CN114681424A - Ibutotinib capsule and preparation method thereof - Google Patents
Ibutotinib capsule and preparation method thereof Download PDFInfo
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- CN114681424A CN114681424A CN202011644290.5A CN202011644290A CN114681424A CN 114681424 A CN114681424 A CN 114681424A CN 202011644290 A CN202011644290 A CN 202011644290A CN 114681424 A CN114681424 A CN 114681424A
- Authority
- CN
- China
- Prior art keywords
- ibrutinib
- ibutinib
- glyceride
- capsule
- capsule according
- 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.)
- Pending
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- 239000002775 capsule Substances 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title abstract description 31
- 238000002156 mixing Methods 0.000 claims abstract description 52
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 claims abstract description 51
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 claims abstract description 50
- 229960001507 ibrutinib Drugs 0.000 claims abstract description 50
- 125000005456 glyceride group Chemical group 0.000 claims abstract description 29
- 239000007962 solid dispersion Substances 0.000 claims abstract description 23
- 239000000314 lubricant Substances 0.000 claims abstract description 10
- 229920000642 polymer Polymers 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 7
- 239000000463 material Substances 0.000 claims abstract description 6
- 238000007873 sieving Methods 0.000 claims description 34
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 30
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 21
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 21
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 21
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 21
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 16
- 238000010438 heat treatment Methods 0.000 claims description 16
- 238000002844 melting Methods 0.000 claims description 16
- 230000008018 melting Effects 0.000 claims description 16
- -1 polyoxyethylene Polymers 0.000 claims description 16
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 15
- 235000019359 magnesium stearate Nutrition 0.000 claims description 15
- 239000012943 hotmelt Substances 0.000 claims description 14
- 239000002202 Polyethylene glycol Substances 0.000 claims description 13
- 229920001223 polyethylene glycol Polymers 0.000 claims description 13
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 12
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 12
- 239000004480 active ingredient Substances 0.000 claims description 12
- 239000008101 lactose Substances 0.000 claims description 12
- 229920002472 Starch Polymers 0.000 claims description 11
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 11
- 239000008107 starch Substances 0.000 claims description 11
- 235000019698 starch Nutrition 0.000 claims description 11
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 10
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 10
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 10
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 9
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 9
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 9
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical group OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 9
- 239000000945 filler Substances 0.000 claims description 7
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 7
- 239000000377 silicon dioxide Substances 0.000 claims description 7
- 239000011734 sodium Substances 0.000 claims description 7
- 229910052708 sodium Inorganic materials 0.000 claims description 7
- 239000007884 disintegrant Substances 0.000 claims description 6
- 125000002669 linoleoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 229920001531 copovidone Polymers 0.000 claims description 5
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 5
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 5
- 229920006316 polyvinylpyrrolidine Polymers 0.000 claims description 5
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 5
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- 125000000400 lauroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 4
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 claims description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 3
- 239000004375 Dextrin Substances 0.000 claims description 3
- 229920001353 Dextrin Polymers 0.000 claims description 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 3
- 229960000913 crospovidone Drugs 0.000 claims description 3
- 235000019425 dextrin Nutrition 0.000 claims description 3
- 229940100242 glycol stearate Drugs 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- 125000002811 oleoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 3
- 238000010298 pulverizing process Methods 0.000 claims description 3
- 229940032147 starch Drugs 0.000 claims description 3
- 235000014113 dietary fatty acids Nutrition 0.000 claims 2
- 239000000194 fatty acid Substances 0.000 claims 2
- 229930195729 fatty acid Natural products 0.000 claims 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 239000000454 talc Substances 0.000 claims 1
- 229910052623 talc Inorganic materials 0.000 claims 1
- 238000011049 filling Methods 0.000 abstract description 14
- 238000005469 granulation Methods 0.000 abstract description 9
- 230000003179 granulation Effects 0.000 abstract description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 8
- 238000004090 dissolution Methods 0.000 abstract description 7
- 239000004094 surface-active agent Substances 0.000 abstract description 5
- 239000003960 organic solvent Substances 0.000 abstract description 4
- 239000012738 dissolution medium Substances 0.000 abstract description 2
- 238000009474 hot melt extrusion Methods 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 12
- 238000001816 cooling Methods 0.000 description 11
- 229960001375 lactose Drugs 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 9
- 238000001035 drying Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 229940083542 sodium Drugs 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 229960001866 silicon dioxide Drugs 0.000 description 5
- 235000012239 silicon dioxide Nutrition 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000011812 mixed powder Substances 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 3
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 239000005642 Oleic acid Substances 0.000 description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
- PHYFQTYBJUILEZ-UHFFFAOYSA-N Trioleoylglycerol Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(OC(=O)CCCCCCCC=CCCCCCCCC)COC(=O)CCCCCCCC=CCCCCCCCC PHYFQTYBJUILEZ-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
- 238000007922 dissolution test Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 2
- 229940074076 glycerol formal Drugs 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
- 229940057948 magnesium stearate Drugs 0.000 description 2
- 229960001855 mannitol Drugs 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 229940083466 soybean lecithin Drugs 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 206010070840 Gastrointestinal tract irritation Diseases 0.000 description 1
- PMZXXNPJQYDFJX-UHFFFAOYSA-N acetonitrile;2,2,2-trifluoroacetic acid Chemical compound CC#N.OC(=O)C(F)(F)F PMZXXNPJQYDFJX-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 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
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 210000003194 forelimb Anatomy 0.000 description 1
- RZRNAYUHWVFMIP-HXUWFJFHSA-N glycerol monolinoleate Natural products CCCCCCCCC=CCCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-HXUWFJFHSA-N 0.000 description 1
- 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 1
- 229920000578 graft copolymer Polymers 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 229940031705 hydroxypropyl methylcellulose 2910 Drugs 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000002563 ionic surfactant Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- GRRYSIXDUIAUGY-UHFFFAOYSA-N n-methylcarbamoyl chloride Chemical compound CNC(Cl)=O GRRYSIXDUIAUGY-UHFFFAOYSA-N 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000012088 reference solution Substances 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 150000003384 small molecules Chemical group 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007779 soft material Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1611—Inorganic 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—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
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides an ibrutinib capsule. Preparing the ibrutinib and the macromolecular polymer into a solid dispersion by a hot-melt extrusion method, crushing, adding a certain amount of fatty glyceride and other auxiliary materials for granulation, adding a lubricant, uniformly mixing, and filling into capsules. The ibrutinib capsule prepared by the invention has high dissolution rate, can be quickly dissolved without adding a surfactant when water is used as a dissolution medium, and further improves the bioavailability by adding fatty glyceride for granulation. The preparation method of the ibrutinib capsule provided by the invention does not need micronization treatment, is simple to operate, does not use an organic solvent, and is high in safety.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an ibrutinib capsule and a preparation method thereof.
Background
Ibrutinib is a small molecule inhibitor of BTK. Ibrutinib forms a covalent bond with a cysteine residue of the BTK active site, resulting in inhibition of BTK enzyme activity. It is a white to off-white solid with the molecular formula C25H24N6O2And the molecular weight is 440.50. Is easily soluble in dimethyl sulfoxide, is easily soluble in methanol and is almost insoluble in water. The Ibutotinib is available in the form of capsule with specification of 140 mg/granule, the adjuvants include sodium carboxymethylcellulose, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate, and a large amount of surfactant is added to some extentThe solubility of the raw materials is improved, but the risk of gastrointestinal irritation is also brought. Furthermore, the degree of biological activity of ibrutinib is low, the absolute bioavailability of oral ibrutinib capsules is only 2.9% in the fasting state, and the absolute bioavailability after taking food is 2 times that in the fasting state.
The patent CN111000806A discloses an ibrutinib tablet composition, wherein each thousand tablets contain 140g of ibrutinib, 26-40 g of microcrystalline cellulose, 12-22 g of croscarmellose sodium, 0.8-1.5 g of sodium dodecyl sulfate, 60007-12 g of polyethylene glycol, 0.8-1.8 g of soybean lecithin, 7-15 g of sodium alginate, 0.8-1.8 g of magnesium stearate and 4-8 g of superfine silica powder.
The patent CN106619643A discloses a pharmaceutical composition containing ibrutinib, which comprises 13-15 parts of ibrutinib, 30-35 parts of a solvent, 20-30 parts of a solubilizer, 8-12 parts of a filler, 6-10 parts of a disintegrant and 21-26 parts of a medicinal organic acid, wherein the used solvent is glycerol formal, and the medicinal organic acid is a mixture of 1.7-2.1: 1 a mixture of oleic acid and glyceryl oleate; the ibrutinib preparation is still slow to dissolve out, and a large amount of used solvent and surfactant also bring about a certain safety hazard.
Patent CN109010844A discloses an ibutinib phospholipid complex and a preparation method thereof, wherein the complex can significantly improve the solubility of a drug and improve the bioavailability of the drug, but the prepared phospholipid complex is easily oxidized and degraded, an organic solvent is used in the preparation process, and the industrial process is complex.
Generally, the existing oral preparation of ibrutinib has the technical problems of slow dissolution and large amount of surfactant, and the bioavailability of the oral preparation needs to be further improved.
Disclosure of Invention
In view of the defects of the prior art, the invention provides an ibrutinib capsule. Preparing the ibrutinib and the macromolecular polymer into a solid dispersion through hot melting and extrusion, then crushing, adding a certain amount of fatty glyceride and other auxiliary materials for granulation, adding a lubricant, uniformly mixing, and filling into hard capsules. The preparation process of the invention does not use organic solvent, and the obtained ibutinib capsule can be quickly dissolved without adding surfactant when water is used as a dissolving medium, and has high bioavailability.
Specifically, the purpose of the invention is realized by the following technical scheme:
an ibrutinib capsule comprises an ibrutinib solid dispersion, fatty glyceride and other pharmaceutically acceptable auxiliary materials.
The ibrutinib solid dispersion comprises an active ingredient ibrutinib and a macromolecular polymer; the macromolecular polymer is selected from hydroxypropyl methylcellulose AFFINISOLTMOne of polyvinylpyrrolidone K30, copovidone VA64 or S630, preferably hydroxypropyl methylcellulose AFFINISOLTM。
According to the ibrutinib solid dispersion, the weight ratio of an active ingredient ibrutinib to a macromolecular polymer is 1: 1-4; preferably 1: 2.
The fatty glyceride is selected from one or more of oleoyl polyoxyethylene glyceride, linoleoyl polyoxyethylene glyceride, caprylic capric polyethylene glycol glyceride, polyethylene glycol stearate, and lauroyl polyoxyethylene glyceride.
The weight ratio of the active ingredient ibutinib to the fatty glyceride is 1: 0.02 to 0.2.
Preferably, the weight ratio of the active ingredient ibutinib to the fatty glyceride is 1: 0.02 to 0.1.
Further preferably, the weight ratio of the active ingredient ibutinib to the fatty glyceride is 1: 0.05.
the pharmaceutically acceptable auxiliary materials comprise a filling agent, a disintegrating agent and a lubricating agent.
The filler is selected from one or more of microcrystalline cellulose, lactose, mannitol, starch and dextrin.
Preferably, the weight ratio of the active ingredient ibutinib to the filler is 1: 0.5 to 3, and more preferably 1:1 to 2.
The disintegrant is selected from one or more of sodium carboxymethyl starch, croscarmellose sodium, crospovidone and low-substituted hydroxypropyl cellulose.
Preferably, the weight ratio of the active ingredient namely the ibrutinib to the disintegrant is 1: 0.05 to 1.5, more preferably 1: 0.1 to 1.
The lubricant is selected from one or more of magnesium stearate, talcum powder, sodium stearyl fumarate, silicon dioxide and polyethylene glycol.
Preferably, the weight ratio of the active ingredient ibutinib to the lubricant is 1: 0.1 to 0.2.
The invention also provides a method for preparing the ibrutinib capsule, which comprises the following specific steps: heating and melting the ibrutinib and the macromolecular polymer at 110-150 ℃ by using a hot-melt extruder, and extruding to prepare a solid dispersion; pulverizing the solid dispersion, sieving, mixing with other pharmaceutically acceptable adjuvants, granulating with fatty glyceride, adding lubricant, mixing, and making into capsule; preferably, the heating temperature is 115-140 ℃.
