CN115364108A - Composition containing CYP inhibitor and delivery agent and preparation method thereof - Google Patents
Composition containing CYP inhibitor and delivery agent and preparation method thereof Download PDFInfo
- Publication number
- CN115364108A CN115364108A CN202110545746.0A CN202110545746A CN115364108A CN 115364108 A CN115364108 A CN 115364108A CN 202110545746 A CN202110545746 A CN 202110545746A CN 115364108 A CN115364108 A CN 115364108A
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- China
- Prior art keywords
- abiraterone acetate
- composition
- delivery agent
- parts
- solid dispersion
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- 239000000203 mixture Substances 0.000 title claims abstract description 46
- 229940124447 delivery agent Drugs 0.000 title claims abstract description 27
- 239000003112 inhibitor Substances 0.000 title claims abstract description 10
- 238000002360 preparation method Methods 0.000 title abstract description 43
- 229960004103 abiraterone acetate Drugs 0.000 claims abstract description 69
- 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 abstract description 69
- 239000007962 solid dispersion Substances 0.000 claims abstract description 21
- 239000000463 material Substances 0.000 claims abstract description 7
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 27
- 229920001531 copovidone Polymers 0.000 claims description 25
- 239000000314 lubricant Substances 0.000 claims description 25
- 238000010438 heat treatment Methods 0.000 claims description 14
- 239000012943 hotmelt Substances 0.000 claims description 14
- 239000000945 filler Substances 0.000 claims description 11
- 239000011734 sodium Substances 0.000 claims description 10
- 229910052708 sodium Inorganic materials 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 239000007884 disintegrant Substances 0.000 claims description 6
- -1 2-hydroxyphenyl Chemical group 0.000 claims description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group 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 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- GHVNFZFCNZKVNT-UHFFFAOYSA-M decanoate Chemical compound CCCCCCCCCC([O-])=O GHVNFZFCNZKVNT-UHFFFAOYSA-M 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 abstract description 24
- 239000003814 drug Substances 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 6
- 235000013305 food Nutrition 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 238000002156 mixing Methods 0.000 description 35
- 239000003826 tablet Substances 0.000 description 18
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 16
- 238000002844 melting Methods 0.000 description 14
- 229920002472 Starch Polymers 0.000 description 13
- 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 13
- 230000008018 melting Effects 0.000 description 13
- 239000008107 starch Substances 0.000 description 13
- 235000019698 starch Nutrition 0.000 description 13
- 229960000853 abiraterone Drugs 0.000 description 12
- UOENJXXSKABLJL-UHFFFAOYSA-M sodium;8-[(2-hydroxybenzoyl)amino]octanoate Chemical compound [Na+].OC1=CC=CC=C1C(=O)NCCCCCCCC([O-])=O UOENJXXSKABLJL-UHFFFAOYSA-M 0.000 description 12
- 235000012438 extruded product Nutrition 0.000 description 11
- 229920002785 Croscarmellose sodium Polymers 0.000 description 9
- 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 9
- 229960001681 croscarmellose sodium Drugs 0.000 description 9
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 8
- 239000008101 lactose Substances 0.000 description 8
- 235000019359 magnesium stearate Nutrition 0.000 description 8
- 229940083542 sodium Drugs 0.000 description 8
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 239000008108 microcrystalline cellulose Substances 0.000 description 7
- 229940016286 microcrystalline cellulose Drugs 0.000 description 7
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 7
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 7
- 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 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 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 5
- 229930195725 Mannitol Natural products 0.000 description 5
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 239000000594 mannitol Substances 0.000 description 5
- 235000010355 mannitol Nutrition 0.000 description 5
- 229960001855 mannitol Drugs 0.000 description 5
- 239000003960 organic solvent 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
- 239000000853 adhesive Substances 0.000 description 4
- 230000001070 adhesive effect Effects 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 229960000913 crospovidone Drugs 0.000 description 3
- 238000007922 dissolution test Methods 0.000 description 3
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 3
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 3
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- 238000012360 testing method Methods 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
- 102000001854 Steroid 17-alpha-Hydroxylase Human genes 0.000 description 2
- 108010015330 Steroid 17-alpha-Hydroxylase Proteins 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 125000005456 glyceride group Chemical group 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 2
- 229940057948 magnesium stearate Drugs 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000006069 physical mixture Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000013558 reference substance 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
- 229940032147 starch Drugs 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000006190 sub-lingual tablet Substances 0.000 description 2
- 229940098466 sublingual tablet Drugs 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- NZJXADCEESMBPW-UHFFFAOYSA-N 1-methylsulfinyldecane Chemical compound CCCCCCCCCCS(C)=O NZJXADCEESMBPW-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 229940124766 Cyp17 inhibitor Drugs 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
- 206010061818 Disease progression Diseases 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940099418 d- alpha-tocopherol succinate Drugs 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000006185 dispersion Substances 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
- 229960003668 docetaxel 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
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000009246 food effect Effects 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 210000003194 forelimb Anatomy 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 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
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 235000012054 meals Nutrition 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
- 239000006070 nanosuspension Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 229940113116 polyethylene glycol 1000 Drugs 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged 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
- 239000012488 sample solution Substances 0.000 description 1
- XUHVCHNJCBBXMP-UHFFFAOYSA-M sodium;10-[(2-hydroxybenzoyl)amino]decanoate Chemical compound [Na+].OC1=CC=CC=C1C(=O)NCCCCCCCCCC([O-])=O XUHVCHNJCBBXMP-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000011973 solid acid Substances 0.000 description 1
- 238000001694 spray drying 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
- 239000012085 test solution Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 229940051084 zytiga Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—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
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicinal Preparation (AREA)
Abstract
The application belongs to the field of pharmaceutical preparations, and particularly relates to a composition containing a CYP inhibitor and a delivery agent and a preparation method thereof. The pharmaceutical composition comprises an abiraterone acetate solid dispersion, a delivery agent and pharmaceutically common auxiliary materials. The pharmaceutical composition has stable physical and chemical properties and simple preparation process, so as to increase the dissolution rate and bioavailability of the abiraterone acetate, remarkably reduce the influence of food on the bioavailability of the abiraterone acetate and improve the medication safety of patients.
Description
Technical Field
The invention belongs to the field of medicinal preparations, and particularly relates to a composition containing a delivery agent, in particular to a composition containing a CYP inhibitor and the delivery agent and a preparation method thereof.
Background
Abiraterone acetate is an oral CYP17 inhibitor (inhibiting C17, C20-lyase and 17 alpha-hydroxylase), with high affinity and high selectivity for CYP17, developed by the centrocor Ortho company and marketed under the FDA approval of usa on 28.4.2011 under the trade name zeke (Zytiga), in combination with prednisone for castration-resistant prostate cancer (cRPC) where docetaxel fails to control disease progression. The abiraterone acetate is taken as a prodrug of the abiraterone, can be rapidly absorbed after being taken orally, and is deacetylated in the liver to obtain an active component, namely the abiraterone.
Abiraterone acetate is white crystalline powder, has solubility of 0.02mg/ml in aqueous medium, is slightly soluble in 0.1N hydrochloric acid, and is easily soluble in organic solvents such as tetrahydrofuran, dichloromethane, etc., especially alcohols; the abiraterone acetate has the characteristics of water insolubility and fat insolubility, so that the abiraterone acetate has low permeability and poor bioavailability, and the absolute bioavailability is about 45%, so the bottleneck of pharmaceutical preparation research is how to improve the dissolution rate and the bioavailability.
CN103070828A prepares a solid dispersion, dissolving 1. Although the dissolution rate is improved, the solid dispersion prepared by the process uses chloroform as a solvent, is not beneficial to safe production in a workshop and labor protection of workers, and has limited dissolution improvement, namely 64% is dissolved in a medium with pH4.5 and added with a surfactant within 10 min.
CN106913537A discloses an abiraterone acetate sublingual tablet, which is prepared by heating and melting abiraterone acetate and solid acid, mixing with filler, disintegrant and adhesive, granulating, drying, adding lubricant, and tabletting.
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 filling agent and a disintegrating agent, then a lubricating agent is added for mixing and tabletting, although complete dissolution can be realized within 15min, a large amount of organic solvent can not be avoided, the labor protection is not facilitated, the impurity content is obviously increased in the long-term storage process, and the stability is poor.
CN110354094A discloses an abiraterone acetate capsule, which is prepared by dissolving abiraterone acetate in fatty glyceride, and the soft capsule is prepared by using the fatty glyceride, so that the dissolution rate and solubility in vivo are improved, the retention time in the stomach and intestine is prolonged, lymphatic transport is stimulated, the metabolic influence is reduced, and the bioavailability of the abiraterone acetate is further improved.
CN109125276A discloses an abiraterone acetate tablet, which is prepared by preparing solid dispersion from copovidone and abiraterone acetate, and then preparing the solid dispersion, diluent, adhesive, disintegrant and lubricant into mixture and tabletting. Although the stability is improved to some extent, the dissolution rate of the tablets obtained by the preparation method is too low, about 25% in hydrochloric acid solution with pH of 1.0%, about 50% in pure water (0.5% SDS), and the dissolution rate is to be improved.
CN110917152A discloses an abiraterone acetate tablet, which is prepared by preparing solid dispersion from abiraterone acetate and copovidone by a hot-melt extrusion method, and then preparing the tablet with other auxiliary materials, wherein the dissolution of the abiraterone acetate tablet can be greatly improved, and the bioavailability of the abiraterone acetate is further improved.
CN111012745A discloses an abiraterone oral emulsion, which comprises abiraterone or abiraterone acetate, a solubilizer, an emulsifier and an antioxidant. The oral emulsion is stable and has small influence on digestion, the adverse influence of abiraterone acetate hydrolysis on medicine dissolution is reduced, the medicine dissolution in gastrointestinal tracts can be improved, the medicine absorption is promoted, and the bioavailability is improved, but a large amount of emulsifying agents and solubilizing agents taking surfactants as components are required to be added, and the safety of clinical medication cannot be guaranteed.
CN111617257A discloses an abiraterone or its derivative pharmaceutical composition, which contains abiraterone or its derivative, an absorption enhancer and lactose, wherein the dosage of lactose accounts for 15-80% of the total weight of the pharmaceutical composition, the optimal formula (formula 2) of the obtained preparation has a poor dissolution rate, the dissolution rate is 95% at 60min in vitro dissolution test, and the dissolution rate reflects the bioavailability to a certain extent, so the bioavailability thereof still needs to be improved.
CN111617258A discloses a method for preparing abiraterone or its derivative pharmaceutical composition, which comprises mixing a nano suspension containing abiraterone or its derivative with an absorption enhancer and optionally at least one excipient, and granulating by a fluidized bed, wherein the particle size D90 value of the abiraterone or its derivative is less than 1000nm, preferably 400-600 nm, the obtained pharmaceutical composition has improved bioavailability and improved individual variability of administration patients compared with the commercially available preparation, but the dissolution rate of the obtained preparation (for example, formula 1) is still poor, and the dissolution rate is 98% at 60min in an in vitro dissolution experiment, which is not favorable for improving the bioavailability.
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, and the problems of residual solvent and the hidden trouble of reducing the dispersion degree of the drug by recrystallization of the drug exist; in long-term storage, the impurity content of the abiraterone acetate tablet is easy to increase, and the stability is poor. In addition, in the existing preparation, the abiraterone acetate preparation must be taken on an empty stomach, because compared with the empty stomach, the Cmax and AUC of the abiraterone taken by a meal are respectively increased to 17 times and 10 times, so that the safety risk of taking the abiraterone acetate preparation is increased. Therefore, the abiraterone acetate preparation with high dissolution rate, high bioavailability and high medication safety needs to be provided, and a better treatment scheme is provided for clinic.
Disclosure of Invention
In view of the drawbacks of the prior art, the present invention aims to provide a composition containing a CYP inhibitor and a delivery agent, which has stable physicochemical properties and a simple preparation process, so as to achieve an improvement in the dissolution rate and bioavailability of abiraterone acetate, and to improve the effect of food intake on Cmax and exposure of abiraterone in plasma.
The technical scheme of the invention is as follows: a composition containing a CYP inhibitor and a delivery agent comprises an abiraterone acetate solid dispersion, the delivery agent and pharmaceutically common auxiliary materials.
Preferably, in the composition, the delivery agent is sodium N- [8- (2-hydroxyphenyl) amino ] caprylate (SNAC for short) or/and sodium N- (10- [ 2-hydroxybenzoyl ] amino) caprate (SNAD for short) or a pharmaceutically acceptable salt thereof; further preferably, the delivery agent is SNAC.
Preferably, in the composition, the weight ratio of the abiraterone acetate solid dispersion to the delivery agent is 1; further preferably, the weight ratio of the abiraterone acetate solid dispersion to the delivery agent is 1.
Preferably, in the composition, the solid dispersion comprises abiraterone acetate and copovidone; further preferably, the weight ratio of the abiraterone acetate to the copovidone is 1; more preferably, the copovidone is copovidone VA64 or copovidone S630.
Preferably, in the composition, the pharmaceutically common auxiliary materials comprise a filler, a disintegrant and a lubricant.
Further preferably, in the composition, the filler is one or more of mannitol, microcrystalline cellulose, starch, pregelatinized starch and starch lactose complex.
Further preferably, in the composition, the disintegrant is one or more of sodium carboxymethyl starch, croscarmellose sodium, crospovidone and low-substituted hydroxypropyl cellulose.
Further preferably, in the composition, the lubricant is one or more of magnesium stearate, sodium stearyl fumarate and zinc stearate.
Preferably, the composition is a tablet or capsule; further preferably, the composition is a tablet.
Preferably, the composition comprises the following components in parts by weight: 10 parts of abiraterone acetate solid dispersion, 1-20 parts of delivery agent, 10-40 parts of filler, 0.5-2.0 parts of disintegrating agent and 0.2-0.4 part of lubricant.
Further preferably, the composition comprises the following components in parts by weight: 10 parts of abiraterone acetate solid dispersion, 2-6 parts of delivery agent, 20-30 parts of filler, 1.0-1.5 parts of disintegrating agent and 0.3 part of lubricant.
The invention also provides a method of preparing a composition comprising a CYP inhibitor and a delivery agent: the abiraterone acetate and the copovidone are heated and melted by a hot-melt extruder at the temperature of 115-125 ℃, extruded, crushed and mixed with the delivery agent, the filler and the disintegrating agent, and then added with the lubricant for mixing and tabletting to obtain the tablet.
The positive effects of the invention are that the composition of the CYP inhibitor and the delivery agent has high dissolution rate, and can significantly reduce the influence of food on the bioavailability of abiraterone and improve the medication safety of patients.
Detailed Description
The present invention is further described by the following embodiments, which do not limit the scope of the present invention in any way, and those skilled in the art can make various modifications or improvements based on the basic idea of the present invention, but within the scope of the present invention, as long as they do not depart from the basic idea of the present invention.
Example 1
1) Prescription
2) Preparation process
The preparation method comprises the following steps of heating and melting abiraterone acetate and copovidone according to the prescription amount by using a hot-melt extruder at the temperature of 123 ℃, extruding, crushing an extruded product, mixing with SNAC, 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 and copovidone according to the prescription amount by using a hot-melt extruder at 120 ℃, extruding, crushing an extruded product, mixing with SNAC, 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 and copovidone according to the prescription amount by using a hot-melt extruder at 125 ℃, extruding, crushing the extruded product, mixing with SNAC, 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 and copovidone according to the prescription amount by using a hot-melt extruder at 115 ℃, extruding, crushing the extruded product, mixing with SNAC, mannitol and crospovidone, adding a lubricant 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 and copovidone according to the prescription amount by using a hot-melt extruder at 125 ℃, extruding, crushing an extruded product, mixing with SNAC, starch and low-substituted hydroxypropyl cellulose, adding a lubricant, namely 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, copovidone and SNAC according to the prescription amount by using a hot-melting extruder at the temperature of 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 7
1) Prescription
2) Preparation process
The preparation method comprises the following steps of heating and melting abiraterone acetate, copovidone and SNAC (7 g) according to the prescription amount by using a hot-melt extruder at 120 ℃, extruding, crushing the extruded product, mixing with the rest SNAC (7 g), microcrystalline cellulose and croscarmellose sodium, adding a lubricant zinc stearate, mixing, and tabletting.
Example 8
1) Prescription
2) Preparation process
The preparation method comprises the following steps of heating and melting abiraterone acetate and copovidone according to the prescription amount by using a hot-melt extruder at the temperature of 123 ℃, extruding, crushing an extruded product, mixing with SNAC, a starch lactose compound and sodium carboxymethyl starch, adding a lubricant magnesium stearate, mixing, and tabletting.
Example 9
1) Prescription
2) Preparation process
The preparation method comprises the following steps of heating and melting abiraterone acetate and copovidone according to the prescription amount by using a hot-melt extruder at the temperature of 123 ℃, extruding, crushing an extruded product, mixing with SNAC, a starch lactose compound and sodium carboxymethyl starch, adding a lubricant 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 and copovidone according to the prescription amount by using a hot-melt extruder at the temperature of 123 ℃, extruding, crushing an extruded product, mixing with decyl methyl sulfoxide, a starch lactose compound and sodium carboxymethyl starch, adding a lubricant magnesium stearate, mixing, and tabletting.
