CN113384532A - CYP17 inhibitor solid dispersion and preparation method thereof - Google Patents
CYP17 inhibitor solid dispersion and preparation method thereof Download PDFInfo
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- CN113384532A CN113384532A CN202010178409.8A CN202010178409A CN113384532A CN 113384532 A CN113384532 A CN 113384532A CN 202010178409 A CN202010178409 A CN 202010178409A CN 113384532 A CN113384532 A CN 113384532A
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- Prior art keywords
- solid dispersion
- abiraterone acetate
- cyp17 inhibitor
- tablet
- inhibitor solid
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Links
- 239000007962 solid dispersion Substances 0.000 title claims abstract description 40
- 229940124766 Cyp17 inhibitor Drugs 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title abstract description 48
- 238000000034 method Methods 0.000 claims abstract description 10
- 229960004103 abiraterone acetate Drugs 0.000 claims description 63
- UVIQSJCZCSLXRZ-UBUQANBQSA-N abiraterone acetate Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CC[C@@H](CC4=CC[C@H]31)OC(=O)C)C=C2C1=CC=CN=C1 UVIQSJCZCSLXRZ-UBUQANBQSA-N 0.000 claims description 63
- 238000002156 mixing Methods 0.000 claims description 41
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 32
- 229920001531 copovidone Polymers 0.000 claims description 29
- 239000000314 lubricant Substances 0.000 claims description 29
- 239000012943 hotmelt Substances 0.000 claims description 18
- 229920002472 Starch Polymers 0.000 claims description 16
- 239000008107 starch Substances 0.000 claims description 16
- 235000019698 starch Nutrition 0.000 claims description 16
- 235000012438 extruded product Nutrition 0.000 claims description 15
- 239000003963 antioxidant agent Substances 0.000 claims description 13
- 230000003078 antioxidant effect Effects 0.000 claims description 13
- 235000006708 antioxidants Nutrition 0.000 claims description 13
- 239000000945 filler Substances 0.000 claims description 13
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 11
- 239000007884 disintegrant Substances 0.000 claims description 11
- 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 9
- 229930195725 Mannitol Natural products 0.000 claims description 9
- 239000000594 mannitol Substances 0.000 claims description 9
- 235000010355 mannitol Nutrition 0.000 claims description 9
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 8
- 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 claims description 8
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 8
- 229960000913 crospovidone Drugs 0.000 claims description 8
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 8
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 claims description 8
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 8
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 8
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 8
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 6
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 claims description 6
- VFPFQHQNJCMNBZ-UHFFFAOYSA-N ethyl gallate Chemical compound CCOC(=O)C1=CC(O)=C(O)C(O)=C1 VFPFQHQNJCMNBZ-UHFFFAOYSA-N 0.000 claims description 6
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 claims description 6
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 6
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 6
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 6
- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 claims description 5
- 235000010354 butylated hydroxytoluene Nutrition 0.000 claims description 5
- YBMTWYWCLVMFFD-UHFFFAOYSA-N 3-methylbutyl 3,4,5-trihydroxybenzoate Chemical compound CC(C)CCOC(=O)C1=CC(O)=C(O)C(O)=C1 YBMTWYWCLVMFFD-UHFFFAOYSA-N 0.000 claims description 4
- 108010024636 Glutathione Proteins 0.000 claims description 4
- 229960003180 glutathione Drugs 0.000 claims description 4
- 235000010378 sodium ascorbate Nutrition 0.000 claims description 4
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 claims description 4
- 229960005055 sodium ascorbate Drugs 0.000 claims description 4
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 claims description 4
- 229940032147 starch Drugs 0.000 claims description 4
- 239000004262 Ethyl gallate Substances 0.000 claims description 3
- 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 claims description 3
- 229920000881 Modified starch Polymers 0.000 claims description 3
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 claims description 3
- 235000019277 ethyl gallate Nutrition 0.000 claims description 3
- 235000004515 gallic acid Nutrition 0.000 claims description 3
- 229940074391 gallic acid Drugs 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- NRPKURNSADTHLJ-UHFFFAOYSA-N octyl gallate Chemical compound CCCCCCCCOC(=O)C1=CC(O)=C(O)C(O)=C1 NRPKURNSADTHLJ-UHFFFAOYSA-N 0.000 claims description 3
