CN116033925A - Abiraterone acetate soft capsule and preparation method and application thereof - Google Patents
Abiraterone acetate soft capsule and preparation method and application thereof Download PDFInfo
- Publication number
- CN116033925A CN116033925A CN202280003906.1A CN202280003906A CN116033925A CN 116033925 A CN116033925 A CN 116033925A CN 202280003906 A CN202280003906 A CN 202280003906A CN 116033925 A CN116033925 A CN 116033925A
- Authority
- CN
- China
- Prior art keywords
- abiraterone acetate
- content
- accounts
- total mass
- soft capsule
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 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 title claims abstract description 167
- 229960004103 abiraterone acetate Drugs 0.000 title claims abstract description 134
- 239000007901 soft capsule Substances 0.000 title claims abstract description 98
- 238000002360 preparation method Methods 0.000 title claims abstract description 37
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 36
- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 claims abstract description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000002775 capsule Substances 0.000 claims abstract description 23
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 claims abstract description 22
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims abstract description 22
- 229920000053 polysorbate 80 Polymers 0.000 claims abstract description 22
- 108010010803 Gelatin Proteins 0.000 claims abstract description 17
- 239000008273 gelatin Substances 0.000 claims abstract description 17
- 229920000159 gelatin Polymers 0.000 claims abstract description 17
- 235000019322 gelatine Nutrition 0.000 claims abstract description 17
- 235000011852 gelatine desserts Nutrition 0.000 claims abstract description 17
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 claims abstract description 15
- 235000011187 glycerol Nutrition 0.000 claims abstract description 15
- 239000000463 material Substances 0.000 claims abstract description 14
- 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 abstract description 9
- WSWCOQWTEOXDQX-MQQKCMAXSA-M (E,E)-sorbate Chemical compound C\C=C\C=C\C([O-])=O WSWCOQWTEOXDQX-MQQKCMAXSA-M 0.000 claims abstract description 7
- 229940075554 sorbate Drugs 0.000 claims abstract description 7
- 239000000243 solution Substances 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 13
- 206010060862 Prostate cancer Diseases 0.000 claims description 12
- 239000006187 pill Substances 0.000 claims description 12
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 11
- 239000003292 glue Substances 0.000 claims description 10
- 239000003963 antioxidant agent Substances 0.000 claims description 9
- 230000003078 antioxidant effect Effects 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- 238000011049 filling Methods 0.000 claims description 7
- 238000007872 degassing Methods 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 238000002844 melting Methods 0.000 claims description 6
- 230000008018 melting Effects 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 3
- 230000001394 metastastic effect Effects 0.000 claims description 3
- 206010061289 metastatic neoplasm Diseases 0.000 claims description 3
- 238000011282 treatment Methods 0.000 claims description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 48
- 229940051084 zytiga Drugs 0.000 abstract description 34
- 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 abstract description 29
- 229960000853 abiraterone Drugs 0.000 abstract description 27
- 238000000227 grinding Methods 0.000 abstract description 27
- 210000002784 stomach Anatomy 0.000 abstract description 16
- 235000012054 meals Nutrition 0.000 abstract description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 42
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 28
- 238000012360 testing method Methods 0.000 description 27
- 229940079593 drug Drugs 0.000 description 24
- 241000282472 Canis lupus familiaris Species 0.000 description 20
- 238000004090 dissolution Methods 0.000 description 18
- 239000004094 surface-active agent Substances 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 10
- 235000013305 food Nutrition 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 210000002381 plasma Anatomy 0.000 description 10
- 229960004063 propylene glycol Drugs 0.000 description 10
- 235000013772 propylene glycol Nutrition 0.000 description 10
- 239000004359 castor oil Substances 0.000 description 9
- 235000019438 castor oil Nutrition 0.000 description 9
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 9
- 230000007774 longterm Effects 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 238000003860 storage Methods 0.000 description 9
- 238000010521 absorption reaction Methods 0.000 description 8
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 230000000291 postprandial effect Effects 0.000 description 6
- 230000001133 acceleration Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000839 emulsion Substances 0.000 description 5
- 230000002496 gastric effect Effects 0.000 description 5
- 238000007789 sealing Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-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
- 238000013461 design Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 4
- 241000282465 Canis Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- -1 acetate-polyethylene Chemical group 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 230000003204 osmotic effect Effects 0.000 description 3
- 230000008855 peristalsis Effects 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 229960003604 testosterone Drugs 0.000 description 3
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-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
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000004945 emulsification Methods 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000007902 hard capsule Substances 0.000 description 2
- 210000002490 intestinal epithelial cell Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000007908 nanoemulsion Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000007427 paired t-test Methods 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 210000001550 testis Anatomy 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- 239000000263 2,3-dihydroxypropyl (Z)-octadec-9-enoate Substances 0.000 description 1
- RZRNAYUHWVFMIP-GDCKJWNLSA-N 3-oleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-GDCKJWNLSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- SHBUUTHKGIVMJT-UHFFFAOYSA-N Hydroxystearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OO SHBUUTHKGIVMJT-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ORNBQBCIOKFOEO-YQUGOWONSA-N Pregnenolone Natural products O=C(C)[C@@H]1[C@@]2(C)[C@H]([C@H]3[C@@H]([C@]4(C)C(=CC3)C[C@@H](O)CC4)CC2)CC1 ORNBQBCIOKFOEO-YQUGOWONSA-N 0.000 description 1
- 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 1
- 239000002253 acid Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- AEMFNILZOJDQLW-QAGGRKNESA-N androst-4-ene-3,17-dione Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 AEMFNILZOJDQLW-QAGGRKNESA-N 0.000 description 1
- 229960005471 androstenedione Drugs 0.000 description 1
- AEMFNILZOJDQLW-UHFFFAOYSA-N androstenedione Natural products O=C1CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 AEMFNILZOJDQLW-UHFFFAOYSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000007957 coemulsifier Substances 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- FMGSKLZLMKYGDP-USOAJAOKSA-N dehydroepiandrosterone Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC=C21 FMGSKLZLMKYGDP-USOAJAOKSA-N 0.000 description 1
- 229960003964 deoxycholic acid Drugs 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003989 dielectric material Substances 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000009506 drug dissolution testing Methods 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 230000009246 food effect Effects 0.000 description 1
- 235000021471 food effect Nutrition 0.000 description 1
