CN113384532B - CYP17 inhibitor solid dispersion and preparation method thereof - Google Patents
CYP17 inhibitor solid dispersion and preparation method thereof Download PDFInfo
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- CN113384532B CN113384532B CN202010178409.8A CN202010178409A CN113384532B CN 113384532 B CN113384532 B CN 113384532B CN 202010178409 A CN202010178409 A CN 202010178409A CN 113384532 B CN113384532 B CN 113384532B
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- Prior art keywords
- abiraterone acetate
- solid dispersion
- mixing
- copovidone
- prescription
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- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- 239000007962 solid dispersion Substances 0.000 title claims abstract description 34
- 229940124766 Cyp17 inhibitor Drugs 0.000 title claims abstract description 20
- 229960004103 abiraterone acetate Drugs 0.000 claims description 62
- 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 62
- 238000002156 mixing Methods 0.000 claims description 44
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 37
- 229920001531 copovidone Polymers 0.000 claims description 29
- 239000000314 lubricant Substances 0.000 claims description 29
- 238000010438 heat treatment Methods 0.000 claims description 18
- 239000012943 hotmelt Substances 0.000 claims description 18
- 238000002844 melting Methods 0.000 claims description 18
- 230000008018 melting Effects 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
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- 239000000945 filler Substances 0.000 claims description 13
- 239000003963 antioxidant agent Substances 0.000 claims description 12
- 230000003078 antioxidant effect Effects 0.000 claims description 12
- 235000006708 antioxidants Nutrition 0.000 claims description 12
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 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
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 8
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 8
- 229920000036 polyvinylpyrrolidone Polymers 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 7
- 229940069328 povidone Drugs 0.000 claims description 7
- 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
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 6
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 6
- 229940016286 microcrystalline cellulose Drugs 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
- 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
- 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
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 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
- -1 lactose compound Chemical class 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 abstract description 18
- 238000000034 method Methods 0.000 abstract description 8
- 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
- 238000010298 pulverizing process Methods 0.000 description 11
- 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
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000002245 particle Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 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 5
- 229960001681 croscarmellose sodium Drugs 0.000 description 5
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 239000013558 reference substance Substances 0.000 description 5
- 238000007873 sieving Methods 0.000 description 5
- 239000004094 surface-active agent Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 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
- 238000001035 drying Methods 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 239000006190 sub-lingual tablet Substances 0.000 description 4
- 229940098466 sublingual tablet Drugs 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 108010024636 Glutathione Proteins 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
- GZOSMCIZMLWJML-VJLLXTKPSA-N abiraterone Chemical class 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
- 229960000913 crospovidone Drugs 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 229960003180 glutathione Drugs 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000002904 solvent Substances 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
- 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
- 229960000853 abiraterone Drugs 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
- 239000012738 dissolution medium Substances 0.000 description 2
- 238000007922 dissolution test Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 210000003608 fece Anatomy 0.000 description 2
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- 239000002609 medium Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
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- 239000012488 sample solution Substances 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- 229940083575 sodium dodecyl sulfate Drugs 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
- 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
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 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
- 238000010521 absorption reaction Methods 0.000 description 1
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- 229940030486 androgens Drugs 0.000 description 1
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- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
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- 238000006731 degradation reaction Methods 0.000 description 1
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- 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
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- 239000000706 filtrate Substances 0.000 description 1
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- 238000005469 granulation Methods 0.000 description 1
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- 238000000227 grinding 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
- 239000013038 irreversible inhibitor Substances 0.000 description 1
- 150000002634 lipophilic molecules Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 239000011812 mixed powder Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 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
- 238000001953 recrystallisation Methods 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
- 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
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- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 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
- 229940099039 velcade Drugs 0.000 description 1
- 238000012795 verification 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)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (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 in particular relates to a CYP17 inhibitor solid dispersion and a preparation method thereof. The tablet has high dissolution speed, good stability and good process reproducibility, and is suitable 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 irreversible inhibitor of the CYP17 enzyme for oral administration, reduces the androgen level by inhibiting C17, C20-lyase and 17 alpha-hydroxylase in the CYP17 key enzyme for androgen synthesis, has an inhibitory effect on androgens of testes and other parts of the body, and is used for treating advanced prostate cancer, and the structural formula is as follows:
abiraterone acetate is a lipophilic compound, is easily dissolved 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 dissolved in 0.1N hydrochloric acid; the biopharmaceutical classification system (BCS class) belongs to four classes, namely low-solubility-low-permeability drugs, so the bottleneck in drug formulation research is how to improve its dissolution and bioavailability.