- 235000010387 octyl gallate Nutrition 0.000 claims description 3
- 239000000574 octyl gallate Substances 0.000 claims description 3
- 235000010388 propyl gallate Nutrition 0.000 claims description 3
- 239000000473 propyl gallate Substances 0.000 claims description 3
- 229940075579 propyl gallate Drugs 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 abstract description 17
- 230000008569 process Effects 0.000 abstract description 5
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- 239000003826 tablet Substances 0.000 description 23
- 238000010438 heat treatment Methods 0.000 description 16
- 238000002844 melting Methods 0.000 description 16
- 230000008018 melting Effects 0.000 description 16
- 239000000203 mixture Substances 0.000 description 13
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 11
- 239000003814 drug Substances 0.000 description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- 229960001855 mannitol Drugs 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 6
- 239000002245 particle Substances 0.000 description 6
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000007873 sieving Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 4
- 239000000853 adhesive Substances 0.000 description 4
- 230000001070 adhesive effect Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 239000013558 reference substance Substances 0.000 description 4
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 239000004094 surface-active agent Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 102000001854 Steroid 17-alpha-Hydroxylase Human genes 0.000 description 3
- 108010015330 Steroid 17-alpha-Hydroxylase Proteins 0.000 description 3
- 229960000853 abiraterone Drugs 0.000 description 3
- GZOSMCIZMLWJML-VJLLXTKPSA-N abiraterone Chemical compound C([C@H]1[C@H]2[C@@H]([C@]3(CC[C@H](O)CC3=CC2)C)CC[C@@]11C)C=C1C1=CC=CN=C1 GZOSMCIZMLWJML-VJLLXTKPSA-N 0.000 description 3
- 239000003098 androgen Substances 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 239000006190 sub-lingual tablet Substances 0.000 description 3
- 229940098466 sublingual tablet Drugs 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XQVWYOYUZDUNRW-UHFFFAOYSA-N N-Phenyl-1-naphthylamine Chemical compound C=1C=CC2=CC=CC=C2C=1NC1=CC=CC=C1 XQVWYOYUZDUNRW-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000007922 dissolution test Methods 0.000 description 2
- 210000003608 fece Anatomy 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 229940057948 magnesium stearate Drugs 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000006069 physical mixture Substances 0.000 description 2
- 229940069328 povidone Drugs 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 229940083575 sodium dodecyl sulfate Drugs 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001694 spray drying Methods 0.000 description 2
- 238000010922 spray-dried dispersion Methods 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- IELOKBJPULMYRW-NJQVLOCASA-N D-alpha-Tocopheryl Acid Succinate Chemical compound OC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C IELOKBJPULMYRW-NJQVLOCASA-N 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- LUQSJWRTYLGZJB-VJLLXTKPSA-N [(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-pyridin-3-yl-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl] hydrogen sulfate Chemical compound C[C@]12CC[C@H]3[C@@H](CC=C4C[C@H](CC[C@]34C)OS(O)(=O)=O)[C@@H]1CC=C2c1cccnc1 LUQSJWRTYLGZJB-VJLLXTKPSA-N 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229940030486 androgens Drugs 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229940099418 d- alpha-tocopherol succinate Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000009775 high-speed stirring Methods 0.000 description 1
- 238000009474 hot melt extrusion Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000013038 irreversible inhibitor Substances 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- -1 lactose compound Chemical class 0.000 description 1
- 150000002634 lipophilic molecules Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229940113116 polyethylene glycol 1000 Drugs 0.000 description 1
- 229940057838 polyethylene glycol 4000 Drugs 0.000 description 1
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000012088 reference solution Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 239000011973 solid acid Substances 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 238000005303 weighing Methods 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- 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
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a CYP17 inhibitor solid dispersion and a preparation method thereof. The tablet has the advantages of high dissolution rate, good stability and process reproducibility, and suitability for large-scale production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a CYP17 inhibitor solid dispersion and a preparation method thereof.