- 230000005176 gastrointestinal motility Effects 0.000 description 1
- 229920000578 graft copolymer Polymers 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 235000009200 high fat diet Nutrition 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 229940072106 hydroxystearate Drugs 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000013038 irreversible inhibitor Substances 0.000 description 1
- 229960001021 lactose monohydrate Drugs 0.000 description 1
- 150000002634 lipophilic molecules Chemical class 0.000 description 1
- 235000015263 low fat diet Nutrition 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- 229940057917 medium chain triglycerides Drugs 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- RZRNAYUHWVFMIP-UHFFFAOYSA-N monoelaidin Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-UHFFFAOYSA-N 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- HGASFNYMVGEKTF-UHFFFAOYSA-N octan-1-ol;hydrate Chemical compound O.CCCCCCCCO HGASFNYMVGEKTF-UHFFFAOYSA-N 0.000 description 1
- 230000010494 opalescence Effects 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 230000002572 peristaltic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor 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
- 229960000249 pregnenolone Drugs 0.000 description 1
- ORNBQBCIOKFOEO-QGVNFLHTSA-N pregnenolone Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 ORNBQBCIOKFOEO-QGVNFLHTSA-N 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- GHBFNMLVSPCDGN-UHFFFAOYSA-N rac-1-monooctanoylglycerol Chemical compound CCCCCCCC(=O)OCC(O)CO GHBFNMLVSPCDGN-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- FHHPUSMSKHSNKW-SMOYURAASA-M sodium deoxycholate Chemical compound [Na+].C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 FHHPUSMSKHSNKW-SMOYURAASA-M 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 229960005196 titanium dioxide Drugs 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
Images
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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- 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)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
An abiraterone acetate soft capsule and a preparation method thereof are provided, wherein the capsule consists of a content and a capsule shell, and the content comprises abiraterone acetate, caprylic capric acid mono-diglyceride, tween 80, span 80 and butyl hydroxy anisole; the capsule shell is made of soft capsule materials and comprises the following components: gelatin, water, glycerin and sorbitan sorbate solution, wherein the proportion of each component is 1:0.74:0.35:0.35. After the abiraterone acetate soft capsule is orally taken on an empty stomach, compared with the original grinding medicament Zytiga, the oral bioavailability is improved to 12.5 times, the inter-individual variability is low, and the phenomenon that the exposure of the abiraterone is obviously increased when the original grinding medicament Zytiga is administrated after meal is taken is eliminated.
Description
The invention belongs to the field of pharmaceutical preparations, and in particular relates to an abiraterone acetate soft capsule, a preparation method and application thereof.
Abiraterone acetate (Abiraterone Acetate) is a white to off-white, non-hygroscopic crystalline powder. Abiraterone acetate is an Abiraterone prodrug, a selective irreversible inhibitor of 17 alpha-hydroxylase/C17, 20-lyase (CYP 17). The enzyme is expressed in testis and adrenal tissue and catalyzes the conversion of pregnenolone and progesterone to testosterone precursors, DHEA and androstenedione, respectively, by 17 alpha hydroxylation and cleavage of the C17,20 bond. Abiraterone can inhibit the activity of CYP17 and thereby prevent testosterone synthesis in the testes, adrenal glands and tumors. Prostate cancer is an androgen dependent disease and testosterone inhibition is a key pharmacological tool in controlling the progression of prostate cancer. The chemical structure of abiraterone acetate is shown in the following formula 1:
abiraterone acetate is taken as a lipophilic compound, the octanol-water partition coefficient is 5.12 (LogP), the pKa of aromatic nitrogen is 5.19, the Abiraterone acetate is almost insoluble in water (0.01 mg/ml), the osmotic pressure difference is BCS four drugs, and the bioavailability is extremely low when the Abiraterone acetate is orally taken.
The original grinding drug Zytiga abiraterone acetate tablet (specification 250 mg) was developed by Janssen-Cilag International n.v. belgium, inactive ingredients include: colloidal titanium dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium lauryl sulfate. Is approved in the united states for use with prednisone to treat metastatic castration-resistant prostate cancer (mCRPC). The original grinding medicine Zytiga has very low oral bioavailability (less than 10 percent), the daily administration dosage amount reaches 1000mg, but only less than 10 percent of medicines can exert the efficacy.
Prescription information of the original drug Zytiga indicates that the drug must be taken on an empty stomach and that no food should be taken at least 2 hours before and at least 1 hour after the drug administration, indicating that food has a great effect on abiraterone acetate absorption, and that commercial formulations require only a specific period of time before meals. The Zytiga specification emphasizes that abiraterone acetate increases systemic exposure when administered with food. Specifically, abiraterone acetate Cmax and AUC when administered with a low fat diet (7% fat, 300 calories) 0-∞ About 7-fold and 5-fold increase, respectively; abiraterone acetate Cmax and AUC when administered with a high fat diet (57% fat, 825 calories) 0-∞ About 17-fold and 10-fold increase, respectively. Although abiraterone acetate has good effect of orally treating advanced prostate cancer, the characteristics of low solubility and osmotic pressure difference bring about strict formulation developmentThe trouble is serious.
Patent CN106687112a provides an improved abiraterone acetate preparation, by controlling the particle size of abiraterone acetate as a raw material, a unit dosage form of abiraterone is provided, wherein the bioequivalence and bioavailability of the unit dosage form of 500mg dosage and 1000mg dosage of Zytiga in healthy male subjects in a fasting state are improved by 1 time. Although the dosage of the preparation is reduced by 500mg, only abiraterone acetate is crushed, the particle size is controlled in a smaller range, so that dissolution and absorption are facilitated, the permeability of the abiraterone acetate to gastrointestinal epithelial cells cannot be increased, the oral bioavailability is still low, the specific surface area of the abiraterone acetate is overlarge after crushing, and the risk of oxidation of the abiraterone acetate is increased.
Patent CN102961358B relates to an abiraterone acetate liquid capsule, comprising a capsule shell and contents, characterized in that: the content consists of abiraterone acetate, a solvent, single fatty acid glyceride and an antioxidant: the solvent is selected from: diglycerides, triglycerides, 1, 2-propanediol, and mixtures thereof. However, the propylene glycol contained in the liquid capsule can volatilize from the content during the storage process, so that the propylene glycol content in the content can be seriously reduced, and Abiraterone is separated out, which may cause serious quality problems.
Patent document CN107278152a relates to abiraterone acetate complexes, a process for their preparation and pharmaceutical compositions containing them, comprising 5-40% by weight abiraterone acetate, 5-80% by weight polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, 0.1-50% by weight sodium deoxycholate. The compound can reduce the food effect and give up the requirement of taking medicine on an empty stomach, and can improve the oral bioavailability by 5 times at most, but the preparation process of the compound preparation is complex.