The two major circulating metabolites of abiraterone in human plasma are abiraterone sulfate (inactive) and abiraterone oxynitride sulfate (inactive), each accounting for about 43% of the exposure; in addition, following oral administration of abiraterone acetate, approximately 88% of the radioactive dose was recovered in feces and approximately 5% in urine, with the main compounds present in feces being unchanged abiraterone acetate and abiraterone (approximately 55% and 22% of the administered dose, respectively); from this, it can be inferred that the bioavailability of abiraterone acetate by oral absorption is extremely low, which is also a key factor in the need of 1g for single oral dosage of abiraterone acetate tablet.
At present, researchers can solve the problem by adopting methods of preparing solid dispersion and the like such as 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, so that the poorly soluble medicine is dissolved in the micelle, and the dissolution of the medicine is improved by the solubilization of the surfactant, but the safety problem is easily caused by the excessive use amount of the surfactant.
CN102743393a discloses a pharmaceutical composition containing abiraterone acetate and a preparation process, the abiraterone acetate and hydrophilic auxiliary materials are crushed according to a proportion, the particle size of the raw material medicine is 10-30 μm, the dissolution rate and bioavailability of the medicine are improved, although the particle size of the raw material medicine is controlled to be smaller, the improvement of the dissolution rate of the medicine is still limited, and the dissolution rate is only 60% in a medium with a surfactant of pH4.5 added for 15 min.
CN103070828A discloses a solid dispersion, tablet and its preparation method, which comprises abiraterone acetate and povidone in the ratio of 1:0.5-4 are dissolved in chloroform, dried under reduced pressure to obtain solid dispersion, the solid dispersion is dispersed in water, micro-powder grinding is carried out, the particle diameter D (0.9) of the ground dispersion is smaller than 75 microns to obtain solution, the solution is added into filler and disintegrating agent which pass through 100 mesh sieve, granulating, drying, adding lubricant, tabletting, although the dissolution rate is improved, the process needs to prepare solid dispersion, chloroform is used as solvent, the workshop safety production and the labor protection of workers are not facilitated, and the dissolution rate is improved to a limited extent, and 73.7% is dissolved in the medium of adding surfactant with ph of 4.5 for 10 min.
CN106913539a discloses an abiraterone acetate sublingual tablet and a preparation method thereof, abiraterone acetate and polyethylene glycol 1000 vitamin E succinate are dissolved in an organic solvent, the organic solvent is removed by decompression and drying, the dried product is mixed with a filler and a disintegrating agent, then a lubricant is added for mixing, tabletting is carried out, although the abiraterone acetate sublingual tablet can be completely dissolved out for 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 are granulated on mixed powder of filler, disintegrating agent and adhesive, dried, and then added with lubricant for tabletting, thus improving the dissolution rate of the medicine, but the process is more complex, and the sublingual tablet has higher dissolution requirement and is easy to be influenced by environment in the storage and transportation processes.
CN109125276a discloses a pharmaceutical composition of abiraterone acetate tablet and a preparation method thereof, wherein copovidone and abiraterone acetate are prepared into solid dispersion, and then are prepared into mixture with diluent, adhesive, disintegrating agent and lubricant, and then tabletting is carried out. Although stability is improved to a certain extent, the dissolution rate of the tablet obtained by the preparation method is too low, the dissolution rate is about 25% in a hydrochloric acid solution with the pH of 1.0 for 20min, and the dissolution rate is only about 50% in pure water (0.5% SDS) and needs to be improved.