Background
Abiraterone acetate is an oral irreversible inhibitor of CYP17 enzyme, reduces androgen levels by inhibiting C17, C20-lyase and 17 alpha-hydroxylase, which are key enzymes in androgen synthesis, CYP17, and inhibits androgens in testis and other parts of the body, and is used for treating advanced prostate cancer, and the structural formula of the abiraterone acetate is as follows:
abiraterone acetate is a lipophilic compound, is easily soluble in organic solvents such as tetrahydrofuran and dichloromethane, especially alcohols, is almost insoluble in water at 20 ℃ under the condition of pH2-12, and is slightly soluble in 0.1N hydrochloric acid; the biopharmaceutical classification system (BCS classification) belongs to four categories, namely low solubility-low permeability drugs, so the bottleneck in pharmaceutical formulation research is how to improve its dissolution rate and bioavailability.
Abiraterone two major circulating metabolites in human plasma are abiraterone sulfate (inactive) and abiraterone oxynitridosulfate (inactive), each accounting for about 43% of exposure; in addition, approximately 88% of the radioactive dose after oral administration of abiraterone acetate was recovered in the feces and approximately 5% in the urine, with the major compounds present in the feces being unchanged abiraterone acetate and abiraterone (approximately 55% and 22% of the administered dose, respectively); therefore, the bioavailability of the abiraterone acetate orally absorbed is extremely low, which is a key factor that the dosage of the abiraterone acetate needs to reach 1g per oral administration.
At present, researchers can solve the problem by adopting methods such as preparing solid dispersion by using polyethylene glycol 4000 or 6000 and the like, but the problems of poor stability and complex preparation process still exist; in addition, a large amount of surfactant is added in the prescription to dissolve the insoluble drug in the micelle, and the dissolution of the drug is improved by the solubilization of the surfactant, but the problem of safety is easily caused by the excessive use amount of the surfactant.
CN102743393A discloses a medicinal composition containing abiraterone acetate and a preparation process thereof, wherein abiraterone acetate and hydrophilic auxiliary materials are ground according to a proportion, the particle size of the raw material medicine is 10-30 μm, the medicinal composition is used for improving the dissolution rate and bioavailability of the medicament, although the particle size of the raw material medicine is controlled to be smaller, the improvement of the dissolution rate of the medicament is still limited, and the dissolution rate is only 60% in 15min in a medium with a surfactant added at pH 4.5.
CN103070828A discloses a solid dispersion and tablet containing abiraterone acetate and a preparation method thereof, wherein abiraterone acetate and povidone with the ratio of 1: 0.5-4 are dissolved in chloroform, the solid dispersion is obtained through drying under reduced pressure, the solid dispersion is dispersed in water and is subjected to micro-powder grinding, the particle size D (0.9) of the ground dispersion is less than 75 microns to obtain a solution, the solution is added into a filler and a disintegrating agent which are sieved by a 100-mesh sieve, the granulation and the drying are carried out, a lubricant is added, and the tablet is formed.
CN106913539A discloses an abiraterone acetate sublingual tablet and a preparation method thereof, wherein abiraterone acetate and polyethylene glycol 1000 vitamin E succinate are dissolved in an organic solvent, the organic solvent is removed by drying under reduced pressure, the dried substance is mixed with a filler and a disintegrating agent, then a lubricant is added for mixing and tabletting, although complete dissolution can be realized in 15min, a large amount of organic solvent is still used, the labor protection is not facilitated, the impurity content is obviously increased in the long-term storage process, and the stability is poor.
CN106913537A discloses an abiraterone acetate sublingual tablet and a preparation method thereof, wherein abiraterone acetate and solid acid are heated and melted, and then mixed with a filler, a disintegrating agent and an adhesive to be granulated, dried and added with a lubricant to be tabletted, so that the dissolution rate of the drug is improved, but the process is complex, and the sublingual tablet has higher requirements on dissolution and is easily influenced by the environment in the storage and transportation processes.
CN109125276A discloses a medicinal composition of abiraterone acetate tablets and a preparation method thereof, wherein copovidone and abiraterone acetate are prepared into solid dispersion, and then the solid dispersion, diluent, adhesive, disintegrant and lubricant are prepared into a mixture to be tabletted. Although the stability is improved to a certain extent, the dissolution rate of the tablet obtained by the preparation method is too low, the dissolution rate in 20min is about 25% in hydrochloric acid solution with the pH value of 1.0, and the dissolution rate in 20min only reaches about 50% in pure water (0.5% SDS), and the dissolution rate needs to be improved.