The invention relates to the technical field of pharmaceutical preparations, in particular to a pharmaceutical composition containing abiraterone acetate, and a preparation method and application thereof. The pharmaceutical composition comprises: active ingredients: abiraterone acetate; auxiliary materials: at least one oil phase, at least one emulsifier, and at least one emulsifier. The pharmaceutical composition provided by the invention spontaneously disperses under gastrointestinal peristalsis to form O/W type nanoemulsion after being orally taken. The formed nanoemulsion has small particle size, increases the penetrability of intestinal epithelial cells, and can remarkably improve the bioavailability of the medicament. Compared with microemulsion, the self-emulsifying solution has higher stability and can meet the requirement of long-term storage. The medicine composition of the invention has stable content. Compared with the original grinding agent Zytiga, the difference between before meal and after meal is obviously reduced; the pharmaceutical composition can be further prepared into capsules, and the capsules are stable in property. However, the co-emulsifier ethanol, propylene glycol, etc. used in this patent can be exerted from the contents during storage, so that the ethanol or propylene glycol content in the contents can be severely reduced, which may cause precipitation of abiraterone during long-term storage.
In summary, abiraterone acetate has the characteristics of low solubility and osmotic pressure difference, and the problem of poor oral bioavailability cannot be solved obviously by crushing abiraterone acetate and controlling the particle size in a smaller range, so that the oral bioavailability of abiraterone acetate can be improved obviously in theory, and the influence of food is eliminated, but the content in the liquid capsule is easy to volatilize to form propylene glycol or ethanol, and the abiraterone can be separated out in the long-term storage process.
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to provide a soft capsule preparation which can obviously improve the bioavailability of abiraterone acetate by oral absorption, reduce inter-individual variability and eliminate food influence.
The technical scheme provided by the invention is as follows:
the abiraterone acetate soft capsule comprises a content and a capsule shell, wherein the content comprises active ingredients of abiraterone acetate, caprylic-capric acid mono-diglyceride, tween 80, span 80 and an antioxidant.
The antioxidant is butyl hydroxy anisole.
Preferably, the concentration of the abiraterone acetate is between 60 and 100mg/ml in the total volume of the content;
and/or
The abiraterone acetate accounts for 6-10% of the total mass of the content.
Preferably, the mass of the caprylic capric acid mono-diglyceride accounts for 60-77% of the total mass of the content.
More preferably, the content includes: the abiraterone acetate accounts for 6-10% of the total mass of the content, and the caprylic capric acid mono-diglyceride accounts for 60-77% of the total mass of the content.
Preferably, the mass of the tween 80 accounts for 6-15% of the total mass of the content.
Preferably, the span 80 accounts for 7-19% of the total mass of the content.
More preferably, the abiraterone acetate accounts for 6-10% of the total mass of the content, the caprylic capric acid mono-diglyceride accounts for 60-77% of the total mass of the content, the tween 80 accounts for 6-15% of the total mass of the content, and the span 80 accounts for 7-19% of the total mass of the content.
Preferably, the mass of the butyl hydroxy anisole accounts for 0.01 to 0.1 percent of the total mass of the content.
Preferably, the capsule shell is made of soft capsule materials, and the composition comprises: gelatin, water, glycerin and sorbitan solution MDF85, wherein the proportion of the components is 1:0.74:0.35:0.35.
More preferably, the content includes: the abiraterone acetate accounts for 6-10% of the total mass of the content, the caprylic capric acid mono-diglyceride accounts for 60-77% of the total mass of the content, the tween 80 accounts for 6-15% of the total mass of the content, the span 80 accounts for 7-19% of the total mass of the content, and the butyl hydroxy anisole accounts for 0.01% -0.1% of the total mass of the content.
More preferably, the abiraterone acetate soft capsule comprises a content and a capsule shell, wherein the content comprises the following components: the abiraterone acetate accounts for 6-10% of the total mass of the content, the caprylic capric acid mono-diglyceride accounts for 60-77% of the total mass of the content, the tween 80 accounts for 6-15% of the total mass of the content, the span 80 accounts for 7-19% of the total mass of the content, and the butyl hydroxy anisole accounts for 0.01% -0.1% of the total mass of the content; the capsule shell is made of soft capsule materials and comprises the following components: gelatin, water, glycerin and sorbitan sorbitol solution (MDF 85) with the proportion of each component being 1:0.74:0.35:0.35.
The invention also discloses a preparation method for preparing the abiraterone acetate soft capsule, which comprises the following steps: 1) And (3) glue melting: adding the glycerol, the sorbitan sorbate and the water with the prescription amount into a gelatin dissolving barrel, starting stirring, after the temperature in the barrel is raised to 75-80 ℃, uniformly mixing the materials, adding the gelatin with the prescription amount, vacuumizing to-0.05 to-0.06 MPa, keeping negative pressure stirring for 25-35min, opening a top filling respirator until vacuum disappears, and preserving heat and degassing at 55-60 ℃ for later use; 2) Preparation of the content: abiraterone acetate is dissolved in mixed solution of caprylic capric acid mono-diglyceride, tween 80, span 80 and antioxidant which are heated to 50 ℃ and stirred uniformly for later use; 3) Preparing pills: making into pill with soft capsule machine; 4) And (5) drying.
Wherein, the abiraterone soft capsule is calculated by abiraterone acetate, and the single oral dose is 36-60mg.
The invention also discloses an application of the abiraterone acetate soft capsule in preparation of a pharmaceutical preparation;
preferably, the use in the manufacture of a pharmaceutical formulation for the treatment of prostate cancer;
more preferably, the prostate cancer is one or both of a self-castration resistant prostate cancer and a metastatic high risk castration sensitive prostate cancer.
The auxiliary materials of the content provided by the invention can be used as carriers of hydrophobic, insoluble or easily-hydrolyzed medicines. After oral administration, O/W emulsion drops are formed by spontaneous dispersion under gastrointestinal peristalsis, so that penetrability of intestinal epithelial cells is improved, dissolution and absorption of the medicine are improved, bioavailability of the medicine is remarkably improved, and contents are directly filled into soft capsules, so that the requirement of long-term stable storage can be met.