Compared with the prior art, the invention has the following advantages:
(1) the ibutinib has high bioavailability;
(2) the medicine has high dissolution rate and rapid dissolution;
(3) no complex micronization process is required;
(4) no ionic surfactant and no organic solvent are added, so that the safety is high.
Detailed Description
The following examples further illustrate the benefits of the present invention, and the examples are for illustrative purposes only and do not limit the scope of the present invention, and variations and modifications apparent to those of ordinary skill in the art in light of the present disclosure are intended to be included within the scope of the present invention.
Example 1
Prescription:
the preparation process comprises the following steps:
the prescribed amount of hydroxypropyl methylcellulose AFFINSOLTMMixing with ibrutinib uniformly, heating and melting at 140 ℃ by using a hot-melt extruder, extruding to prepare a solid dispersion, cooling, crushing, sieving with a 80-mesh sieve, adding the microcrystalline cellulose and the sodium carboxymethyl starch according to the prescription amount, mixing uniformly, adding the oleoyl polyoxyethylene glyceride for granulation, sieving with a 20-mesh sieve, adding the silicon dioxide according to the prescription amount, mixing uniformly, and filling into capsules.
Example 2
Prescription:
the preparation process comprises the following steps:
the prescribed amount of hydroxypropyl methylcellulose AFFINSOLTMMixing with ibrutinib uniformly, heating and melting at 135 ℃ by using a hot-melt extruder, extruding to prepare a solid dispersion, cooling, crushing, sieving with a 80-mesh sieve, adding lactose, microcrystalline cellulose and croscarmellose sodium according to the formula amount, uniformly mixing, adding caprylic capric polyethylene glycol glyceride for granulation, sieving with a 20-mesh sieve, adding silicon dioxide according to the formula amount, uniformly mixing, and filling into capsules.
Example 3
Prescription:
the preparation process comprises the following steps:
uniformly mixing the copovidone S630 and the ibrutinib according to the prescription amount, heating and melting at 125 ℃ by using a hot-melt extruder, extruding to prepare a solid dispersion, cooling, crushing and sieving by using a 80-mesh sieve, adding the microcrystalline cellulose and the sodium carboxymethyl starch according to the prescription amount, uniformly mixing, heating and melting the polyethylene glycol stearate at 60 ℃, adding the mixture into the mixed powder while the mixture is hot, granulating, sieving by using a 20-mesh sieve, adding the magnesium stearate according to the prescription amount, uniformly mixing, and filling into capsules.
Example 4
Prescription:
the preparation process comprises the following steps:
uniformly mixing the copovidone VA64 and the ibrutinib according to the prescription amount, preparing a solid dispersion at 115 ℃ by using a hot-melt extruder, cooling, crushing, sieving by using a 80-mesh sieve, adding the starch, the lactose and the low-substituted hydroxypropyl cellulose according to the prescription amount, uniformly mixing, adding the linoleoyl polyoxyethylene glyceride for granulation, sieving by using a 20-mesh sieve, adding the sodium stearyl fumarate according to the prescription amount, uniformly mixing, and filling into capsules.
Example 5
Prescription:
the preparation process comprises the following steps:
the prescribed amount of hydroxypropyl methylcellulose AFFINSOLTMMixing with ibrutinib uniformly, preparing a solid dispersion at 140 ℃ by using a hot-melt extruder, cooling, crushing, sieving with a 80-mesh sieve, adding dextrin, lactose and crospovidone according to the prescription amount, mixing uniformly, adding linoleoyl polyoxyethylene glyceride and caprylic capric acid polyethylene glycol glyceride, granulating, sieving with a 20-mesh sieve, adding polyethylene glycol according to the prescription amount, mixing uniformly, and filling into capsules.