In the prior art, in order to solve the dissolution problem of the abiraterone acetate tablet, a solid dispersion technology is mostly used, but the dissolution rate of the prepared abiraterone acetate tablet is still to be improved, and an organic solvent is required to be added, so that the cost is increased, the abiraterone acetate tablet is difficult to remove, the problem of residual solvent exists, and the hidden trouble that the drug is recrystallized to reduce the dispersion degree of the drug is caused; during long-term storage, the impurity content of the abiraterone acetate tablet is increased; and in the solid dispersion preparation technology, if an excessively high operation temperature is used, the solid dispersion carrier can be promoted to degrade, so that the impurity content in the product is increased, and the stability is poor.
Disclosure of Invention
In view of the defects of the prior art, the inventor provides a CYP17 inhibitor solid dispersion, and particularly provides a tablet of abiraterone acetate solid dispersion, wherein the solid dispersion is prepared by the abiraterone acetate, copovidone and an antioxidant through a hot-melt extrusion method, and then the solid dispersion is mixed with a filler, a disintegrant and a lubricant for tabletting.
The invention is realized by the following scheme:
a CYP17 inhibitor solid dispersion comprises abiraterone acetate, copovidone and an antioxidant.
The weight ratio of the abiraterone acetate to the copovidone in the CYP17 inhibitor solid dispersion is 1: 4-7.
Preferably, the weight ratio of abiraterone acetate to copovidone in the CYP17 inhibitor solid dispersion is 1: 5-6.
Preferably, the copovidone model is copovidone VA64 or copovidone S630.
The antioxidant is one or more of dibutyl hydroxy toluene, tert-butyl p-hydroxyanisole, gallic acid, ethyl gallate, propyl gallate, octyl gallate, isoamyl gallate, sodium ascorbate, and glutathione.
In the CYP17 inhibitor solid dispersion, the weight ratio of the abiraterone acetate to the antioxidant is 1: 0.002-0.2.
Preferably, in the CYP17 inhibitor solid dispersion, the weight ratio of the abiraterone acetate to the antioxidant is 1: 0.01-0.1.
Further preferably, the weight ratio of the abiraterone acetate to the antioxidant is 1: 0.05.
It will be appreciated that the solid dispersion may be used to prepare tablets and the like of common formulations.
The invention also provides a tablet containing the CYP17 inhibitor solid dispersion, which comprises the CYP17 inhibitor solid dispersion, a filler, a disintegrant and a lubricant.
The filler is one or more of mannitol, microcrystalline cellulose, starch, pregelatinized starch, and starch lactose complex.
The disintegrant is one or more of sodium carboxymethyl starch, croscarmellose sodium, crospovidone, and low-substituted hydroxypropyl cellulose.
The lubricant is one or more of magnesium stearate, sodium stearyl fumarate and zinc stearate.
The tablet specifically comprises the following components in parts by weight: 10 parts of CYP17 inhibitor solid dispersion, 10-40 parts of filler, 0.5-2.0 parts of disintegrant and 0.2-0.4 parts of lubricant.
Preferably, the tablet specifically comprises the following components in parts by weight: 10 parts of abiraterone acetate solid dispersion, 20-30 parts of filler, 1.0-1.5 parts of disintegrant and 0.3 part of lubricant.
The invention also provides a preparation method of the tablet containing the CYP17 inhibitor solid dispersion, which comprises the following specific steps: the abiraterone acetate, the antioxidant and the copovidone are heated and melted at the temperature of 115-125 ℃ by a hot-melt extruder, extruded, crushed, mixed with the filler and the disintegrant, then added with the lubricant, mixed and tableted to obtain the tablet.
Compared with the prior art, the invention has the following advantages:
(1) no complex micronization process is required;
(2) the product has no irritation and high stability;
(3) no solvent is required to be added, so that the stability of the tablet is improved;
(4) and an antioxidant is added, so that the preparation and storage stability of the product is further improved.