In the prior art, in order to solve the dissolution problem of abiraterone acetate tablets, a solid dispersion technology is mostly used, but the dissolution degree of the prepared abiraterone acetate tablets still needs to be improved, and an organic solvent is needed to be added, so that the cost is increased, the abiraterone acetate tablets are difficult to remove, the problem of residual solvent exists, and the hidden danger of drug dispersion degree is reduced due to drug recrystallization; the impurity content of the abiraterone acetate tablet shows an increasing trend in long-term placement and storage; in addition, in the solid dispersion preparation technology, if an excessively high operation temperature is used, degradation of a solid dispersion carrier can be promoted, so that the impurity content in a product is increased, and the stability is poor.
Disclosure of Invention
In view of the shortcomings of the prior art, the inventor provides a CYP17 inhibitor solid dispersion, and particularly provides a tablet of abiraterone acetate solid dispersion, which is prepared by a hot melt extrusion method through abiraterone acetate, copovidone and an antioxidant, and then mixed with a filler, a disintegrating agent and a lubricant for tabletting.
The invention is realized by the following scheme:
a CYP17 inhibitor solid dispersion, the CYP17 inhibitor solid dispersion comprising 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 abiraterone acetate to antioxidant is 1:0.05.
It will be appreciated that the solid dispersion may be used to prepare tablets and other common dosage forms.
The invention also provides a tablet containing the CYP17 inhibitor solid dispersion, and the tablet contains the CYP17 inhibitor solid dispersion, a filler, a disintegrating agent and a lubricant.
The filler is one or more of mannitol, microcrystalline cellulose, starch, pregelatinized starch and starch lactose complex.
The disintegrating agent is one or more of sodium carboxymethyl starch, crosslinked sodium carboxymethyl cellulose, crosslinked povidone 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 disintegrating agent and 0.2-0.4 parts of lubricant.
Preferably, the tablet specifically contains 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 disintegrating agent and 0.3 parts of lubricant.
The invention also provides a preparation method of the tablet containing the CYP17 inhibitor solid dispersion, which comprises the following specific steps: heating and melting abiraterone acetate, antioxidant and copovidone at 115-125deg.C with a hot melt extruder, extruding, pulverizing the extrudate, mixing with filler and disintegrating agent, adding lubricant, mixing, and tabletting.
Compared with the prior art, the invention has the following advantages:
(1) Complex micronization is not required;
(2) The product has no stimulation and high stability;
(3) Any solvent is not needed 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 are further improved.
Detailed Description
The invention is further illustrated by the following examples. It should be correctly understood that: the examples of the present invention are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, and therefore, simple modifications to the invention that are set forth herein are intended to be within the scope of the appended claims.
Example 1
1) Prescription of prescription
2) Preparation process
Heating and melting abiraterone acetate, gallic acid and copovidone VA64 with a hot-melt extruder at 123 ℃, extruding, pulverizing the extrudate, mixing with starch lactose compound and sodium carboxymethyl starch, adding lubricant magnesium stearate, mixing, and tabletting.
Example 2
1) Prescription of prescription
2) Preparation process
Heating and melting abiraterone acetate, tert-butyl p-hydroxyanisole and copovidone VA64 with a hot-melt extruder at 120 ℃, extruding, crushing the extrudate, mixing with microcrystalline cellulose and croscarmellose sodium, adding lubricant zinc stearate, mixing, and tabletting.
Example 3
1) Prescription of prescription
2) Preparation process
Heating and melting abiraterone acetate, dibutyl hydroxy toluene and copovidone S630 with a hot-melt extruder at 125 ℃, extruding, pulverizing the extrudate, mixing with mannitol and croscarmellose sodium, adding lubricant zinc stearate, mixing, and tabletting.
