, uniformly mixing the rest mannitol and low-substituted hydroxypropyl cellulose, and adding sodium stearyl fumarate for uniform mixing.
3. Tabletting the uniformly mixed materials by a tabletting machine.
Example 43
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making 1000 bags.
The preparation process comprises the following steps:
1. taking the thienopyridine composition raw material in example 27 as a raw material, and weighing according to the formula amount of the example;
2. weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% of mannitol in total, uniformly mixing the thienopyridine composition with mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and crospovidone, and then adding sodium stearyl fumarate for uniform mixing.
3. And filling the uniformly mixed materials into bags by a particle filling machine.
Example 44
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making 1000 bags.
The preparation process comprises the following steps:
1. taking the thienopyridine composition raw material in example 27 as a raw material, and weighing according to the formula amount of the example;
2. weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% of mannitol in total, uniformly mixing the thienopyridine composition with mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and croscarmellose sodium, and then adding sodium stearyl fumarate for uniform mixing.
3. And filling the uniformly mixed materials into bags by a particle filling machine.
Example 45
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making 1000 bags.
The preparation process comprises the following steps:
1. taking the thienopyridine composition raw material in example 27 as a raw material, and weighing according to the formula amount of the example;
2. weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% of mannitol in total, uniformly mixing the thienopyridine composition with mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and carboxymethyl starch sodium, and then adding sodium stearyl fumarate for uniform mixing.
3. And filling the uniformly mixed materials into bags by a particle filling machine.
Example 46
The embodiment discloses the preparation of a solid preparation of the thienopyridine composition, which comprises the following specific steps:
prescription:
making 1000 bags.
The preparation process comprises the following steps:
1. taking the thienopyridine composition raw material in example 16 as a raw material, and weighing according to the formula amount of the example;
2. weighing raw materials and auxiliary materials, premixing the thienopyridine composition and 30% of mannitol in total, uniformly mixing the thienopyridine composition with mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding magnesium stearate for uniform mixing.
3. And filling the uniformly mixed materials into bags by a particle filling machine.
The solid preparation samples prepared in examples 5 to 46 were measured for dissolution rate at 0 day and 6 months acceleration, and the results are shown in tables 6 and 7.
TABLE 6 0 day dissolution test data sheet
| Examples | Example 5 | Example 6 | Example 7 | Example 8 | Example 9 | Example 10 | Example 11 | Example 12 | Example 13 |
| Dissolution (%) | 96 | 93 | 91 | 90 | 89 | 88 | 87 | 86 | 86 |
| Examples | Example 14 | Example 15 | Example 16 | Example 17 | Example 18 | Example 19 | Example 20 | Example 21 | Example 22 |
| Dissolution (%) | 87 | 87 | 87 | 87 | 87 | 87 | 86 | 86 | 86 |
| Examples | Example 23 | Example 24 | Example 25 | Example 26 | Example 27 | Example 28 | Example 29 | Example 30 | Example 31 |
| Dissolution (%) | 86 | 86 | 86 | 86 | 86 | 88 | 85 | 86 | 86 |
| Examples | Example 32 | Example 33 | Example 34 | Example 35 | Example 36 | Example 37 | Example 38 | Example 39 | Example 40 |
| Dissolution (%) | 87 | 86 | 87 | 86 | 86 | 86 | 86 | 87 | 87 |
| Examples | Example 41 | Example 42 | Example 43 | Example 44 | Example 45 | Example 46 | / | / | / |
| Dissolution (%) | 87 | 86 | 86 | 86 | 84 | 85 | / | / | / |
TABLE 7 data sheet for accelerated 6 month dissolution test
As is clear from tables 6 and 7, the dissolution rates of the solid preparation of the present invention were 80% or more under the condition of acceleration for 6 months, which indicates that the stability of the solid preparation of the present invention was good.
The above embodiment is only one of the preferred embodiments of the present invention, and should not be used to limit the scope of the present invention, but all the insubstantial modifications or color changes made in the main design concept and spirit of the present invention are still consistent with the present invention, and all the technical problems to be solved are included in the scope of the present invention.
Claims (9)
1. A solid preparation containing a poorly soluble thienopyridine composition, characterized in that the composition comprises a compound with a structure shown in formula I and a compound with a structure shown in formula ii:
The mass ratio of the compound of formula II to the compound of formula I is less than 1:100.
2. the solid formulation according to claim 1, wherein the mass ratio of the compound of formula ii to the compound of formula I is less than 0.5:100.
3. the solid formulation according to claim 1 or 2, wherein the composition has a particle size distribution ranging from: d90 is less than or equal to 150 mu m.
4. A solid formulation according to claim 3, wherein the composition has a particle size distribution ranging from: d90 is less than or equal to 100 mu m.
5. A solid formulation according to claim 3, wherein the composition has a particle size distribution ranging from: d90 is less than or equal to 50 mu m.
6. The solid preparation according to claim 1, further comprising any one or more of a release agent, a disintegrant, and a lubricant.
7. The solid preparation according to claim 6, wherein the mass content of the composition is 2% to 30% based on 100% of the mass of the solid preparation.
8. The solid preparation according to claim 6, wherein the mass content of the composition is 4% to 20% based on 100% of the mass of the solid preparation.
9. The method for producing a solid preparation according to claim 6, comprising the steps of:
Step 1, crushing the raw materials of the composition to obtain crushed raw materials;
step 2, uniformly mixing the crushed raw materials and auxiliary materials to prepare a mixture;
and 3, tabletting, granulating or encapsulating the mixture prepared in the step 2.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104245707A (en) * | 2011-06-27 | 2014-12-24 | Ipca实验室有限公司 | Anti-thrombotic compounds |
| CN108685913A (en) * | 2018-07-31 | 2018-10-23 | 成都施贝康生物医药科技有限公司 | The composition and preparation method and application of oxygen-containing pyrrole Gray optical isomer or its salt |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104245707A (en) * | 2011-06-27 | 2014-12-24 | Ipca实验室有限公司 | Anti-thrombotic compounds |
| CN108685913A (en) * | 2018-07-31 | 2018-10-23 | 成都施贝康生物医药科技有限公司 | The composition and preparation method and application of oxygen-containing pyrrole Gray optical isomer or its salt |
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