Detailed Description
The invention is further illustrated by the following examples. It should be properly understood that: the examples of the present invention are given solely for the purpose of illustration and not as limitations of the present invention, and therefore, simple modifications of the present invention in the context of the methods of the present invention are intended to fall within the scope of the claims.
Example 1
1) Prescription
2) Preparation process
The preparation method comprises the following steps of heating and melting abiraterone acetate, gallic acid and copovidone VA64 according to the prescription amount by using a hot-melt extruder at 123 ℃, extruding, crushing an extruded product, mixing with a starch lactose compound and sodium carboxymethyl starch, adding a lubricant magnesium stearate, mixing, and tabletting.
Example 2
1) Prescription
2) Preparation process
The preparation method comprises the following steps of heating and melting abiraterone acetate, tert-butyl p-hydroxyanisole and copovidone VA64 according to the prescription amount by using a hot-melt extruder at 120 ℃, extruding, crushing an extruded product, mixing with microcrystalline cellulose and croscarmellose sodium, adding a lubricant zinc stearate, mixing, and tabletting.
Example 3
1) Prescription
2) Preparation process
The preparation method comprises the following steps of heating and melting abiraterone acetate, dibutyl hydroxy toluene and copovidone S630 according to the prescription amount by using a hot-melt extruder at 125 ℃, extruding, crushing an extruded product, mixing with mannitol and croscarmellose sodium, adding a lubricant zinc stearate, mixing, and tabletting.
Example 4
1) Prescription
2) Preparation process
The preparation method comprises the following steps of heating and melting abiraterone acetate, ethyl gallate and copovidone S630 according to the prescription dose by using a hot-melt extruder at 115 ℃, extruding, crushing the extruded product, mixing with mannitol and crospovidone, adding a lubricant, namely sodium stearyl fumarate, mixing, and tabletting.
Example 5
1) Prescription
2) Preparation process
The preparation method comprises the following steps of heating and melting abiraterone acetate, propyl gallate and copovidone S630 according to the prescription dose by a hot-melt extruder at 125 ℃, extruding, crushing an extruded product, mixing with starch and low-substituted hydroxypropyl cellulose, adding a lubricant zinc stearate, mixing, and tabletting.
Example 6
1) Prescription
2) Preparation process
The preparation method comprises the following steps of heating and melting abiraterone acetate, octyl gallate and copovidone S630 according to the prescription dose by a hot-melt extruder at 125 ℃, extruding, crushing an extruded product, mixing with pregelatinized starch and low-substituted hydroxypropyl cellulose, adding a lubricant zinc stearate, mixing, and tabletting.
Example 7
1) Prescription
2) Preparation process
The preparation method comprises the following steps of heating and melting abiraterone acetate, isoamyl gallate and copovidone S630 according to the prescription amount by using a hot-melt extruder at 125 ℃, extruding, crushing an extruded product, mixing with starch and low-substituted hydroxypropyl cellulose, adding a lubricant, namely zinc stearate, mixing, and tabletting.
Example 8
1) Prescription
2) Preparation process
The tablet is prepared by heating and melting abiraterone acetate, sodium ascorbate, dibutyl hydroxy toluene and copovidone S630 with a hot melt extruder at 115 ℃, extruding, crushing the extrudate, mixing with mannitol, starch and crospovidone, adding lubricant sodium stearyl fumarate, mixing, and tabletting.
Example 9
1) Prescription
2) Preparation process
The preparation method comprises the following steps of heating and melting abiraterone acetate, glutathione and copovidone S630 according to the prescription amount by using a hot-melt extruder at 125 ℃, extruding, crushing an extruded product, mixing with starch and low-substituted hydroxypropyl cellulose, mixing with crospovidone, adding a lubricant zinc stearate and magnesium stearate, mixing, and tabletting.
Example 10
1) Prescription
2) Preparation process
The preparation method comprises the following steps of heating and melting abiraterone acetate, isoamyl gallate and copovidone S630 according to the prescription amount by using a hot-melt extruder at 140 ℃, extruding, crushing an extruded product, mixing with starch and low-substituted hydroxypropyl cellulose, adding a lubricant zinc stearate, mixing, and tabletting.