Example 4
1) Prescription of prescription
2) Preparation process
Heating and melting abiraterone acetate, ethyl gallate and copovidone S630 with a hot melt extruder at 115 ℃, extruding, pulverizing the extrudate, mixing with mannitol and crospovidone, adding lubricant sodium stearyl fumarate, mixing, and tabletting.
Example 5
1) Prescription of prescription
2) Preparation process
Heating and melting abiraterone acetate, propyl gallate and copovidone S630 with a hot-melt extruder at 125 deg.C, extruding, pulverizing the extrudate, mixing with starch and low-substituted hydroxypropyl cellulose, adding lubricant zinc stearate, mixing, and tabletting.
Example 6
1) Prescription of prescription
2) Preparation process
Heating and melting abiraterone acetate, octyl gallate and copovidone S630 with a hot-melt extruder at 125 ℃, extruding, pulverizing the extrudate, mixing with pregelatinized starch and low-substituted hydroxypropyl cellulose, adding lubricant zinc stearate, mixing, and tabletting.
Example 7
1) Prescription of prescription
2) Preparation process
Heating and melting abiraterone acetate, isoamyl gallate and copovidone S630 with a hot-melt extruder at 125 deg.C, extruding, pulverizing the extrudate, mixing with starch and low-substituted hydroxypropyl cellulose, adding lubricant such as new zinc stearate, mixing, and tabletting.
Example 8
1) Prescription of prescription
2) Preparation process
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 cross-linked povidone, adding lubricant sodium stearyl fumarate, mixing, and tabletting.
Example 9
1) Prescription of prescription
2) Preparation process
Heating and melting abiraterone acetate, glutathione and copovidone S630 with a hot-melt extruder at 125 ℃, extruding, crushing the extrudate, mixing with starch and low-substituted hydroxypropyl cellulose, mixing with cross-linked povidone, adding lubricant zinc stearate and magnesium stearate, mixing, and tabletting.
Example 10
1) Prescription of prescription
2) Preparation process
Heating and melting abiraterone acetate, isoamyl gallate and copovidone S630 with a hot-melt extruder at 140 ℃, extruding, pulverizing the extrudate, mixing with starch and low-substituted hydroxypropyl cellulose, adding lubricant zinc stearate, mixing, and tabletting.
Example 11
1) Prescription of prescription
2) Preparation process
Heating and melting abiraterone acetate, sodium ascorbate and copovidone S630 with a hot-melt extruder at 100deg.C, extruding, pulverizing, mixing with starch and low-substituted hydroxypropyl cellulose, adding lubricant zinc stearate, mixing, and tabletting.
Example 12
1) Prescription of prescription
2) Preparation process
Heating and melting abiraterone acetate, glutathione and copovidone S630 with a hot-melt extruder at 125 ℃, extruding, crushing the extrudate, mixing with mannitol and crospovidone, adding lubricant sodium stearyl fumarate, mixing, and tabletting.
Example 13
1) Prescription of prescription
2) Preparation process
Heating and melting abiraterone acetate, dibutyl hydroxy toluene and copovidone S630 with a hot-melt extruder at 125 ℃, extruding, pulverizing the extrudate, mixing with mannitol and cross-linked povidone, adding lubricant sodium stearyl fumarate, mixing, and tabletting.
Example 14
1) Prescription of prescription
2) Preparation process
Heating and melting abiraterone acetate, phenyl-1-naphthylamine and copovidone S630 with a hot melt extruder at 125 ℃, extruding, pulverizing the extrudate, mixing with dextrin and dry starch, adding lubricant zinc stearate, mixing, and tabletting.
Comparative example 1
1) Prescription of prescription
2) The preparation process comprises the following steps:
heating and melting the prescription amount of copovidone, adding abiraterone acetate, stirring uniformly, and extruding particles by using an extruder; mixing the granule with microcrystalline cellulose, crospovidone, and magnesium stearate, and tabletting.
Comparative example 2
1) Prescription of prescription
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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 methanol to acetone (2:1) solvent followed by spray drying the mixture to form a Spray Dried Dispersion (SDD) Drug Product Intermediate (DPI). And (5) after drying, mixing the obtained granules with other auxiliary materials and tabletting.
Comparative example 3
1) Prescription of prescription
2) The preparation process comprises the following steps:
abiraterone acetate is combined with an intragranular excipient, after dry granulation, the extragranular excipient is added to blend the croscarmellose sodium and the sodium stearyl fumarate, and the mixture is compressed into tablets in a rotary tablet press.
Comparative example 4
1) Prescription of prescription
/>
2) The preparation process comprises the following steps:
the abiraterone acetate and the sodium dodecyl sulfate are weighed and mixed according to the feeding amount, and are ground and pass through a 200-mesh vortex oscillating screen; respectively sieving mannitol, microcrystalline cellulose, silicon dioxide, crosslinked sodium carboxymethyl cellulose and magnesium stearate with 80 mesh vortex shaking sieve; mixing abiraterone acetate, sodium dodecyl sulfate, mannitol, microcrystalline cellulose, croscarmellose sodium and silicon dioxide with a mixer, sieving with 80 mesh sieve, and mixing; adding the premixed raw materials and auxiliary materials into a high-speed stirring granulator, adding 8% PVP k29/32 adhesive ethanol water solution, preparing particles, and sieving with a 24-mesh sieve; after the granulation is finished, transferring the mixture to a fluidized bed, and drying until the moisture of the granules is less than or equal to 1.5%; sieving the dried granular stainless steel screen to obtain granules; adding the additional auxiliary materials, mixing uniformly and tabletting.
Comparative example 5
1) Prescription of prescription
2) Preparation process
Heating and melting abiraterone acetate and povidone with a prescription amount by a hot-melt extruder at 125 ℃, extruding, crushing the extrudate, mixing with starch and croscarmellose sodium, adding lubricant zinc stearate, mixing, and tabletting.
Comparative example 6
1) Prescription of prescription
2) Preparation process
Mixing abiraterone acetate and copovidone uniformly to prepare a physical mixture; setting the extrusion temperature of a double-screw hot-melt extruder to be 100 ℃, starting a screw after reaching a preset temperature, adding the obtained physical mixture into the extruder, and extruding a strip-shaped object through the screw; crushing the strip-shaped object, and sieving the crushed strip-shaped object 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; tabletting the mixture to obtain tablet.
Verification embodiment
1. Dissolution test
Abiraterone acetate tablets obtained in examples 1 to 14 and comparative examples 1 to 6 were measured for dissolution by the following method.
Taking the product, taking 500ml of acetate with pH of 4.5 and 0.25% SDS as a dissolution medium according to a dissolution rate measurement method, rotating at 50 revolutions per minute, performing normal operation, taking 10ml of solution after 20 minutes, filtering, and taking the subsequent filtrate as a sample solution. And (3) 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 dissolution medium for diluting to the scale, and shaking the abiraterone acetate reference substance to be uniform to obtain a reference substance solution. Taking 10 μl of each of the sample solution and the reference solution according to chromatographic conditions under the content measurement item, injecting into a liquid chromatograph, recording the chromatogram, and calculating the dissolution of each tablet according to external standard method with peak area. The limit is 80% of the indicated amount, which should be in compliance with the regulations.
TABLE 1 dissolution test results
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2. Stability test
To further demonstrate the superiority of the present invention, the inventors conducted the present invention on the product obtained in the examples and on the commercially available abiraterone acetate tablet (trade name: velcade) @ ) Long-term stability experiments were performed.