The abiraterone acetate-containing soft capsule provided by the invention has at least one of the following properties:
1) Abiraterone acetate is prepared into soft capsules, so that the dissolution of the medicine is increased, and emulsion drops with high clarity and stable properties can be formed spontaneously after the medicine is mixed with water;
2) The quality is stable and controllable when stored at room temperature, and the quality is better than that of the example 1 of the patent CN110538150A within 6 months of acceleration;
3) The prescription of the content of the patent CN110538150A contains propylene glycol and ethanol, and the propylene glycol and the ethanol possibly penetrate through the capsule shell to volatilize along with the extension of the storage time, so that the solubility of the medicine is reduced, and the abiraterone acetate is caused to precipitate;
4) Compared with the original grinding agent Zytiga, the difference between the preprandial and the postprandial is obviously reduced, and the variability among individuals is reduced;
5) Compared with the original grinding medicine Zytiga, the Abiraterone acetate soft capsule is orally taken on an empty stomach, the dissolution step of the original grinding medicine Zytiga is not needed on the alimentary canal, and the oral bioavailability is improved to 12.5 times;
6) All components in the prescription are conventional auxiliary materials, are easy to obtain, have simple preparation process and stable product quality, and are easy for commercial production.
Determination of solvent
The Abiraterone soft capsule preparation consists of the content of Abiraterone soft capsule and soft capsule shell, and needs to study the content prescription at the same time, and firstly, the solvent of the self-grinding preparation is determined. The experiment researches the dissolution condition of the bulk drug in various solvents in the content of the Abiraterone soft capsule. In this test, 10g of purified water, ethanol, caster oil, capmul MCM (caprylic/capric acid mono/diglyceride), hydrogenated castor oil and medium chain triglyceride were taken, respectively, and the dissolution of abiraterone Acetate (API) in these solvents was studied, and is shown in Table 1.
TABLE 1 dissolution of Abiraterone acetate
As is clear from Table 1, (1) abiraterone acetate has high solubility in ethanol, castor oil, caprylic/capric acid mono-diglyceride, but when ethanol is used as a solvent, a large amount of crystals are precipitated after the solution is left for 24 hours at room temperature; only 3% was dissolved in medium chain triglycerides (25 ℃), hardly in hydrogenated castor oil and purified water. (2) Generally speaking, the self-microemulsifying drug delivery system is finally prepared into soft capsules or hard capsules, if ethanol and other volatile components are contained, the substances possibly penetrate through capsule shells to reduce the solubility of the drug, so that the lipophilic drug is precipitated, i.e. if the self-developing agent adopts ethanol as a solvent, the ethanol is easy to exude from the capsule shells and volatilize, and the proportion of the ethanol in the content can be seriously reduced in the preparation and storage processes, so that the crystallization of the drug can be caused; (3) compared with the dissolution of abiraterone acetate in castor oil and caprylic/capric acid mono-diglyceride, the abiraterone acetate is found to be more soluble in the caprylic/capric acid mono-diglyceride, and the caprylic/capric acid mono-diglyceride has a certain emulsification effect, so that the self-grinding preparation can be spontaneously dispersed to form O/W type emulsion drops under gastrointestinal peristalsis. Therefore, the preparation adopts caprylic capric acid mono-diglyceride as the solvent of the self-grinding preparation.
Determination of surfactant
In order to ensure that the self-developed agent spontaneously disperses under the gastrointestinal motility to form O/W emulsion drops after being orally taken, the surfactant is mostly a nonionic surfactant with higher hydrophilic-lipophilic balance (HLB) value (generally 9-20), has low toxicity, is relatively stable in solution, is not influenced by strong dielectrics, inorganic salts, acid and alkali, has good compatibility with other types of surfactants, has small hemolysis, can be compatible with most medicaments, and can cause reversible transformation of permeability of gastrointestinal walls. At the same time, the surfactant is selected to take into account the match with the oil phase. This test selects surfactants such as polyoxyethylated castor oil (EL-40), span 80, tween 80 and polyethylene glycol-15 hydroxystearate (Solutol), and organically combines two or three of these surfactants, unexpectedly found that when polyoxyethylated castor oil: tween 80: span 80=1:1:0.25 and tween 80: at span 80=1:1.25, the emulsification effect is best, and the emulsion drops with blue opalescence are formed by slight oscillation and can exist stably. Details are shown in Table 2.
TABLE 2 selection of surfactants
The composition of the 2 surfactants is adopted to prepare soft capsules, and the influence of the soft capsules on the quality of products is examined.
TABLE 3 influence of surfactants on product quality (40 ℃ C.+ -. 2 ℃ C./75% RH.+ -. 5% RH)
As can be seen from table 3, the different surfactant compositions, for different product quality, when tween 80: span 80=1:1.25, its product quality meets the requirements, and at 3 months of acceleration, its total impurities are significantly lower than prescription 2.
In summary, the surfactant composition of the self-grinding preparation is span 80 and tween 80, and the dosage of each surfactant is further optimized on the basis, and the specific details are shown in examples 1-4.
FIG. 1 is a graph showing the time profile of abiraterone in plasma after a canine empty stomach oral self-primer soft capsule (T) of example 1;
FIG. 2 is a graph showing the time profile of abiraterone in plasma after oral administration of Zytiga tablet soft capsules (R1 st) on an empty stomach in dogs as in example 1;
FIG. 3 is a graph showing the time profile of abiraterone in plasma after oral administration of Zytiga tablet soft capsules (R2 nd) on an empty stomach in dogs as in example 1;
FIG. 4 is a graph of Mean time to drug (mean+SD) for abiraterone in plasma after fasting oral administration of different formulations to 6 dogs in example 1;
fig. 5 is the Mean time profile (mean+sd) of abiraterone in plasma after fasting or postprandial oral self-grinding of 8 dogs in example 1.
The following description of the embodiments of the present invention will be made clearly and fully with reference to the accompanying drawings, in which embodiments of the invention are shown, and in which embodiments are shown, by way of illustration, only, of some, but not all embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
The embodiment provides an abiraterone acetate soft capsule (batch: 1000) with the contents comprising the following components:
the above pharmaceutical composition is filled as a content in a soft capsule shell comprising the components of: gelatin, water, glycerin and sorbitan solution MDF85, wherein the proportion of the components is 1:0.74:0.35:0.35.
The preparation method is as follows:
1) And (3) glue melting: adding the glycerol, the sorbitan sorbate and the water with the prescription amount into a glue dissolving barrel, starting stirring, sealing and heating to 75 ℃, uniformly mixing the materials, adding the gelatin with the prescription amount, vacuumizing to-0.05 to-0.06 MPa, keeping negative pressure stirring for 25-35min, opening a top filling respirator until vacuum disappears, and preserving heat and degassing at 55-60 ℃ for later use; 2) Preparation of the content: abiraterone acetate is dissolved in mixed solution of caprylic capric acid mono-diglyceride, tween 80, span 80 and antioxidant which are heated to 50 ℃ and stirred uniformly for later use; 3) Preparing pills: making into pill with soft capsule machine; 4) And (5) drying.