Example 6
Prescription:
the preparation process comprises the following steps:
the prescription amount of hydroxypropyl methylcellulose AFFINSOLTMMixing with ibrutinib uniformly, heating and melting at 140 ℃ by using a hot-melt extruder, extruding to prepare a solid dispersion, cooling, crushing, sieving with a 80-mesh sieve, adding the microcrystalline cellulose and the croscarmellose sodium according to the formula amount, uniformly mixing, adding the linoleoyl polyoxyethylene glyceride for granulation, sieving with a 20-mesh sieve, adding the magnesium stearate according to the formula amount, uniformly mixing, and filling into capsules.
Example 7
Prescription:
the preparation process comprises the following steps:
uniformly mixing polyvinylpyrrolidone K30, sorbitol and ibrutinib according to the prescription amount, heating and melting at 130 ℃ by using a hot-melt extruder, extruding to prepare a solid dispersion, cooling, crushing, sieving by using a 80-mesh sieve, adding mannitol, microcrystalline cellulose and sodium carboxymethyl starch according to the prescription amount, uniformly mixing, heating and melting lauroyl polyoxyethylene glyceride at 50 ℃, adding the mixture into mixed powder, granulating, sieving by using a 20-mesh sieve, adding talcum powder according to the prescription amount, uniformly mixing, and filling into capsules.
Example 8
Prescription:
the preparation process comprises the following steps:
uniformly mixing the copovidone VA64 and the ibrutinib according to the prescription amount, heating and melting at 110 ℃ by using a hot-melt extruder, extruding to prepare a solid dispersion, cooling, crushing and sieving by using a 80-mesh sieve, adding the starch, the lactose and the cross-linked polyvinylpyrrolidone according to the prescription amount, uniformly mixing, adding the linoleoyl polyoxyethylene glyceride for granulation, then sieving by using a 20-mesh sieve, adding the sodium stearyl fumarate according to the prescription amount, uniformly mixing and filling into capsules.
Example 9
Prescription:
the preparation process comprises the following steps:
uniformly mixing Soluplus and ibrutinib according to the prescription amount, heating and melting at 135 ℃ by using a hot-melt extruder, extruding to prepare a solid dispersion, cooling, crushing, sieving by using a 80-mesh sieve, adding lactose, microcrystalline cellulose and croscarmellose sodium according to the prescription amount, uniformly mixing, adding glycerol monooleate, granulating, sieving by using a 20-mesh sieve, adding magnesium stearate according to the prescription amount, uniformly mixing, and filling into capsules.
Example 10
Prescription:
the preparation process comprises the following steps:
uniformly mixing polyvinylpyrrolidone K30, sorbitol and ibrutinib according to the prescription amount, heating and melting at 130 ℃ by using a hot-melt extruder, extruding to prepare a solid dispersion, cooling, crushing, sieving with a 80-mesh sieve, adding microcrystalline cellulose and croscarmellose sodium according to the prescription amount, uniformly mixing, heating and melting lauroyl polyoxyethylene glyceride at 50 ℃, adding the mixture into mixed powder, granulating, sieving with a 20-mesh sieve, adding magnesium stearate according to the prescription amount, uniformly mixing, and filling into capsules.
Example 11
Prescription:
the preparation process comprises the following steps:
the prescribed amount of hydroxypropyl methylcellulose AFFINSOLTMMixing with Ibutotinib, heating and melting at 150 deg.C with hot melt extruder, extruding, preparing solid dispersion, coolingThen crushing and sieving the mixture by a sieve of 80 meshes, adding lactose, microcrystalline cellulose and sodium carboxymethyl starch according to the prescription amount, uniformly mixing, adding caprylic capric acid polyethylene glycol glyceride for granulation, sieving the mixture by a sieve of 20 meshes, adding sodium stearyl fumarate according to the prescription amount, uniformly mixing and filling the mixture into capsules.
Comparative example 1
Prescription:
the preparation process comprises the following steps:
micronizing Ibutotinib, adding polyvinylpyrrolidone K30, microcrystalline cellulose, lactose and low-substituted hydroxypropyl cellulose, mixing, granulating with water, sieving with 20 mesh sieve, drying, adding magnesium stearate, mixing, and tabletting.