Comparative example 1
1) Prescription
2) Preparation process
The preparation method comprises the following steps of heating and melting abiraterone acetate and copovidone 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.
Comparative example 2
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 3
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). After drying, the obtained granules are further mixed with other auxiliary materials for tabletting.
Comparative example 4
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 5
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 the granulation is finished, transferring the granules to a fluidized bed, and drying until the moisture of the granules is less than or equal to 1.5%; sieving and granulating the dried particles by a stainless steel screen; adding adjuvants, mixing, and tabletting.
Comparative example 6
1) Prescription
2) Preparation process
The abiraterone acetate and the povidone with the prescription amount are heated and melted by a hot-melt extruder at 125 ℃, extruded, crushed and mixed with starch and croscarmellose sodium, then added with lubricant zinc stearate for mixing, and tableted to obtain the tablet.
Comparative example 7
1) Prescription
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 10 and comparative examples 1 to 7 were measured by the following methods. Taking the product, determining according to dissolution method, taking 500ml of pure water as dissolution medium, rotating speed is 50 rpm, operating according to the method, taking 10ml of solution after 15 minutes, filtering, and taking the subsequent filtrate as sample solution. Taking another appropriate amount of abiraterone acetate reference substance, placing in a 10ml measuring flask, adding methanol for dissolving and diluting to scale, precisely measuring 1ml, placing in a 10ml measuring flask, adding dissolved medium for diluting to scale, shaking up to obtain 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, and the result is shown in table 1. The limit is 80% of the indicated amount and should be met.
Table 1 dissolution test results
2. Pharmacokinetic testing
Taking 6 healthy Beagle dogs in each group, weighing 12.5-15Kg, taking the formulation prepared in the invention and commercially available zeek @ once 12h before taking the formulation, taking the formulation for another group 30 minutes after taking the formulation, respectively taking 250mg of abiraterone acetate orally, simultaneously taking 25ml of warm water, collecting blood in forelimb subcutaneously for about 3ml after 5min, 15min, 30min, 45min, 60min, 90min, 120min, 240min, 480min and 720min after taking the formulation, placing the obtained blood in heparinized test tubes, measuring the blood concentration, calculating Cmax and AUC, comparing the blood concentration with the commercially available abiraterone acetate (trade name: zekin @), and further calculating the ratio of the Cmax and the AUC for zekin @ or fasting, and the result is shown in Table 2.
TABLE 2 pharmacokinetic testing results
Claims (10)
1. A composition containing CYP inhibitor and delivery agent is characterized by comprising an abiraterone acetate solid dispersion, the delivery agent and pharmaceutically commonly used auxiliary materials.
2. The composition of claim 1 wherein the delivery agent is sodium N- [8- (2-hydroxyphenyl) amino ] caprylate or/and sodium N- (10- [ 2-hydroxybenzoyl ] amino) caprate or a pharmaceutically acceptable salt thereof.
3. The composition of claim 1, wherein the pharmaceutically acceptable excipients comprise a filler, a disintegrant and a lubricant.
4. The composition of claim 1, wherein the weight ratio of the abiraterone acetate solid dispersion to the delivery agent in the composition is 1.
5. The composition of claim 4, wherein the weight ratio of the abiraterone acetate solid dispersion to the delivery agent in the composition is from 1.
6. The composition of claim 1, wherein the solid dispersion comprises abiraterone acetate and copovidone.
7. The composition of claim 6, wherein the weight ratio of abiraterone acetate to copovidone in the composition is 1.
8. The composition according to any one of claims 3 to 7, wherein the composition comprises the following components in parts by weight: 10 parts of abiraterone acetate solid dispersion, 1-20 parts of delivery agent, 10-40 parts of filler, 0.5-2.0 parts of disintegrating agent and 0.2-0.4 part of lubricant.
9. The composition of claim 8, wherein the composition comprises the following components in parts by weight: 10 parts of abiraterone acetate solid dispersion, 2-6 parts of delivery agent, 20-30 parts of filler, 1.0-1.5 parts of disintegrating agent and 0.3 part of lubricant.
10. A process for preparing a composition comprising a CYP inhibitor and a delivery agent according to claim 1, wherein abiraterone acetate and copovidone are melted by heating in a hot melt extruder at 115-125 ℃, extruded, the extrudate is pulverized and mixed with the delivery agent, filler and disintegrant, and then mixed with a lubricant and compressed into tablets.
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