Example 2
The embodiment provides an abiraterone acetate soft capsule (batch: 1000) with the contents comprising the following components:
the above pharmaceutical composition is filled as a content in a soft capsule shell comprising the components of: gelatin, water, glycerin and sorbitan solution MDF85, wherein the proportion of the components is 1:0.74:0.35:0.35.
The preparation method is as follows:
1) And (3) glue melting: adding the glycerol, the sorbitan sorbate and the water with the prescription amount into a glue dissolving barrel, starting stirring, sealing and heating to 75 ℃, uniformly mixing the materials, adding the gelatin with the prescription amount, vacuumizing to-0.05 to-0.06 MPa, keeping negative pressure stirring for 25-35min, opening a top filling respirator until vacuum disappears, and preserving heat and degassing at 55-60 ℃ for later use; 2) Preparation of the content: abiraterone acetate is dissolved in mixed solution of caprylic capric acid mono-diglyceride, tween 80, span 80 and antioxidant which are heated to 50 ℃ and stirred uniformly for later use; 3) Preparing pills: making into pill with soft capsule machine; 4) And (5) drying.
Example 3
The embodiment provides an abiraterone acetate soft capsule (batch: 1000) with the contents comprising the following components:
the above pharmaceutical composition is filled as a content in a soft capsule shell comprising the components of: gelatin, water, glycerin and sorbitan solution MDF85, wherein the proportion of the components is 1:0.74:0.35:0.35.
The preparation method is as follows:
1) And (3) glue melting: adding the glycerol, the sorbitan sorbate and the water with the prescription amount into a glue dissolving barrel, starting stirring, sealing and heating to 75 ℃, uniformly mixing the materials, adding the gelatin with the prescription amount, vacuumizing to-0.05 to-0.06 MPa, keeping negative pressure stirring for 25-35min, opening a top filling respirator until vacuum disappears, and preserving heat and degassing at 55-60 ℃ for later use; 2) Preparation of the content: abiraterone acetate is dissolved in mixed solution of caprylic capric acid mono-diglyceride, tween 80, span 80 and antioxidant which are heated to 50 ℃ and stirred uniformly for later use; 3) Preparing pills: making into pill with soft capsule machine; 4) And (5) drying.
Example 4
The embodiment provides an abiraterone acetate soft capsule (batch: 1000) with the contents comprising the following components:
the above pharmaceutical composition is filled as a content in a soft capsule shell comprising the components of: gelatin, water, glycerin and sorbitan solution MDF85, wherein the proportion of the components is 1:0.74:0.35:0.35.
The preparation method is as follows:
1) And (3) glue melting: adding the glycerol, the sorbitan sorbate and the water with the prescription amount into a glue dissolving barrel, starting stirring, sealing and heating to 75 ℃, uniformly mixing the materials, adding the gelatin with the prescription amount, vacuumizing to-0.05 to-0.06 MPa, keeping negative pressure stirring for 25-35min, opening a top filling respirator until vacuum disappears, and preserving heat and degassing at 55-60 ℃ for later use; 2) Preparation of the content: abiraterone acetate is dissolved in mixed solution of caprylic capric acid mono-diglyceride, tween 80, span 80 and antioxidant which are heated to 50 ℃ and stirred uniformly for later use; 3) Preparing pills: making into pill with soft capsule machine; 4) And (5) drying.
Comparative example 1
Referring to patent CN110538150a, example 1, a prescription process of comparative example 1 is provided, the contents of which include the following components:
this comparative example 1 further provides an abiraterone acetate capsule having the above pharmaceutical composition as a content filled in a capsule shell.
The preparation method is as follows:
taking hydrogenated castor oil/castor oil, glyceryl monooleate and polyoxyethylene castor oil EL35, adding abiraterone acetate, performing ultrasonic treatment under light-shielding condition for 10min, mechanically stirring (300 rpm) for 20min, adding propylene glycol and ethanol after fully dissolving to form transparent uniform self-emulsifying solution, filling into soft capsule or sealing in hard capsule under nitrogen protection condition, and preserving.
Example 5
This test example provides dissolution testing of abiraterone acetate soft capsules and as-ground drug Zytiga tablets provided in examples 1-4 and comparative example 1.
The testing method comprises the following steps: abiraterone acetate soft capsules are tested for dissolution according to the second method of the general rule 0931 of the fourth edition of 2015 of Chinese pharmacopoeia, and dissolution tests are carried out on Abiraterone acetate soft capsules (prepared in examples 1 and 2) and original ground drug Zytiga tablets respectively under the conditions of 37 ℃ and 900ml of SDS medium with pH of 4.5-0.25% and 50 revolutions/min.
Wherein, the pH is 4.5-0.25% SDS medium: weighing 6.78g of anhydrous sodium dihydrogen phosphate, adding 1000ml of water for dissolution, adjusting the pH value to 4.5 by using 5mol/L sodium hydroxide solution to obtain a buffer solution, weighing 2.5g of sodium dodecyl sulfate, adding the buffer solution, and dissolving to obtain the finished product.
The specific method is as follows:
TABLE 1-1 dissolution of Abiturin acetate Soft Capsule and Zytiga tablet (%)
| Sampling point/min | Zytiga | Example 1 | Example 2 | Example 3 | Example 4 | Comparative example 1 |
| 5 | 13.77 | 69.01 | 68.61 | 71.51 | 72.01 | 73 |
| 10 | 28.03 | 93.51 | 92.01 | 93.15 | 94.51 | 93 |
| 15 | 41.78 | 95.83 | 94.91 | 96.41 | 96.83 | 96 |
| 20 | 57.99 | 97.62 | 96.72 | 97.52 | 98.05 | 98 |
| 30 | 79.15 | 98.70 | 99.10 | 99.60 | 98.20 | 99 |
| 45 | 92.88 | 98.52 | 99.52 | 98.41 | 99.12 | 98 |
The comparison results in Table 1-1 show that: (1) the abiraterone acetate soft capsules (examples 1,2, 3 and 4) are basically completely dissolved in a medium for 15min (the standard of dissolution rate of original grinding drug Zytiga is not less than 85.0% of the marked amount in 45 min), but the dissolution rate of the abiraterone acetate tablets Zytiga on the market still cannot reach 85.0% in 30 min; (2) the dissolution rate of the abiraterone acetate soft capsules (examples 1,2, 3 and 4) of the invention is not significantly different from that of comparative example 1. Therefore, the abiraterone acetate capsule can effectively improve the dissolution rate of abiraterone, and remarkably improve the oral bioavailability of abiraterone acetate.