Comparative example 2
Prescription:
the preparation process comprises the following steps:
micronizing ibrutinib, adding hydroxypropyl methylcellulose 2910, microcrystalline cellulose and sodium carboxymethyl starch, mixing, granulating with caprylic/capric macrogol glyceride, sieving with 20 mesh sieve, adding magnesium stearate, mixing, and tabletting.
Comparative example 3
Prescription:
the preparation process comprises the following steps:
the preparation method comprises the following steps of adding ibutinib, oleic acid, glyceryl oleate and polyoxyethylene fatty alcohol ether in the formula amount into glycerol formal, uniformly mixing, uniformly spraying the mixed solution onto N-methylamino formyl chloride by using a fluidized bed, granulating, drying, adding carboxymethylcellulose calcium and microcrystalline cellulose, uniformly mixing, and tabletting.
Comparative example 4
Prescription:
the preparation process comprises the following steps:
dissolving a prescribed amount of ibutinib and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer in acetone, and performing spray drying at a nozzle size of 1.5mm and a nozzle pressure of 20psi at a speed of 15mL/min, wherein the inlet temperature is set to 70-80 ℃, the outlet temperature is set to 10-45 ℃, and the flow of drying gas is maintained at 35m3Second drying at 40 ℃ for about 16h in an oven, blending with lactose, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide and 0.05g magnesium stearate in a V blender for 10 minutes, sieving through a 20 mesh screen, adding an additional 0.05g magnesium stearate to the sieved blend and blending for an additional 3 minutes, rolling the final blend using a roller or single press station to obtain a tape or rod, grinding the compacted tape or rod in a grinding granulator, sieving through a 20 mesh screen, and tabletting.
Comparative example 5
Prescription:
the preparation process comprises the following steps:
the preparation method comprises the steps of adding the Ibutotinib and the povidone with the prescription amount into a proper amount of purified water to form a mixed solution, putting the microcrystalline cellulose into a high-shear stirrer to be stirred, spraying the mixed solution onto microcrystalline cellulose particles while keeping the microcrystalline cellulose moving, drying, mixing with lactose, low-substituted hydroxypropyl cellulose, magnesium stearate and silicon dioxide, and filling into capsules.
Comparative example 6
Prescription:
the preparation process comprises the following steps:
100 tablets were prepared as follows:
(1) sieving ibutinib with a 120-mesh sieve, and sieving other auxiliary materials with a 80-mesh sieve;
(2) uniformly mixing the prescription amount of ibrutinib with the prescription amount of sodium dodecyl sulfate, micropowder silica gel and soybean lecithin; moistening with 55% ethanol water solution for softening; drying at 60 ℃, granulating and sieving by a 60-mesh sieve;
(3) wetting the mixture obtained in the step (2) with a prescribed amount of microcrystalline cellulose, croscarmellose sodium, polyethylene glycol 6000 and 55% ethanol water solution to prepare soft materials; drying at 60 ℃, granulating and sieving by a 40-mesh sieve;
(4) and (4) adding magnesium stearate in the prescription amount, uniformly mixing, and tabletting.
Comparative example 7
Prescription:
the preparation process comprises the following steps:
the prescribed amount of hydroxypropyl methylcellulose AFFINSOLTMMixing with Ibutotinib, heating and melting at 135 deg.C with hot melt extruder, extruding, preparing solid dispersion, cooling, pulverizing, sieving with 80 mesh sieve, adding lactose, microcrystalline cellulose and croscarmellose sodium, mixing, adding polyoxyethylene hydrogenated castor oil, granulating, sieving with 20 mesh sieve, adding magnesium stearate, mixing, and making into capsule.
Verification of the embodiments
1. Dissolution test
Dissolution rates of the ibrutinib preparations obtained in examples 1 to 11 and comparative examples 1 to 7 were measured by the following method. Taking the product, according to dissolution determination method, using 900mL of pure water as dissolution medium, rotating at 75 r/min, operating according to the method, taking 10mL of solution at 5min, 10 min and 30min respectively, filtering, and taking the subsequent filtrate as the test solution. And taking another appropriate amount of the ibrutinib reference substance, placing the appropriate amount of the ibrutinib reference substance into a 10mL measuring flask, adding methanol for dissolving and diluting to a scale, precisely measuring 1mL, placing the measuring flask into the 10mL measuring flask, adding a dissolving medium for diluting to the scale, and shaking up to be used as a reference substance solution. And (3) taking 10 mu L of each of the test solution and the reference solution, injecting into a liquid chromatograph, recording a chromatogram, and calculating the dissolution rate of each tablet by peak area according to an external standard method. The limit is 80% of the indicated amount and should be met.