Example 11
1) Prescription
2) Preparation process
The preparation method comprises the following steps of heating and melting abiraterone acetate, sodium ascorbate and copovidone S630 according to the prescription amount by using a hot-melt extruder at 100 ℃, extruding, crushing an extruded product, mixing with starch and low-substituted hydroxypropyl cellulose, adding a lubricant zinc stearate, mixing, and tabletting.
Example 12
1) Prescription
2) Preparation process
The preparation method comprises the following steps of heating and melting abiraterone acetate, glutathione and copovidone S630 according to the prescription amount by using a hot-melt extruder at 125 ℃, extruding, crushing an extruded product, mixing with mannitol and crospovidone, adding a lubricant sodium stearyl fumarate, mixing, and tabletting.
Example 13
1) Prescription
2) Preparation process
The preparation method comprises the following steps of heating and melting abiraterone acetate, dibutyl hydroxy toluene and copovidone S630 according to the prescription amount by using a hot-melt extruder at 125 ℃, extruding, crushing the extruded product, mixing with mannitol and crospovidone, adding a lubricant sodium stearyl fumarate, mixing, and tabletting.
Example 14
1) Prescription
2) Preparation process
The preparation method comprises the following steps of heating and melting abiraterone acetate, phenyl-1-naphthylamine and copovidone S630 according to the prescription amount by using a hot-melt extruder at 125 ℃, extruding, crushing an extruded product, mixing with dextrin and dry starch, adding a lubricant zinc stearate, mixing, and tabletting.
Comparative example 1
1) Prescription
2) The preparation process comprises the following steps:
heating and melting the copovidone with the formula amount, adding the abiraterone acetate, uniformly stirring, and extruding particles by using an extruder; mixing the granules with microcrystalline cellulose, crospovidone and magnesium stearate according to the prescription amount, and tabletting.
Comparative example 2
1) Prescription
2) The preparation process comprises the following steps:
the samples were vacuum dried in an oven at 50 ℃ after spray drying by mixing abiraterone acetate with copovidone in a mixture of solvents methanol: acetone (2:1) followed by spray drying the mixture to form a Spray Dried Dispersion (SDD) Drug Product Intermediate (DPI). After drying, the obtained granules are further mixed with other auxiliary materials for tabletting.
Comparative example 3
1) Prescription
2) The preparation process comprises the following steps:
abiraterone acetate is combined with an intragranular excipient, after dry granulation, an extragranular excipient, namely croscarmellose sodium and sodium stearyl fumarate, is added and blended, and the mixture is pressed into tablets in a rotary tablet press.
Comparative example 4
1) Prescription
2) The preparation process comprises the following steps:
weighing and mixing abiraterone acetate and sodium dodecyl sulfate according to the feeding amount, and grinding the mixture through a 200-mesh vortex oscillating screen; respectively sieving mannitol, microcrystalline cellulose, silicon dioxide, croscarmellose sodium and magnesium stearate with 80 mesh vortex oscillating screen; uniformly mixing abiraterone acetate, sodium dodecyl sulfate, mannitol, microcrystalline cellulose, croscarmellose sodium and silicon dioxide by using a mixer, sieving the mixture by using an 80-mesh sieve, and uniformly mixing again; adding the premixed raw and auxiliary materials into a high-speed stirring granulator, adding 8% of PVP k29/32 adhesive ethanol water solution, preparing granules, and sieving with a 24-mesh sieve; after granulation is finished, transferring the mixture to a fluidized bed, and drying the mixture until the moisture of the granules is less than or equal to 1.5 percent; sieving and granulating the dried particles by a stainless steel screen; adding adjuvants, mixing, and tabletting.
Comparative example 5
1) Prescription
2) Preparation process
The preparation method comprises the following steps of heating and melting abiraterone acetate and povidone according to the prescription amount by using a hot-melt extruder at 125 ℃, extruding, crushing an extruded product, mixing with starch and croscarmellose sodium, adding a lubricant zinc stearate, mixing, and tabletting.
Comparative example 6
1) Prescription
2) Preparation process
Uniformly mixing abiraterone acetate and copovidone to prepare a physical mixture; setting the extrusion temperature of a double-screw hot-melt extruder to be 100 ℃, starting a screw when the preset temperature is reached, adding the obtained physical mixture into the extruder, and extruding strips through the screw; crushing the strips, and sieving the crushed strips with a 40-mesh sieve to obtain a solid dispersion with uniform particle size distribution; uniformly mixing the obtained solid dispersion with a diluent, an adhesive, a disintegrating agent and a lubricant according to the weight percentage in the prescription; the mixture is compressed into tablets.
Verification examples
1. Dissolution test
Dissolution rates of abiraterone acetate tablets obtained in examples 1 to 14 and comparative examples 1 to 6 were measured by the following method.
Taking the product, determining according to dissolution method, taking 500ml of 0.25% SDS acetate with pH4.5 as dissolution medium, rotating at 50 rpm, taking 10ml of solution after 20 minutes, filtering, and taking the subsequent filtrate as sample solution. Taking a proper amount of abiraterone acetate reference substance, placing the abiraterone acetate reference substance into a 10ml measuring flask, adding methanol for dissolving and diluting to a scale, precisely measuring 1ml, placing the abiraterone acetate reference substance into the 10ml measuring flask, adding a dissolving medium for diluting to the scale, and shaking up to obtain a reference substance solution. According to the chromatographic conditions under the content determination item, 10 mul of each of the test solution and the reference solution is taken and injected into a liquid chromatograph, the chromatogram is recorded, and the dissolution rate of each tablet is calculated by the peak area according to an external standard method. The limit is 80% of the indicated amount and should be met.
Table 1 dissolution test results
2. Stability test
To further demonstrate the superiority of the present invention, the inventors prepared the product obtained in the examples of the present invention and a commercially available abiraterone acetate (trade name: zeke;)@) Long-term stability experiments were performed.
The abiraterone acetate tablets prepared in the embodiments 1-14 of the invention are examined in the conditions of 40 ℃ +/-2 ℃ and 75% RH +/-5% RH without packaging, and the related substances of the reserved samples are respectively measured in 0 month, 3 months and 6 months, and the specific data are shown in the following table:
TABLE 2 stability test results
Claims (10)
1. A CYP17 inhibitor solid dispersion, wherein the CYP17 inhibitor solid dispersion comprises abiraterone acetate, copovidone and an antioxidant.
2. The CYP17 inhibitor solid dispersion of claim 1, wherein the weight ratio of abiraterone acetate and copovidone in said CYP17 inhibitor solid dispersion is 1: 4-7.
3. The CYP17 inhibitor solid dispersion of claim 1, wherein said antioxidant is one or more of dibutyl hydroxytoluene, tert-butyl p-hydroxyanisole, gallic acid, ethyl gallate, propyl gallate, octyl gallate, isoamyl gallate, sodium ascorbate, glutathione.
4. The CYP17 inhibitor solid dispersion of claim 1, 2 or 3, wherein the weight ratio of abiraterone acetate to antioxidant is 1: 0.002-0.2.
5. A tablet comprising the CYP17 inhibitor solid dispersion of claim 1 or 2 or 3, wherein said tablet comprises CYP17 inhibitor solid dispersion, a filler, a disintegrant, and a lubricant.
6. The CYP17 inhibitor solid dispersion of claim 5, wherein the weight ratio of abiraterone acetate to antioxidant is 1: 0.002-0.2.
7. The tablet of claim 5, wherein the filler is one or more of mannitol, microcrystalline cellulose, starch, pregelatinized starch, starch lactose complex.
8. The tablet according to claim 5, wherein the disintegrant is one or more of sodium carboxymethyl starch, croscarmellose sodium, crospovidone, and low substituted hydroxypropyl cellulose.
9. The tablet according to claim 5, wherein the tablet comprises the following components in parts by weight: 10 parts of CYP17 inhibitor solid dispersion, 10-40 parts of filler, 0.5-2.0 parts of disintegrant and 0.2-0.4 parts of lubricant.
10. A method for preparing the tablet of claim 5, wherein the abiraterone acetate, the antioxidant and the copovidone are heated and melted at 115-125 ℃ by a hot-melt extruder, and are extruded, the extruded product is crushed and then mixed with the filler and the disintegrant, and then the lubricant is added for mixing and tabletting.
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