Example 6
The test examples provide stability (long-term test and acceleration test) tests of the abiraterone acetate soft capsules provided in examples 1-4, and the detection results are shown in tables 2-1 and 2-2.
TABLE 2-1 stability of samples in long term test (25 ℃ C.+ -. 2 ℃ C./60% RH.+ -. 5% RH)
Note that: "-" represents: the solution is clarified, and the medicine is not precipitated;
"+" represents: the clear solution and the medicine are separated out in small quantity.
TABLE 2 stability of samples under accelerated test (40 ℃ C.+ -. 2 ℃ C./75% RH.+ -. 5% RH)
Note that: "ND" represents undetected; "NA" represents undetected.
The comparison results in Table 2-1 show that: the abiraterone acetate soft capsules (examples 1,2, 3 and 4) of the invention have no significant change in content properties within 9 months of a long term, and comparative example 1 has no significant difference within 6 months of a long term, but a small amount of medicine is precipitated within 9 months of a long term, which is caused by the following reasons: the formulation of the contents of comparative example 1 contained propylene glycol and ethanol, which may penetrate the capsule shell and volatilize with the lapse of storage time, decreasing the solubility of the drug, resulting in precipitation of abiraterone acetate.
The comparison results in Table 2-2 show that: (1) the abiraterone acetate soft capsules (examples 1,2, 3 and 4) have a general impurity increasing trend within 6 months of acceleration, and meet the product quality requirement (the general impurity in the original grinding medicament Zytiga quality standard is not more than 2.0 percent); (2) the Abiraterone acetate soft capsules (examples 1,2, 3 and 4) of the invention have obviously smaller total impurity increase amplitude than that of comparative example 1 within 6 months of acceleration
Example 7
The test examples provide self-emulsifying capacity and stability tests of abiraterone acetate soft capsules provided in examples 1-4.
The abiraterone acetate soft capsules prepared in examples 1-4 were added to purified water, and appearance was observed after gentle shaking, as well as solution stability at room temperature. Details are shown in Table 3-1
TABLE 3-1 self-emulsifying ability of samples and stability results
Example 8
This test example provides a pharmacokinetic test of example 1 and abiraterone acetate Long Yuan for the drug Zytiga.
And (3) test design: because the original grinding medicine Zytiga (abiraterone acetate tablet) has large in vivo variability, the pharmacokinetic study adopts a three-period cross test of 6 dogs, a hollow oral administration of 1 time of abiraterone acetate soft capsule (specification: 40 mg) and 2 times of original grinding medicine Zytiga (specification: 250mg, 2 tablets each time) is carried out, blood samples are collected, the concentration of abiraterone in blood plasma is measured, and main pharmacokinetic parameters are calculated. Details are shown in Table 4-1.
Test object: healthy beagle dogs were randomly divided into 3 groups of 2, 3 cycle crossover tests were performed. During the test, the water is freely drunk, the administration is fasted for more than 12 hours before each period of administration, and the preparation is taken with 20ml of water when the administration is carried out, and the administration is carried out after 6 hours. The period of the week washing was 7 days.
Table 4-1 comparative pharmacokinetic study group design
Note that: t: abiraterone acetate soft capsules are administered to 1 granule/dog, namely 40 mg/dog;
r: abiraterone acetate tablet is administered to 2 animals/dog, i.e. 500 mg/dog.
TABLE 4-2 original grinding Zytiga 500mg contrast Abiraterone acetate soft capsule 40mg pharmacokinetic parameters (empty stomach test)
Note that: tmax is the peak time, cmax is the maximum blood concentration (peak concentration), AUClast is the AUC (time-to-drug curve area) of the duration from the start of administration to the last point;
as can be seen from Table 4-2, the oral bioavailability (AUClast) of the beagle dogs for empty stomach oral administration of 1 abiraterone acetate soft capsule (40 mg) in comparison with the original grinding Zytiga (R1 st) and the original grinding Zytiga (R2 nd) reaches 101.9% and 95.3%, respectively. Compared with the original grinding medicament Zytiga (specification 250 mg), the abiraterone acetate soft capsule has the advantages that the oral bioavailability is improved to 12.5 times, and the variability of AUClast is smaller.
As can be seen from fig. 1,2 and 3, the curves of abiraterone acetate soft capsules are similar to each other when different individuals are administered with abiraterone acetate soft capsules, while the curves of the original grinding medicament Zytiga are more discrete when different individuals are administered with abiraterone acetate soft capsules. The reason for this is probably that the soft capsule dosage form does not need to undergo the dissolution step of the original grinding drug Zytiga on the digestive tract, but the step directly affects the absorption of the drug, thereby improving the bioavailability and reducing the individual difference.
In summary, (1) after the oral abiraterone acetate soft capsule is taken orally on an empty stomach of a dog, the dissolution step of the original grinding medicament Zytiga is skipped on the alimentary canal, the oral bioavailability (AUClast) of the abiraterone acetate soft capsule is 12.5 times of that of the original grinding medicament Zytiga, and the abiraterone acetate soft capsule can obtain more consistent T among individuals max 、C max And AUC, thereby facilitating the implementation of clinical treatments and control of safety risks.
Example 9
This test example provides an absorption influence test of food on example 1.
And (3) test design: 8 dogs were subjected to double-cycle crossover test, respectively, orally taken abiraterone acetate soft capsules on an empty stomach and after meal, blood samples were collected, the concentration of abiraterone in plasma was measured, and main pharmacokinetic parameters were calculated. Details are shown in Table 5-1.
Test object: healthy beagle dogs were randomly divided into 2 groups of 4, and 3 cycle crossover experiments were performed. Free drinking water during the test. Fasting administration is carried out for more than 12 hours before administration, and the preparation is taken with 20ml of water when administration is carried out, and is fed after administration for 6 hours; the stomach tube is fed quantitatively 30 minutes before the administration after meal administration. The period of the week washing was 7 days.
Table 5-1 food influence study group design
Note that: t: abiraterone acetate soft capsules are administered to 1 granule/dog, i.e. 40 mg/dog.