Chromatographic conditions are as follows: octadecylsilane chemically bonded silica chromatographic column with mobile phase of 0.1% TFA deionized water solution and 0.1% TFA acetonitrile solution, gradient elution, flow rate of 1.5mL/min, column temperature of 40 deg.C, and detection wavelength of 260 nm. Three replicates were run and the results averaged.
The test results are shown in table 1.
Table 1 dissolution test results
2. Pharmacokinetic testing
Pharmacokinetic experiments were carried out on examples 1 to 11 and comparative examples 1 to 7, 6 healthy Beagle dogs in each group were fed 12.5 to 15kg in body weight, once 12 hours before dosing, orally administered with 140mg of ibrutinib in a dose of 25mL warm water, and after 15min, 30min, 45min, 60min, 90min, 120min, 240min, 480min, 720min after dosing, the forelimb was subjected to subcutaneous intravenous blood collection for about 3mL and placed in the liverIn the test tube, blood concentration was measured, and Cmax and AUC were calculated, and the calculated values were compared with those of a commercially available ibutinib tablet (trade name:
) Comparison, further calculation for
The ratio of Cmax to AUC of (c).
The test results are shown in table 2.
TABLE 2 pharmacokinetic determination results
Claims (10)
1. An ibrutinib capsule comprises an ibrutinib solid dispersion, fatty glyceride and other pharmaceutically acceptable auxiliary materials.
2. The ibrutinib capsule according to claim 1, wherein the ibrutinib solid dispersion comprises ibrutinib and a macromolecular polymer; the macromolecular polymer is selected from hydroxypropyl methylcellulose AFFINISOLTMOne or more of polyvinylpyrrolidone K30, copovidone VA64 or S630.
3. The ibutinib capsule according to claim 2, wherein the weight ratio of the ibutinib to the macromolecular polymer is 1:1 to 4.
4. The ibutinib capsule according to claim 1, wherein the fatty acid glyceride is selected from one or more of oleoyl polyoxyethylene glyceride, linoleoyl polyoxyethylene glyceride, caprylic capric polyethylene glycol glyceride, polyethylene glycol stearate, lauroyl polyoxyethylene glyceride.
5. The ibutinib capsule according to claim 1, wherein the weight ratio of the active ingredients ibutinib to fatty acid glycerides is from 1: 0.02 to 0.2.
6. The ibutinib capsule according to claim 1, wherein said pharmaceutically acceptable excipients comprise fillers, disintegrants and lubricants.
7. The ibrutinib capsule according to claim 6 wherein the filler is selected from one or more of microcrystalline cellulose, lactose, mannitol, starch and dextrin; the weight ratio of the active ingredient ibutinib to the filler is 1: 0.5 to 3.
8. The ibrutinib capsule according to claim 6, wherein the disintegrant is selected from one or more of sodium carboxymethyl starch, croscarmellose sodium, crospovidone, and low substituted hydroxypropyl cellulose; the weight ratio of the active ingredient ibutinib to the disintegrant is 1: 0.05 to 1.5.
9. The ibrutinib capsule according to claim 6, wherein the lubricant is selected from one or more of magnesium stearate, talc, sodium stearyl fumarate, silica, polyethylene glycol; the weight ratio of the active ingredient ibutinib to the lubricant is 1: 0.1 to 0.2.
10. A method for preparing ibutinib capsules according to any one of claims 1 to 9, comprising the following steps: heating and melting the ibrutinib and the macromolecular polymer at 110-150 ℃ by using a hot-melt extruder, and extruding to prepare a solid dispersion; pulverizing the solid dispersion, sieving, mixing with other pharmaceutically acceptable adjuvants, granulating with fatty glyceride, adding lubricant, and making into capsule.
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