The abiraterone acetate tablets prepared in examples 1-14 of the invention were not packaged, and examined under conditions of 40 ℃ + -2 ℃ and 75%RH+ -5%RH, and the related substances of the reserved samples were measured at 0 month, 3 months and 6 months respectively, and specific data are shown in the following table:
TABLE 2 stability test results
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Claims (1)
1. The tablet of the CYP17 inhibitor solid dispersion is characterized by comprising the CYP17 inhibitor solid dispersion, a filler, a disintegrating agent and a lubricant, wherein the CYP17 inhibitor solid dispersion is prepared from abiraterone acetate, copovidone and an antioxidant, and the weight ratio of the abiraterone acetate to the copovidone in the CYP17 inhibitor solid dispersion is 1:4-7; 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; the weight ratio of the abiraterone acetate to the antioxidant is 1:0.002-0.1; the filler is one or more of mannitol, microcrystalline cellulose, starch, pregelatinized starch and starch lactose compound; the disintegrating agent is one or more of sodium carboxymethyl starch, crosslinked sodium carboxymethyl cellulose, crosslinked povidone and low-substituted hydroxypropyl cellulose; 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 disintegrating agent and 0.2-0.4 parts of lubricant; the preparation method of the tablet comprises the steps of heating and melting abiraterone acetate, an antioxidant and copovidone by a hot melt extruder at 115-125 ℃, extruding, crushing the extrudate, mixing with a filler and a disintegrating agent, adding a lubricant, mixing, and tabletting.
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Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014009437A1 (en) * | 2012-07-11 | 2014-01-16 | Sandoz Ag | Oxidation stability of abiraterone acetate |
CN104434857A (en) * | 2014-12-25 | 2015-03-25 | 贾红瑞 | Orally taken solid preparation containing lovastatin and preparation process of orally taken solid preparation |
WO2015114314A1 (en) * | 2014-01-28 | 2015-08-06 | Cipla Limited | Pharmaceutical composition comprising abiraterone |
CN106539765A (en) * | 2015-09-18 | 2017-03-29 | 天津市汉康医药生物技术有限公司 | A kind of Abiraterone Acetate Tablets and preparation method thereof |
CN109125276A (en) * | 2017-06-19 | 2019-01-04 | 齐鲁制药有限公司 | A kind of pharmaceutical composition and preparation method thereof of Abiraterone acetate tablet |
CN109125320A (en) * | 2017-06-15 | 2019-01-04 | 成都苑东生物制药股份有限公司 | A kind of pharmaceutical composition of pyridine compounds and their |
CN110917152B (en) * | 2019-02-01 | 2021-07-02 | 鲁南制药集团股份有限公司 | CYP17 inhibitor tablet and preparation method thereof |
-
2020
- 2020-03-14 CN CN202010178409.8A patent/CN113384532B/en active Active
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014009437A1 (en) * | 2012-07-11 | 2014-01-16 | Sandoz Ag | Oxidation stability of abiraterone acetate |
WO2015114314A1 (en) * | 2014-01-28 | 2015-08-06 | Cipla Limited | Pharmaceutical composition comprising abiraterone |
CN104434857A (en) * | 2014-12-25 | 2015-03-25 | 贾红瑞 | Orally taken solid preparation containing lovastatin and preparation process of orally taken solid preparation |
CN106539765A (en) * | 2015-09-18 | 2017-03-29 | 天津市汉康医药生物技术有限公司 | A kind of Abiraterone Acetate Tablets and preparation method thereof |
CN109125320A (en) * | 2017-06-15 | 2019-01-04 | 成都苑东生物制药股份有限公司 | A kind of pharmaceutical composition of pyridine compounds and their |
CN109125276A (en) * | 2017-06-19 | 2019-01-04 | 齐鲁制药有限公司 | A kind of pharmaceutical composition and preparation method thereof of Abiraterone acetate tablet |
CN110917152B (en) * | 2019-02-01 | 2021-07-02 | 鲁南制药集团股份有限公司 | CYP17 inhibitor tablet and preparation method thereof |
Non-Patent Citations (1)
Title |
---|
陆彬,等.《药物新剂型与新技术》.人民卫生出版社,1998,第10页. * |
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