TABLE 5-2 pharmacokinetic parameters of Abiraterone in plasma after oral Abiraterone acetate Soft Capsule on empty stomach in dogs
TABLE 5-3 pharmacokinetic parameters of Abiraterone in plasma after oral Abiraterone acetate Soft Capsule after Canine postprandial
* Relative bioavailability f= (abiraterone acetate soft capsule postprandial AUC of each individual) 0-t Fasting AUC 0-t )*100％
As is clear from tables 5-2 and 5-3, the relative bioavailability of the oral abiraterone acetate soft capsule after 30 minutes after a meal of dogs is 79.19% (44.45% -106.80%) compared with the oral abiraterone acetate soft capsule. The paired t-test results after natural logarithmic transformation of the principal pharmacokinetic parameters are shown in tables 5-4.
Table 5-4 main pharmacokinetic parameters of abiraterone in plasma after oral administration of abiraterone acetate soft capsule on empty stomach or after meal paired t-test results
As can be seen from tables 5-4, the difference in Cmax was significant (P < 0.01) after oral administration of the soft capsule after dogs' meal, compared with the empty oral abiraterone acetate soft capsule, whereas the difference between AUC0-t and AUCinf was not statistically significant.
The literature reports that the exposure of the original grinding drug Zytiga high-fat postprandial abiraterone can reach 10 times of the fasting exposure. In the test, after the oral abiraterone acetate soft capsule is taken orally on a canine empty stomach or after meal, the exposure of the abiraterone acetate is not increased, and the reason is probably that the abiraterone acetate soft capsule does not need to go through the dissolution step of the original grinding drug Zytiga on the alimentary canal, the higher exposure can be achieved without dissolving the drug by means of fat in food, and the absorption degree of the drug can not be increased any more due to the existence of food. The relative bioavailability of the postprandial abiraterone is slightly lower than that of the fasting, probably because food promotes peristaltic emptying of the digestive tract, so that the residence time of the drug in the main absorption site is shortened.
In conclusion, compared with the empty stomach, the exposure of the abiraterone is slightly reduced after the oral self-development agent is taken after dogs are taken after meals, and the phenomenon that the exposure of the abiraterone is obviously increased when the original development agent Zytiga is taken after meals is avoided. Thus, abiraterone acetate soft capsules can reduce dietary-related safety risks associated with abiraterone exposure.
While the invention has been described in detail in the foregoing general description, specific embodiments and experiments, it will be apparent to those skilled in the art that modifications thereto are possible. Accordingly, such modifications and improvements can be made without departing from the spirit of the invention and are intended to be within the scope of the invention as claimed.
Claims (16)
- The abiraterone acetate soft capsule comprises a content and a capsule shell, and is characterized in that the content comprises active ingredients of abiraterone acetate, caprylic capric acid mono-diglyceride, tween 80, span 80 and butyl hydroxy anisole.
- An abiraterone acetate soft capsule as claimed in claim 1, wherein: the concentration of abiraterone acetate is between 60-100mg/ml based on the total volume of the contents;and/orThe abiraterone acetate accounts for 6-10% of the total mass of the content.
- An abiraterone acetate soft capsule as in claim 1, wherein the caprylic capric acid mono-diglyceride accounts for 60-77% of the total mass of the contents.
- An abiraterone acetate soft capsule as claimed in claim 1, wherein the abiraterone acetate accounts for 6-10% of the total mass of the content, and the caprylic-capric acid mono-diglyceride accounts for 60-77% of the total mass of the content.
- The abiraterone acetate soft capsule of claim 1, wherein the tween 80 accounts for 6-15% of the total mass of the content.
- An abiraterone acetate soft capsule as in claim 1, wherein the span 80 comprises 7-19% of the total mass of the contents.
- The abiraterone acetate soft capsule of claim 1, wherein the abiraterone acetate accounts for 6-10% of the total mass of the content, the caprylic capric acid mono-diglyceride accounts for 60-77% of the total mass of the content, the tween 80 accounts for 6-15% of the total mass of the content, and the span 80 accounts for 7-19% of the total mass of the content.
- An abiraterone acetate soft capsule as claimed in claim 1, wherein the butyl hydroxy anisole accounts for 0.01% -0.1% of the total mass of the contents.
- The abiraterone acetate soft capsule of claim 1, wherein the abiraterone acetate accounts for 6-10% of the total mass of the content, the caprylic capric acid mono-diglyceride accounts for 60-77% of the total mass of the content, the tween 80 accounts for 6-15% of the total mass of the content, the span 80 accounts for 7-19% of the total mass of the content, and the butyl hydroxy anisole accounts for 0.01% -0.1% of the total mass of the content.
- The abiraterone acetate soft capsule of claim 1, wherein the capsule shell is composed of a soft capsule material and comprises: gelatin, water, glycerin and sorbitan solution MDF85, wherein the proportion of the components is 1:0.74:0.35:0.35.
- An abiraterone acetate soft capsule as in claim 1, wherein in the contents: the abiraterone acetate accounts for 6-10% of the total mass of the content, the caprylic capric acid mono-diglyceride accounts for 60-77% of the total mass of the content, the tween 80 accounts for 6-15% of the total mass of the content, the span 80 accounts for 7-19% of the total mass of the content, and the butyl hydroxy anisole accounts for 0.01% -0.1% of the total mass of the content; the capsule shell is made of soft capsule materials and comprises the following components: gelatin, water, glycerin and sorbitan sorbitol solution (MDF 85) with the proportion of each component being 1:0.74:0.35:0.35.
- A process for preparing an abiraterone acetate soft capsule according to any one of claims 1-11, the process comprising: 1) And (3) glue melting: adding the glycerol, the sorbitan sorbate and the water with the prescription amount into a gelatin dissolving barrel, starting stirring, after the temperature in the barrel is raised to 75-80 ℃, uniformly mixing the materials, adding the gelatin with the prescription amount, vacuumizing to-0.05 to-0.06 MPa, keeping negative pressure stirring for 25-35min, opening a top filling respirator until vacuum disappears, and preserving heat and degassing at 55-60 ℃ for later use; 2) Preparation of the content: abiraterone acetate is dissolved in mixed solution of caprylic capric acid mono-diglyceride, tween 80, span 80 and antioxidant which are heated to 50 ℃ and stirred uniformly for later use; 3) Preparing pills: making into pill with soft capsule machine; 4) And (5) drying.
- Use of an abiraterone acetate soft capsule according to any one of claims 1-11 in the manufacture of a pharmaceutical formulation for the treatment of prostate cancer.
- Use of abiraterone acetate soft-capsules according to claim 13 for the preparation of a pharmaceutical formulation, wherein the prostate cancer is one or both of autorotation-removal potential-resistant prostate cancer and metastatic high-risk castration-sensitive prostate cancer.
- Use of abiraterone acetate soft-capsules according to claim 13 or 14 in the preparation of a pharmaceutical formulation, wherein the single oral dose is 36-60mg in terms of abiraterone acetate.
- Use of abiraterone acetate soft-capsules according to claim 15 for the preparation of a pharmaceutical formulation, wherein the single oral dose is 40mg, calculated as abiraterone acetate.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110831056.1A CN113616614A (en) | 2021-07-22 | 2021-07-22 | Abiraterone acetate soft capsule and preparation method thereof |
| CN2021108310561 | 2021-07-22 | ||
| PCT/CN2022/099013 WO2023000873A1 (en) | 2021-07-22 | 2022-06-15 | Abiraterone acetate soft capsule and preparation method therefor and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN116033925A true CN116033925A (en) | 2023-04-28 |
| CN116033925B CN116033925B (en) | 2024-02-27 |
Family
ID=78380582
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110831056.1A Pending CN113616614A (en) | 2021-07-22 | 2021-07-22 | Abiraterone acetate soft capsule and preparation method thereof |
| CN202280003906.1A Active CN116033925B (en) | 2021-07-22 | 2022-06-15 | Abiraterone acetate soft capsule and preparation method and application thereof |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110831056.1A Pending CN113616614A (en) | 2021-07-22 | 2021-07-22 | Abiraterone acetate soft capsule and preparation method thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (2) | CN113616614A (en) |
| WO (1) | WO2023000873A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113616614A (en) * | 2021-07-22 | 2021-11-09 | 浙江和泽医药科技股份有限公司 | Abiraterone acetate soft capsule and preparation method thereof |
| EP4197541A1 (en) | 2021-12-15 | 2023-06-21 | Hunan Huize Biopharma S&T Co., Ltd | Abiraterone acetate-containing composition and application thereof |
| CN114306236B (en) * | 2021-12-15 | 2022-10-21 | 湖南慧泽生物医药科技有限公司 | Self-microemulsion system for loading abiraterone acetate, composition and application |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110538150A (en) * | 2019-09-26 | 2019-12-06 | 湖南瑞林医药科技有限公司 | Medicinal composition containing abiraterone acetate and preparation method and application thereof |
| CN111012745A (en) * | 2020-01-06 | 2020-04-17 | 深圳海王医药科技研究院有限公司 | Abiraterone oral emulsion and preparation method thereof |
| CN112716956A (en) * | 2021-01-25 | 2021-04-30 | 人福普克药业（武汉）有限公司 | Daily-use compound preparation for treating cold and preparation method thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8486983B2 (en) * | 2005-12-05 | 2013-07-16 | Merck Sharp & Dohme Corp. | Self-emulsifying formulations of CETP inhibitors |
| CN112274492A (en) * | 2020-10-30 | 2021-01-29 | 重庆华邦制药有限公司 | Dutasteride soft capsule, composition and preparation method thereof |
| CN113616614A (en) * | 2021-07-22 | 2021-11-09 | 浙江和泽医药科技股份有限公司 | Abiraterone acetate soft capsule and preparation method thereof |
-
2021
- 2021-07-22 CN CN202110831056.1A patent/CN113616614A/en active Pending
-
2022
- 2022-06-15 CN CN202280003906.1A patent/CN116033925B/en active Active
- 2022-06-15 WO PCT/CN2022/099013 patent/WO2023000873A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110538150A (en) * | 2019-09-26 | 2019-12-06 | 湖南瑞林医药科技有限公司 | Medicinal composition containing abiraterone acetate and preparation method and application thereof |
| CN111012745A (en) * | 2020-01-06 | 2020-04-17 | 深圳海王医药科技研究院有限公司 | Abiraterone oral emulsion and preparation method thereof |
| CN112716956A (en) * | 2021-01-25 | 2021-04-30 | 人福普克药业（武汉）有限公司 | Daily-use compound preparation for treating cold and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| WEERAPOL Y等: "Self-Nanoemulsifying Drug Delivery System of Nifedipine: Impact of Hydrophilic-Lipophilic Balance and Molecular Structure of Mixed Surfactants", 《AAPS PHARMSCITECH》, vol. 15, no. 2, pages 3 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN116033925B (en) | 2024-02-27 |
| CN113616614A (en) | 2021-11-09 |
| WO2023000873A1 (en) | 2023-01-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN116033925B (en) | Abiraterone acetate soft capsule and preparation method and application thereof | |
| EP4035657A1 (en) | Drug composition containing abiraterone acetate, and preparation method therefor and application thereof | |
| US10052386B2 (en) | Progesterone formulations | |
| RU2429850C2 (en) | Pharmaceutical delivery systems for hydrophobic therapeutic agents and compositions containing it | |
| CN103381142B (en) | A kind of ginsenoside Rh1self-emulsion composition and its production and use | |
| KR101679992B1 (en) | Pharmaceutical composition comprising dutasteride and propylene glycol monolaurate and preparation method of the same | |
| CN101217963A (en) | Pharmaceutical delivery systems for hydrophobic drugs and compositions comprising same | |
| EP2779997B1 (en) | Liquid-filled hard gel capsule pharmaceutical formulations | |
| CN104784197A (en) | EGCG and beta-glucan composition, and preparation method, and medical application thereof | |
| CN113750032A (en) | Oral abiraterone medicinal composition and preparation method and application thereof | |
| JP7301883B2 (en) | HC-1119 Formulations and Methods of Making and Using Themselves | |
| CN114948885B (en) | Improved abirater acetate Long Nami crystal oral preparation and preparation method thereof | |
| RU2269342C9 (en) | Pharmaceutical combination of ethynylestradiol and drospirenone for using as contraceptive | |
| KR102199667B1 (en) | Pharmaceutical composition comprising dutasteride | |
| TWI834862B (en) | Formulation for oral delivery of proteins, peptides and small molecules with poor permeability | |
| EP2435022B1 (en) | Self-microemulsifying mitotane composition | |
| EP4197541A1 (en) | Abiraterone acetate-containing composition and application thereof | |
| KR102329411B1 (en) | Pharmaceutical Composition Comprising R-Thioctic Acid, Oil and Dispersing Agent | |
| CN101756898B (en) | Lansoprazole sodium suspension preparation for injection and new application thereof | |
| CN113133984A (en) | CYP17 inhibitor preparation | |
| CN117257736A (en) | Engliflozin liposome, preparation method and preparation | |
| CN114762693A (en) | Abiraterone pharmaceutical composition with high drug loading rate as well as preparation method and application thereof | |
| CN113133983A (en) | Pharmaceutical composition for treating prostate cancer |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |