CN115068432A - Tofacitinib citrate pressed coating sustained release tablet and preparation method thereof - Google Patents
Tofacitinib citrate pressed coating sustained release tablet and preparation method thereof Download PDFInfo
- Publication number
- CN115068432A CN115068432A CN202210921132.2A CN202210921132A CN115068432A CN 115068432 A CN115068432 A CN 115068432A CN 202210921132 A CN202210921132 A CN 202210921132A CN 115068432 A CN115068432 A CN 115068432A
- Authority
- CN
- China
- Prior art keywords
- tofacitinib citrate
- preparation
- percent
- outer coating
- press
- 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
Links
- 229960004247 tofacitinib citrate Drugs 0.000 title claims abstract description 120
- SYIKUFDOYJFGBQ-YLAFAASESA-N tofacitinib citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 SYIKUFDOYJFGBQ-YLAFAASESA-N 0.000 title claims abstract description 120
- 239000007939 sustained release tablet Substances 0.000 title claims abstract description 72
- 238000002360 preparation method Methods 0.000 title claims abstract description 66
- 238000000576 coating method Methods 0.000 title claims description 31
- 239000011248 coating agent Substances 0.000 title claims description 30
- 239000003826 tablet Substances 0.000 claims abstract description 71
- 239000000463 material Substances 0.000 claims abstract description 26
- 238000003825 pressing Methods 0.000 claims abstract description 18
- 150000007524 organic acids Chemical class 0.000 claims abstract description 16
- 239000011247 coating layer Substances 0.000 claims description 75
- 239000012792 core layer Substances 0.000 claims description 52
- 239000002994 raw material Substances 0.000 claims description 46
- 239000011812 mixed powder Substances 0.000 claims description 31
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 30
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 23
- 238000002156 mixing Methods 0.000 claims description 20
- 239000007884 disintegrant Substances 0.000 claims description 17
- 239000000945 filler Substances 0.000 claims description 16
- 239000000314 lubricant Substances 0.000 claims description 16
- 238000011049 filling Methods 0.000 claims description 14
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 12
- 235000019359 magnesium stearate Nutrition 0.000 claims description 12
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 12
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 12
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 12
- 235000015165 citric acid Nutrition 0.000 claims description 10
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 claims description 9
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 9
- 229920002472 Starch Polymers 0.000 claims description 9
- 229940049654 glyceryl behenate Drugs 0.000 claims description 9
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 9
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 9
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 9
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound 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
- 239000008107 starch Substances 0.000 claims description 9
- 235000019698 starch Nutrition 0.000 claims description 9
- 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 8
- 239000008101 lactose Substances 0.000 claims description 8
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 6
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 6
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 6
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims description 6
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 6
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 6
- 229920000896 Ethulose Polymers 0.000 claims description 5
- 239000001856 Ethyl cellulose Substances 0.000 claims description 5
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 5
- 239000001859 Ethyl hydroxyethyl cellulose Substances 0.000 claims description 5
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 claims description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- 229960004106 citric acid Drugs 0.000 claims description 5
- 229960000913 crospovidone Drugs 0.000 claims description 5
- 229920001249 ethyl cellulose Polymers 0.000 claims description 5
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 5
- 235000019326 ethyl hydroxyethyl cellulose Nutrition 0.000 claims description 5
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 5
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 5
- 229940032147 starch Drugs 0.000 claims description 5
- 239000000230 xanthan gum Substances 0.000 claims description 5
- 235000010493 xanthan gum Nutrition 0.000 claims description 5
- 229920001285 xanthan gum Polymers 0.000 claims description 5
- 229940082509 xanthan gum Drugs 0.000 claims description 5
- 239000004012 Tofacitinib Substances 0.000 claims description 4
- 229940093915 gynecological organic acid Drugs 0.000 claims description 4
- 235000005985 organic acids Nutrition 0.000 claims description 4
- 229960001350 tofacitinib Drugs 0.000 claims description 4
- UJLAWZDWDVHWOW-YPMHNXCESA-N tofacitinib Chemical compound C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 UJLAWZDWDVHWOW-YPMHNXCESA-N 0.000 claims description 4
- 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
- 229920001353 Dextrin Polymers 0.000 claims description 3
- 239000004375 Dextrin Substances 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 3
- 229930006000 Sucrose Natural products 0.000 claims description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 3
- 239000001361 adipic acid Substances 0.000 claims description 3
- 235000011037 adipic acid Nutrition 0.000 claims description 3
- 235000010323 ascorbic acid Nutrition 0.000 claims description 3
- 239000011668 ascorbic acid Substances 0.000 claims description 3
- 229960005070 ascorbic acid Drugs 0.000 claims description 3
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 3
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 3
- 235000019425 dextrin Nutrition 0.000 claims description 3
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 3
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 3
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000001530 fumaric acid Substances 0.000 claims description 3
- 235000011087 fumaric acid Nutrition 0.000 claims description 3
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 229940083542 sodium Drugs 0.000 claims description 3
- 235000015424 sodium Nutrition 0.000 claims description 3
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 3
- 239000004334 sorbic acid Substances 0.000 claims description 3
- 235000010199 sorbic acid Nutrition 0.000 claims description 3
- 229940075582 sorbic acid Drugs 0.000 claims description 3
- 239000005720 sucrose Substances 0.000 claims description 3
- 239000000454 talc Substances 0.000 claims description 3
- 229910052623 talc Inorganic materials 0.000 claims description 3
- 239000011975 tartaric acid Substances 0.000 claims description 3
- 235000002906 tartaric acid Nutrition 0.000 claims description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 3
- 229910002012 Aerosil® Inorganic materials 0.000 claims description 2
- 229940095079 dicalcium phosphate anhydrous Drugs 0.000 claims description 2
- 229960000250 adipic acid Drugs 0.000 claims 1
- 229960002598 fumaric acid Drugs 0.000 claims 1
- 229960001367 tartaric acid Drugs 0.000 claims 1
- 239000000843 powder Substances 0.000 abstract description 22
- 239000008187 granular material Substances 0.000 abstract description 14
- 239000003814 drug Substances 0.000 abstract description 10
- 238000001727 in vivo Methods 0.000 abstract description 10
- 238000000338 in vitro Methods 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 5
- 238000003860 storage Methods 0.000 abstract description 4
- 230000003139 buffering effect Effects 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 29
- 230000000052 comparative effect Effects 0.000 description 25
- 238000009472 formulation Methods 0.000 description 24
- 239000000243 solution Substances 0.000 description 13
- 238000007907 direct compression Methods 0.000 description 12
- 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 description 11
- 238000007906 compression Methods 0.000 description 11
- 230000006835 compression Effects 0.000 description 11
- 239000002245 particle Substances 0.000 description 11
- 238000005303 weighing Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000007873 sieving Methods 0.000 description 8
- 238000004090 dissolution Methods 0.000 description 7
- 229960001375 lactose Drugs 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 241000282472 Canis lupus familiaris Species 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 229960004977 anhydrous lactose Drugs 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 229940069328 povidone Drugs 0.000 description 4
- 239000007779 soft material Substances 0.000 description 4
- 239000007909 solid dosage form Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000013270 controlled release Methods 0.000 description 3
- 238000000132 electrospray ionisation Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000005034 decoration Methods 0.000 description 2
- 238000004807 desolvation Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 210000000245 forearm Anatomy 0.000 description 2
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 2
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000002552 multiple reaction monitoring Methods 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- 208000002249 Diabetes Complications Diseases 0.000 description 1
- 206010012655 Diabetic complications Diseases 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 208000003456 Juvenile Arthritis Diseases 0.000 description 1
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- -1 Piperidin-1-yl radical Chemical class 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- 208000024799 Thyroid disease Diseases 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- XBJFCYDKBDVADW-UHFFFAOYSA-N acetonitrile;formic acid Chemical compound CC#N.OC=O XBJFCYDKBDVADW-UHFFFAOYSA-N 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 238000000861 blow drying Methods 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 229960000520 diphenhydramine Drugs 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000005553 drilling Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 238000002101 electrospray ionisation tandem mass spectrometry Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000002409 epiglottis Anatomy 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229910002055 micronized silica Inorganic materials 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 239000003909 protein kinase inhibitor Substances 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 238000002689 xenotransplantation Methods 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/282—Organic compounds, e.g. fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Transplantation (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the technical field of medicine preparation, and particularly relates to tofacitinib citrate press-coated sustained-release tablets and a preparation method thereof. The invention adopts organic acid as pH regulator, has pH buffering capacity, can keep stable preparation microenvironment, can obviously change the pH microenvironment around and in the preparation, keeps the preparation microenvironment at relatively low pH, increases the solubility of tofacitinib citrate in gastrointestinal tract, and releases the tofacitinib citrate more completely, thereby achieving the purpose of preventing the in vitro and in vivo release conditions from being influenced by external conditions. Meanwhile, the preparation of the invention relies on the framework material to control the release, the slow release effect of the drug is good, and the preparation is an asymmetric double-storage reservoir, the burst release is not easy to occur, the safety is good, the reliability is high, and the drug release can be kept unchanged even if the preparation is accidentally damaged. The preparation method provided by the invention wraps the tablet core by pressing the granules and the powder, has the advantages of more reasonable production process, simpler and more convenient operation, lower cost and environmental friendliness, and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of medicine preparation, in particular to tofacitinib citrate press-coated sustained-release tablets and a preparation method thereof.
Background
The chemical name of tofacitinib citrate is 3- [ (3R,4R) -4-methyl-3 [ [ methyl- (7H-pyrrolo [2,3-d ]]Pyrimidin-4-yl) -amino]Piperidin-1-yl radical]-3-oxopropanenitrile citrate with molecular formula C 16 H 20 N 6 O·C 6 H 8 O 7 Molecular weight 504.49g/mol, which is useful as a protein kinase inhibitor and thus as an immunosuppressant in organ transplantation, xenotransplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, psoriatic arthritis, type I diabetes and diabetic complications, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, ankylosing spondylitis, juvenile idiopathic arthritis, crohn's disease, alzheimer's disease, leukemia and other indications where immunosuppression is desired.
Chinese patent publication No. CN111150711A discloses tofacitinib controlled release tablets, a preparation method and applications thereof. The patent does not investigate the pharmacokinetic data of the obtained controlled release tablet of tofacitinib in vivo. Meanwhile, the preparation method of the tofacitinib controlled-release tablet adopts a polymer water dispersion coating technology, and compared with the traditional organic solvent coating, water has higher latent heat of evaporation (2255kJ/kg, which is 2.7 times of ethanol 854 kJ/kg), so the coating drying speed is slow, the coating time is long, and equipment such as a fluidized bed with high-efficiency drying capacity and the like must be selected; an increase in the solids content of the coating solution may reduce the processing time of the aqueous coating, but may increase the viscosity of the coating solution, leading to nozzle clogging; the production steps are still not sufficiently simplified and the coating process may suffer from non-uniform coating.
Disclosure of Invention
In view of the above, the invention aims to provide a tofacitinib citrate press-coated sustained-release tablet and a preparation method thereof. The tofacitinib citrate press-coating sustained-release tablet and the preparation method thereof
The in vitro release degree of XR is similar well, and the bioavailability of the two is equivalent.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a tofacitinib citrate press-coating sustained-release tablet, which consists of a tablet core layer and an outer coating layer;
the sheet core layer comprises the following raw materials in percentage by mass: 2 to 30 percent of tofacitinib citrate, 10 to 30 percent of framework material, 30 to 80 percent of filler, 0.5 to 2 percent of lubricant, 0.5 to 3 percent of disintegrant and 1.7 to 8 percent of pH regulator;
the outer coating layer comprises the following raw materials in percentage by mass: 1 to 10 percent of tofacitinib citrate, 10 to 50 percent of framework material, 20 to 80 percent of filler, 0.5 to 5 percent of lubricant, 0.5 to 5 percent of disintegrant and 1.7 to 10 percent of pH regulator;
the framework material independently comprises one or more of glyceryl behenate, hydroxyethyl methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, ethyl hydroxyethyl cellulose and xanthan gum;
the pH regulators are all organic acids.
Preferably, the mass percentage of the tablet core layer in the tofacitinib citrate press-coated sustained-release tablet is 25-35%, and the mass percentage of the outer coating layer is 65-75%.
Preferably, the hardness of the core layer is 20N-35N, and the hardness of the outer coating layer is 90N-120N.
Preferably, the filler independently comprises one or more of lactose, microcrystalline cellulose, starch, dextrin, sucrose, dibasic calcium phosphate and mannitol.
Preferably, the lubricant independently comprises one or more of magnesium stearate, sodium stearyl fumarate, talc, micronized silica gel, and polyethylene glycol.
Preferably, the disintegrant independently comprises one or more of croscarmellose sodium, starch, crospovidone, sodium carboxymethyl starch, and low substituted hydroxypropylcellulose.
Preferably, the organic acid is a polybasic organic acid; the polybasic organic acid comprises one or more of fumaric acid, citric acid, succinic acid, ascorbic acid, sorbic acid, adipic acid and tartaric acid.
The invention also provides a preparation method of the tofacitinib citrate press-coated sustained-release tablet, which comprises the following steps:
mixing the raw materials of the tablet core layer, and pressing to obtain the tablet core layer;
mixing the raw materials of the outer coating layer to obtain outer coating layer mixed powder;
filling the mixed powder of the first part of the outer coating layer into a mould, placing the tablet core layer in the middle of the mixed powder of the first part of the outer coating layer, filling the mixed powder of the second part of the outer coating layer, and tabletting to obtain the tofacitinib citrate compressed coated sustained release tablet;
the mass ratio of the first part of outer coating layer mixed powder to the second part of outer coating layer mixed powder is 1: 1.
preferably, the pressing pressure is 9-16 kN, and the dwell time is 5-8 ms.
Preferably, the pressure of the tabletting is 10-26 kN, and the pressure maintaining time is 5-8 ms.
The invention provides a tofacitinib citrate press-coating sustained-release tablet, which consists of a tablet core layer and an outer coating layer; the sheet core layer comprises the following raw materials in percentage by mass: 2 to 30 percent of tofacitinib citrate, 10 to 30 percent of framework material, 30 to 80 percent of filler, 0.5 to 2 percent of lubricant, 0.5 to 3 percent of disintegrant and 1.7 to 8 percent of pH regulator; the outer coating layer comprises the following raw materials in percentage by mass: 1 to 10 percent of tofacitinib citrate, 10 to 50 percent of framework material and 20 to 80 percent of filler0.5 to 5 percent of lubricant, 0.5 to 5 percent of disintegrant and 1.7 to 10 percent of pH regulator; the framework material independently comprises one or more of glyceryl behenate, hydroxyethyl methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, ethyl hydroxyethyl cellulose and xanthan gum; the pH regulators are all organic acids. The invention adopts organic acid as pH regulator, has pH buffering capacity, can keep the microenvironment of the tofacitinib citrate press-coated sustained-release tablet stable, can obviously change the pH microenvironment around the tofacitinib citrate press-coated sustained-release tablet and inside the tofacitinib citrate press-coated sustained-release tablet, keeps the microenvironment of the tofacitinib citrate press-coated sustained-release tablet at relatively low pH, increases the solubility of the tofacitinib citrate in gastrointestinal tracts, ensures more complete release, and achieves the aim of preventing the in-vivo and in-vitro release conditions from being influenced by external conditions. Meanwhile, the tofacitinib citrate press-coated sustained-release tablet disclosed by the invention is controlled to release by virtue of a framework material, has a good drug sustained-release effect, is an asymmetric double-storage, is not easy to burst, has good safety and high reliability, and can keep the drug release unchanged even if the tofacitinib citrate press-coated sustained-release tablet is accidentally damaged. It is not always easy to mass-produce solid oral pharmaceutical dosage forms on an industrial scale, and the formulation and method of preparation must be adapted to the whole solid dosage form. In addition, acceptable dissolution and disintegration requirements must be met. The usual fillers, disintegrants and excipients are particularly challenging for preparing high quality solid dosage forms, mainly because the physical properties of the drug affect many aspects of the properties of the solid dosage form. Manufacturers must balance the properties of the drug with each adjuvant in order to produce a safe, effective, and easily absorbed solid dosage form. The invention establishes and verifies an in-vitro analysis method of tofacitinib citrate, researches the compatibility of raw and auxiliary materials, screens proper auxiliary material types and proportions and tabletting force to meet the process requirements of powder pressing and coating, finally achieves good similarity of in-vitro dissolution rate and a reference preparation, and achieves in-vivo bioavailability and in-vivo pharmacokinetics research by using Beagle dogs
XR11mg is equivalent. The press-coated sustained-release tablet of the invention can meet the requirement of clinical effective release.
The invention also provides a preparation method of the tofacitinib citrate press-coated sustained-release tablet, which comprises the following steps: mixing the raw materials of the tablet core layer, and pressing to obtain the tablet core layer; mixing the raw materials of the outer coating layer to obtain outer coating layer mixed powder; filling the first part of outer coating layer mixed powder into a die, placing the tablet core layer in the middle of the first part of outer coating layer mixed powder, filling the second part of outer coating layer mixed powder, and tabletting to obtain the tofacitinib citrate pressed coating sustained release tablet; the mass ratio of the first part of outer coating layer mixed powder to the second part of outer coating layer mixed powder is 1: 1. the preparation method provided by the invention wraps the tablet core by pressing the granules and the powder, has the advantages of more reasonable production process, simpler and more convenient operation, lower cost and environmental friendliness, and is suitable for industrial production.
Drawings
FIG. 1 is a comparison of the dissolution profiles of tofacitinib citrate press-coated sustained release tablets of example 21 and a reference formulation in a phosphate buffered saline solution at a pH of 6.8;
FIG. 2 is a graph comparing the in vivo dosing time curves of the tofacitinib citrate press-coated sustained release tablets of example 21 and a reference formulation.
Detailed Description
The invention provides a tofacitinib citrate press-coating sustained-release tablet, which consists of a tablet core layer and an outer coating layer;
the sheet core layer comprises the following raw materials in percentage by mass: 2 to 30 percent of tofacitinib citrate, 10 to 30 percent of framework material, 30 to 80 percent of filler, 0.5 to 2 percent of lubricant, 0.5 to 3 percent of disintegrant and 1.7 to 8 percent of pH regulator;
the outer coating layer comprises the following raw materials in percentage by mass: 1 to 10 percent of tofacitinib citrate, 10 to 50 percent of framework material, 20 to 80 percent of filler, 0.5 to 5 percent of lubricant, 0.5 to 5 percent of disintegrant and 1.7 to 10 percent of pH regulator;
the framework material independently comprises one or more of glyceryl behenate, hydroxyethyl methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, ethyl hydroxyethyl cellulose and xanthan gum;
the pH regulators are all organic acids.
In the present invention, the starting materials used in the present invention are preferably commercially available products unless otherwise specified.
The tofacitinib citrate press-coating sustained-release tablet comprises a tablet core layer; the mass percentage of the tablet core layer in the tofacitinib citrate press-coated sustained-release tablet is preferably 25-35%, and more preferably 30%. In the present invention, the hardness of the core sheet layer is preferably 20 to 35N, and more preferably 25 to 30N.
In the invention, the tablet core layer comprises the following raw materials in percentage by mass: 2 to 30 percent of tofacitinib citrate, 10 to 30 percent of framework material, 30 to 80 percent of filler, 0.5 to 2 percent of lubricant, 0.5 to 3 percent of disintegrant and 1.7 to 8 percent of pH regulator.
In the invention, the raw material of the tablet core layer comprises 2-30% by mass of tofacitinib citrate, preferably 5-15%.
In the invention, the raw material of the sheet core layer comprises 10-30% of framework material by mass, preferably 15-25%, and more preferably 20%. In the present invention, the skeleton material includes one or more of glyceryl behenate, hydroxyethyl methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, ethyl hydroxyethyl cellulose and xanthan gum, and is further preferably glyceryl behenate.
In the invention, the raw material of the sheet core layer comprises 30-80% by mass of a filler, preferably 40-70%, and more preferably 50-60%. In the present invention, the filler preferably includes one or more of lactose, microcrystalline cellulose, starch, dextrin, sucrose, calcium hydrogen phosphate, and mannitol, and is further preferably lactose and/or microcrystalline cellulose.
In the invention, the raw material of the sheet core layer comprises 0.5-2% by mass of a lubricant, preferably 1.0-1.5%. In the present invention, the lubricant preferably includes one or more of magnesium stearate, sodium stearyl fumarate, talc, aerosil and polyethylene glycol, and is more preferably magnesium stearate.
In the invention, the raw material of the tablet core layer comprises 0.5-3% by mass of a disintegrant, preferably 1.0-2.5%, and more preferably 1.5-2.0%. In the invention, the disintegrant preferably comprises one or more of croscarmellose sodium, starch, crospovidone, sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose, and more preferably is croscarmellose sodium.
In the invention, the raw material of the sheet core layer comprises 1.7-8% by mass of a pH regulator, preferably 2.0-6.0%, and more preferably 3.0-5.0%. In the present invention, the pH adjuster is an organic acid; the organic acid is preferably a polybasic organic acid; the polybasic organic acid preferably comprises one or more of fumaric acid, citric acid, succinic acid, ascorbic acid, sorbic acid, adipic acid and tartaric acid, and further preferably citric acid.
The tofacitinib citrate press-coated sustained-release tablet provided by the invention comprises an outer coating layer; the mass percentage content of the outer coating layer in the tofacitinib citrate press-coated sustained-release tablet is 65-75%, preferably 60%. In the present invention, the hardness of the outer coating layer is preferably 90N to 120N, and more preferably 100 to 110N.
In the invention, the outer coating layer comprises the following raw materials in percentage by mass: 1 to 10 percent of tofacitinib citrate, 10 to 50 percent of framework material, 20 to 80 percent of filler, 0.5 to 5 percent of lubricant, 0.5 to 5 percent of disintegrant and 1.7 to 10 percent of pH regulator.
In the invention, the raw material of the outer coating layer comprises 1-10% by mass of tofacitinib citrate, preferably 2-5%.
In the invention, the raw material of the outer coating layer comprises 10-50% of framework material by mass, preferably 15-40%, and more preferably 20-30%. In the present invention, the kind of the framework material is preferably consistent with the above technical solution, and is not described herein again.
In the present invention, the raw material of the outer coating layer includes 20 to 80 mass% of a filler, preferably 30 to 70 mass%, and more preferably 40 to 50 mass%. In the present invention, the kind of the filler is preferably the same as the above technical solution, and will not be described herein.
In the invention, the raw material of the outer coating layer comprises 0.5-5% of lubricant by mass percentage, preferably 1-2%. In the present invention, the kind of the lubricant is preferably consistent with the above technical solution, and will not be described herein again.
In the invention, the raw material of the outer coating layer comprises 0.5-5% by mass of disintegrant, preferably 1-2%. In the present invention, the kind of the disintegrant is preferably consistent with the above technical scheme, and is not described herein.
In the invention, the raw material of the outer coating layer comprises 1.7-10% by mass of a pH regulator, preferably 2-8%, and more preferably 3-5%. In the present invention, the kind of the pH regulator is preferably consistent with the above technical solution, and will not be described herein.
The invention also provides a preparation method of the tofacitinib citrate press-coated sustained-release tablet, which comprises the following steps:
mixing the raw materials of the tablet core layer, and pressing to obtain the tablet core layer;
mixing the raw materials of the outer coating layer to obtain outer coating layer mixed powder;
filling the first part of outer coating layer mixed powder into a die, placing the tablet core layer in the middle of the first part of outer coating layer mixed powder, filling the second part of outer coating layer mixed powder, and tabletting to obtain the tofacitinib citrate pressed coating sustained release tablet;
the mass ratio of the first part of outer coating layer mixed powder to the second part of outer coating layer mixed powder is 1: 1.
the invention provides a method for preparing a tablet core layer by mixing raw materials of the tablet core layer and pressing.
In the invention, the particle size of tofacitinib citrate in the raw material of the tablet core layer is preferably 20-140 μm, and more preferably 30-90 μm. In the present invention, the particle size of the microcrystalline cellulose in the raw material of the sheet core layer is preferably 90 to 140 μm, and more preferably 100 to 110 μm. In the invention, the particle size of lactose in the raw material of the tablet core layer is preferably 120-180 μm, and more preferably 140-160 μm. In the invention, the grain size of the glyceryl behenate in the raw material of the sheet core layer is preferably 40-60 μm, and more preferably 45-50 μm. In the present invention, the particle size of magnesium stearate in the raw material of the tablet core layer is preferably 10 to 15 μm, and more preferably 12 to 14 μm. In the invention, the particle size of the croscarmellose sodium in the raw material of the tablet core layer is preferably 35-50 μm, and preferably 40-45 μm. In the invention, the particle size of citric acid in the raw material of the tablet core layer is preferably 45-60 μm, and more preferably 50-55 μm.
In the invention, the pressing pressure is preferably 9-16 kN, more preferably 10-15 kN, and even more preferably 12-13 kN; the dwell time is preferably 5 to 8ms, and more preferably 6 to 7 ms.
The raw materials of the outer coating layer are mixed to obtain the mixed powder of the outer coating layer. In the invention, the particle size of tofacitinib citrate in the raw material of the outer coating layer is preferably 20-140 μm, and more preferably 30-90 μm. In the present invention, the particle size of the microcrystalline cellulose in the raw material of the outer coating layer is preferably 90 to 140 μm, and more preferably 100 to 110 μm. In the present invention, the particle size of lactose in the raw material of the outer coating layer is preferably 120 to 180 μm, and more preferably 140 to 160 μm. In the invention, the grain size of the glyceryl behenate in the raw material of the outer coating layer is preferably 40-60 μm, and more preferably 45-50 μm. In the present invention, the particle size of magnesium stearate in the raw material of the outer coating layer is preferably 10 to 15 μm, and more preferably 12 to 14 μm. In the invention, the particle size of the croscarmellose sodium in the raw material of the outer coating layer is preferably 35-50 μm, and preferably 40-45 μm. In the invention, the grain size of citric acid in the raw material of the outer coating layer is preferably 45-60 μm, and more preferably 50-55 μm.
The tablet core layer and the outer coating layer mixed powder are obtained, the first part of the outer coating layer mixed powder is filled into a die, the tablet core layer is arranged in the middle of the first part of the outer coating layer mixed powder, the second part of the outer coating layer mixed powder is filled, and tabletting is carried out to obtain the tofacitinib citrate pressed coating sustained release tablet.
In the invention, the mass ratio of the first part of outer coating layer mixed powder to the second part of outer coating layer mixed powder is 1: 1.
in the invention, the pressure for tabletting is preferably 10-26 kN, and more preferably 15-20 kN; the heat preservation time is preferably 5-8 ms, and more preferably 6-7 ms.
The present invention will be described in detail with reference to the following examples, but they should not be construed as limiting the scope of the present invention.
Comparative example 1
The tofacitinib citrate tablet comprises a tablet core layer and an outer coating layer, wherein both the tablet core layer and the outer coating layer contain tofacitinib citrate; the sustained-release tablet with the outer coating layer outside and the tablet core layer inside is prepared by pressing.
The prescription of the tofacitinib citrate press-coated sustained-release tablet in the case is shown in table 1.
Table 1 comparative example 1 formula of tofacitinib citrate press-coated sustained release tablet
The preparation process of the tofacitinib citrate pressed coating sustained release tablet adopts full-powder direct pressing, and comprises the following steps:
1. preparation of the core layer
a) Weighing tofacitinib citrate (sieved by a 80-mesh sieve), microcrystalline cellulose, lactose, citric acid and hydroxypropyl methylcellulose in a prescription amount, and uniformly mixing according to an equivalent incremental method;
b) adding prescription amount of magnesium stearate into the mixture obtained in a), and mixing for 5 min;
c) the tablet core is obtained by tabletting through a 6mm plane punch die, and the hardness of the tablet core is 25.12 newtons.
2. Preparation of the outer coating layer
a) Weighing tofacitinib citrate (sieved by a 80-mesh sieve), microcrystalline cellulose, lactose, citric acid and hydroxypropyl methylcellulose in a prescription amount, and uniformly mixing according to an equivalent incremental method;
b) adding magnesium stearate with prescription amount into the mixture obtained in a), and mixing for 5min to obtain the outer coating material.
3. Preparation of tofacitinib citrate press-coated sustained-release tablet
Filling 1/2 weight parts of the outer coating powder into a 9mm shallow concave die, adding a core, filling 1/2 weight parts of the outer coating powder around the core, and pressing under a set pressure and time to obtain the tofacitinib citrate pressed coating sustained release tablet with the hardness of 104.76N.
Comparative example 2
The prescription of the tofacitinib citrate press-coating sustained-release tablet of the case is shown in the table 2.
Table 2 comparative example 2 prescription of tofacitinib citrate press-coated sustained-release tablet
The tofacitinib citrate sustained-release tablet is prepared by adopting a full-powder direct compression preparation process. The preparation method comprises the following steps: as in comparative example 1.
Comparative example 3
The prescription of the tofacitinib citrate compression-coated tablet of the present case is shown in table 3:
table 3 comparative example 3 formulation of tofacitinib citrate compression coated tablet
The tofacitinib citrate sustained-release tablet is prepared by adopting a full-powder direct compression preparation process. The preparation method comprises the following steps: as in comparative example 1.
Examples 1 to 2
The formulation of tofacitinib citrate press-coated tablets of this example is shown in table 4:
TABLE 4 examples 1-2 formulation of tofacitinib citrate compression coated tablets
In the embodiment 1-2, the tofacitinib citrate press-coated sustained-release tablet adopts a full-powder direct-compression preparation process. The preparation method comprises the following steps: as in comparative example 1.
Examples 3 to 4
The formulation of tofacitinib citrate press-coated tablets of this example is shown in table 5:
TABLE 5 examples 3-4 formulation of tofacitinib citrate compression coated tablets
In the embodiment 3-4, the tofacitinib citrate press-coated sustained-release tablet adopts a full-powder direct-compression preparation process. The preparation method comprises the following steps: as in comparative example 1.
Examples 5 to 6
The formulation of tofacitinib citrate press-coated tablets of this example is shown in table 6:
TABLE 6 examples 5-6 prescription of tofacitinib citrate press-coated tablets
In the embodiment 5-6, the tofacitinib citrate press-coated sustained-release tablet adopts a full-powder direct-compression preparation process. The preparation method comprises the following steps: as in comparative example 1.
Examples 7 to 8
The formulation of tofacitinib citrate press-coated tablets of this example is shown in table 7:
TABLE 7 examples 7-8 prescription of tofacitinib citrate press-coated tablets
In the embodiment 7-8, the tofacitinib citrate press-coated sustained-release tablet adopts a full-powder direct-compression preparation process. The preparation method comprises the following steps: as in comparative example 1.
Examples 9 to 10
The formulation of tofacitinib citrate press-coated tablets of this example is shown in table 8:
TABLE 8 examples 9-10 prescription of tofacitinib citrate press-coated tablets
In the embodiment 9-10, the tofacitinib citrate press-coated sustained-release tablet adopts a full-powder direct-compression preparation process. The preparation method comprises the following steps: as in comparative example 1.
Examples 11 to 14
The formulation of tofacitinib citrate press-coated tablets of this example is shown in table 9:
TABLE 9 examples 11-14 prescription of Tofacitinib citrate compression coated tablets
Example 11 tofacitinib citrate press-coated sustained release tablets were prepared by a process of whole powder direct compression. The preparation method comprises the following steps: like comparative example 1, the tablet core layer was laminated to a hardness of 23.12N.
Example 12 tofacitinib citrate press-coated sustained release tablets were prepared by a process of whole powder direct compression. The preparation method comprises the following steps: like comparative example 1, the core layer had a hardness of 32.05N.
Example 13 tofacitinib citrate press-coated sustained release tablets were prepared using a full-powder direct compression process. The preparation method comprises the following steps: the whole sheet press hardness was 91.48N as in comparative example 1.
Example 14 tofacitinib citrate press-coated sustained release tablets were prepared using a full-powder direct compression process. The preparation method comprises the following steps: the whole sheet press hardness was 117.64N as in comparative example 1.
Comparative example 4
The formulation of the tofacitinib citrate press-coated tablet of this case is shown in table 10:
table 10 comparative example 4 formulation of tofacitinib citrate compression coated tablet
The wet granulation process adopted in the embodiment comprises the following steps:
1. preparation of the core layer
a) Weighing tofacitinib citrate (sieved by a 80-mesh sieve), microcrystalline cellulose, anhydrous lactose, citric acid, hydroxypropyl methylcellulose and povidone according to the formula amount, and uniformly mixing according to an equivalent incremental method;
b) weighing a proper amount of purified water to prepare soft materials, sieving the soft materials by a 40-mesh sieve, and granulating to form intermediate wet granules.
c) Boiling and drying the wet granules, controlling the water content to be below 5%, adding magnesium stearate according to the prescription amount, uniformly mixing, and sieving by a 40-mesh sieve for finishing granules; the cores were pressed with a 6mm flat punch and had a hardness of 24.93N.
2. Preparation of the outer coating layer
a) Weighing tofacitinib citrate (sieved by a 80-mesh sieve), microcrystalline cellulose, anhydrous lactose, citric acid, hydroxypropyl methylcellulose and povidone according to the formula amount, and uniformly mixing according to an equivalent incremental method;
b) weighing a proper amount of purified water to prepare soft materials, sieving the soft materials by a 40-mesh sieve, and granulating to form intermediate wet granules.
c) Boiling and drying the wet granules, controlling the water content to be below 5%, adding magnesium stearate according to the prescription amount, uniformly mixing, and sieving by a 40-mesh sieve for finishing granules;
3. preparation of tofacitinib citrate press-coated sustained-release tablet
Filling 1/2 weight parts of the outer coating layer granules into a 9mm shallow concave die, adding a core, filling 1/2 weight parts of outer coating layer powder around the core, and pressing under a set pressure and time to obtain the tofacitinib citrate press-coated sustained release tablet with the hardness of 106.49N.
Comparative example 5
The formulation of the tofacitinib citrate press-coated tablet of this case is shown in table 11:
table 11 comparative example 5 formulation of tofacitinib citrate compression coated tablet
The present case employs a dry granulation process comprising the steps of:
1. preparation of the core layer
a) Weighing tofacitinib citrate (passing through a 80-mesh screen), microcrystalline cellulose, anhydrous lactose and hydroxymethyl cellulose according to a prescription amount, and uniformly mixing according to an equivalent increasing method;
b) sieving the materials with a 80-mesh sieve, weighing the crospovidone according to the prescription amount in the dry-process whole granules, sieving with a 200-mesh sieve, adding the povidone and the magnesium stearate into the mixture, and uniformly stirring to form intermediate granules;
c) the cores were pressed with a 6mm flat punch and had a hardness of 23.48N.
2. Preparation of the outer coating layer
a) Weighing tofacitinib citrate (passing through a 80-mesh screen), microcrystalline cellulose, anhydrous lactose and hydroxymethyl cellulose according to a prescription amount, and uniformly mixing according to an equivalent increasing method;
b) sieving the materials with a 80-mesh sieve, weighing crospovidone according to the prescription amount by dry-process whole granules, sieving with a 200-mesh sieve, adding the povidone and the magnesium stearate into the mixture, and uniformly stirring to form intermediate granules;
3. preparation of tofacitinib citrate press-coated sustained-release tablet
Filling 1/2 weight parts of the outer coating layer granules into a 9mm shallow concave die, adding a core, filling 1/2 weight parts of outer coating layer powder around the core, and pressing under a set pressure and time to obtain the tofacitinib citrate press-coated sustained release tablet with the hardness of 108.37N.
Examples 15 to 17
The formulation of the tofacitinib citrate compression coated tablet of this example is shown in table 12:
TABLE 12 prescription of Tufacitinib citrate compression-coated tablets in examples 15-17
The tofacitinib citrate press-coated sustained-release tablet of the embodiment 15-17 is prepared by adopting a full-powder direct-pressing preparation process. The preparation method comprises the following steps: as in comparative example 1.
Examples 18 to 20
The formula of the tofacitinib citrate compression-coated tablets in examples 18-20 of the present embodiment is shown in table 13:
TABLE 13 examples 18-20 prescription of tofacitinib citrate press-coated tablets
In the embodiment, the 18-20 tofacitinib citrate press-coating sustained-release tablet adopts a full-powder direct-pressing preparation process. The preparation method comprises the following steps: as in comparative example 1.
Example 21
The formulation of tofacitinib citrate press-coated tablets of this example is shown in table 14:
table 14 example 21 formulation of tofacitinib citrate compression coated tablets
In this example, the tofacitinib citrate press-coated sustained-release tablet adopts a full-powder direct-compression preparation process. The preparation method comprises the following steps: as in comparative example 1.
Test example 1
The above 26 kinds of tofacitinib citrate are coated in slow released tablet and preparation process
XR in vitro cumulative release assay:
the measurement method is as follows:
taking the product, preparing a buffer solution with pH of 6.8 according to a dissolution determination method (a second method of 0931 dissolution and release determination method in accordance with the general rule of the four ministry of China pharmacopoeia 2020 edition) by using 6.805g of anhydrous potassium dihydrogen phosphate, 0.896g of sodium hydroxide and 1L of deionized water respectively, taking 900mL as a dissolution medium at a rotation speed of 50 revolutions per minute, operating according to the method, respectively taking 6mL of the solution after 1, 2,3, 4, 5, 6 and 8 hours, and measuring absorbance. Octadecylsilane chemically bonded silica chromatographic column is adopted, and the mobile phase is 10mmol/L dipotassium hydrogen phosphate (0.5% triethylamine is added, and the pH value is adjusted to 7.0 by phosphoric acid) -acetonitrile (70: 30, v/v); the flow rate is 1.0 mL/min; the column temperature was 35 ℃; the sample injection amount is 10 mu L; detection wavelength: 289 nm.
By f 2 Comparing by using a similarity factor method;
the release results are shown in table 15:
TABLE 15 Release degree results
The results show that: in vitro release similarity f of the example 21 formulation to a reference formulation 2 Above 50, the similarity is good.
The dissolution curves of the tofacitinib citrate press-coated sustained-release tablet obtained in example 21 and the reference preparation in a phosphate buffer solution with the pH value of 6.8 are compared and shown in figure 1, and it can be seen from figure 1 that: example 21 had similar dissolution effect to the reference formulation.
Test example 2
In vivo bioequivalence comparative studies were performed on tofacitinib citrate press-coated sustained release tablets prepared in example 21 with a reference formulation.
Test design and sample collection:
two-preparation double-period random cross self-contrast experimental design is adopted, and the time interval of the two periods is 7 d. Dividing 5 Beagle dogs into two groups randomly, wherein each group comprises 3 and 2 dogs respectively, after a test Beagle dog is fasted for 12 hours, taking 3mL blank plasma before administration, respectively plugging a reference preparation and a test preparation into the epiglottis of the dog, and taking 40mL warm water, respectively taking 3.0mL forearm venous blood after administration for 15min, 30min, 45min, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 10h, 12h, 14h, 16h, 18h, 24h, 30h, 36h and 48h, placing the forearm venous blood in a heparinized centrifugal test tube, placing the blood sample on ice after collection, centrifugally separating plasma within 30 minutes (centrifugal conditions: 4000rpm, 5min, 2-8 ℃), taking a proper amount of upper plasma, and placing the upper plasma in a refrigerator at-20 ℃ for storage.
LC-MS/MS conditions:
chromatographic conditions are as follows: an ACQUITYUPLC BEH C18 column (50 mm. times.2.1 mm, 1.7 μm, Waters Corp., Milford, MA, USA); the mobile phase is a 0.1% aqueous formic acid-acetonitrile system, the mobile phase A is a 0.1% aqueous formic acid solution, and the mobile phase B is an acetonitrile solution. The mobile phase gradient was as shown in Table 16, the flow rate was 0.2mL/min, the column temperature: 35 ℃, sample chamber temperature: 4 ℃, sample introduction: 5 μ L.
The gradient elution procedure is shown in the following table:
TABLE 16 gradient elution procedure
| Analysis time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 5.0 | 95.0 | |
| 1.50 | 95.0 | 5.0 |
| 2.00 | 95.0 | 5.0 |
| 3.00 | 5.0 | 95.0 |
Mass spectrum conditions: waters achittytmtqd triple quadrupole tandem mass spectrometer (Waters corp. manchester, UK); an electrospray ionization (ESI) interface; ESI source positive ionization mode; capillary voltage of 3.0kV, taper hole voltage of 10V, ion source temperature of 100 deg.C, desolvation gas temperature of 400 deg.C, desolvation gas flow rate of 500L/h, taper hole back-blowing gas flow rate of 50L/hr, and scanning mode is Multiple Reaction Monitoring (MRM).
Tofacitinib citrate mass spectrum parameters are given in the following table:
TABLE 17 Mass Spectrometry Condition analysis (IS) of samples and internal standards
The blood sample pretreatment method comprises the following steps:
100 μ L of the plasma sample to be tested was placed in a 1.5mL EP tube, 10 μ L of the internal standard solution (diphenhydramine solution with a concentration of 100 ng/mL) was added, 10 μ L of methanol and 100 μ L of NaOH solution (0.1M) were added, and the mixture was vortexed for 1min to mix well. Add 1mL of extractant ether solvent mixture, vortex for 5min, centrifuge at 12000rpm for 10 min. Precisely absorb 900 μ L of supernatant into a 1.5mL centrifuge tube, and blow-drying with nitrogen at 40 ℃ to remove organic solvent. Adding 100 mu L of methanol into the residue, vortexing for 5min, mixing uniformly, redissolving, freezing and centrifuging at 12000rpm for 10min, taking 50 mu L of supernate as a sample to be detected, and analyzing by UPLC-ESI-MS/MS. And processing the actually measured blood concentration-time data by DAS2.0 software to obtain a series of pharmacokinetic parameters.
The main pharmacokinetic parameters were as follows:
TABLE 18 pharmacokinetic parameters table
| Parameter(s) | Reference formulation | Example 21 | Ratio/%) |
| t 1/2 (h) | 4.44 | 3.54 | 79.86 |
| T max (h) | 3.50 | 3.50 | 100.00 |
| C max (ng·mL -1 ) | 207.79 | 204.67 | 98.49 |
| AUC 0→t (ng·mL -1 ·h) | 1384.27 | 1245.79 | 90.00 |
| AUC 0→∞ (ng·mL -1 ·h) | 1388.53 | 1246.89 | 89.80 |
The results show that: tofacitinib citrate press-coated sustained release tablets prepared in example 21 and process for preparing the same
XR is bioequivalent in vivo.
Using the Origin software for mapping, the in vivo drug administration time profile 2 of the tofacitinib citrate press-coated sustained release tablet of example 21 and the reference preparation was obtained. As can be seen from fig. 2: tofacitinib citrate press-coated sustained release tablets prepared in example 21 and process for preparing the same
XR has a similar in vivo release effect.
In conclusion, granulation is not needed, glyceryl behenate and the like are used as framework materials to prepare the framework type sustained release tablets, the preparation is of an asymmetric double-storage type, burst release is not easy to occur, even if accidental breakage occurs, drug release can be kept unchanged, and the preparation is safe and reliable; the equipment required by the invention is a common core-spun tablet press, and laser drilling equipment is not required, so that the production cost is reduced; the invention has simple production process without needing semipermeable membrane coating, and
XR adopts acetone as solvent to carry out the coating and compares, has avoided the use of organic solvent, has increased the stability of medicine, reduces its toxic and side effect: the invention relates to in vitro release and
good XR similarity, bodyInner and
XR bioequivalence.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. A tofacitinib citrate pressed coating sustained release tablet is characterized by comprising a tablet core layer and an outer coating layer;
the sheet core layer comprises the following raw materials in percentage by mass: 2 to 30 percent of tofacitinib citrate, 10 to 30 percent of framework material, 30 to 80 percent of filler, 0.5 to 2 percent of lubricant, 0.5 to 3 percent of disintegrant and 1.7 to 8 percent of pH regulator;
the outer coating layer comprises the following raw materials in percentage by mass: 1 to 10 percent of tofacitinib citrate, 10 to 50 percent of framework material, 20 to 80 percent of filler, 0.5 to 5 percent of lubricant, 0.5 to 5 percent of disintegrant and 1.7 to 10 percent of pH regulator;
the framework material independently comprises one or more of glyceryl behenate, hydroxyethyl methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, ethyl hydroxyethyl cellulose and xanthan gum;
the pH regulators are all organic acids.
2. The tofacitinib citrate press-coated sustained-release tablet as claimed in claim 1, wherein the mass percentage of the tablet core layer in the tofacitinib press-coated sustained-release tablet is 25-35%, and the mass percentage of the outer coating layer is 65-75%.
3. The tofacitinib citrate press-coated sustained-release tablet as claimed in claim 1, wherein the hardness of the tablet core layer is 20N-35N, and the hardness of the outer coating layer is 90N-120N.
4. The tofacitinib citrate press-coated sustained-release tablet according to any one of claims 1 to 3, wherein the filler independently comprises one or more of lactose, microcrystalline cellulose, starch, dextrin, sucrose, dibasic calcium phosphate and mannitol.
5. The tofacitinib citrate press-coated sustained-release tablet according to any one of claims 1 to 3, wherein the lubricant independently comprises one or more of magnesium stearate, sodium stearyl fumarate, talc, aerosil and polyethylene glycol.
6. The tofacitinib citrate press-coated sustained-release tablet according to any one of claims 1 to 3, wherein the disintegrant independently comprises one or more of croscarmellose sodium, starch, crospovidone, sodium carboxymethyl starch and low substituted hydroxypropylcellulose.
7. The tofacitinib citrate press-coated sustained-release tablet according to any one of claims 1 to 3, wherein the organic acid is a polybasic organic acid; the polybasic organic acid comprises one or more of fumaric acid, citric acid, succinic acid, ascorbic acid, sorbic acid, adipic acid and tartaric acid.
8. The preparation method of tofacitinib citrate press-coated sustained-release tablets as claimed in any one of claims 1 to 7, characterized by comprising the following steps:
mixing the raw materials of the tablet core layer, and pressing to obtain the tablet core layer;
mixing the raw materials of the outer coating layer to obtain outer coating layer mixed powder;
filling the first part of outer coating layer mixed powder into a die, placing the tablet core layer in the middle of the first part of outer coating layer mixed powder, filling the second part of outer coating layer mixed powder, and tabletting to obtain the tofacitinib citrate pressed coating sustained release tablet;
the mass ratio of the first part of outer coating layer mixed powder to the second part of outer coating layer mixed powder is 1: 1.
9. the method according to claim 8, wherein the pressing pressure is 9 to 16kN and the dwell time is 5 to 8 ms.
10. The process according to claim 8, wherein the pressure for tableting is 10 to 26kN and the dwell time is 5 to 8 ms.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210921132.2A CN115068432A (en) | 2022-08-02 | 2022-08-02 | Tofacitinib citrate pressed coating sustained release tablet and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210921132.2A CN115068432A (en) | 2022-08-02 | 2022-08-02 | Tofacitinib citrate pressed coating sustained release tablet and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115068432A true CN115068432A (en) | 2022-09-20 |
Family
ID=83242237
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210921132.2A Pending CN115068432A (en) | 2022-08-02 | 2022-08-02 | Tofacitinib citrate pressed coating sustained release tablet and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115068432A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115887408A (en) * | 2022-11-29 | 2023-04-04 | 江苏慧聚药业股份有限公司 | Pharmaceutical composition and pharmaceutical preparation comprising tofacitinib |
| CN115887408B (en) * | 2022-11-29 | 2024-05-24 | 江苏慧聚药业股份有限公司 | Pharmaceutical compositions and pharmaceutical formulations comprising tofacitinib |
Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110787145A (en) * | 2019-12-17 | 2020-02-14 | 南京康川济医药科技有限公司 | Tofacitinib citrate sustained-release tablet and preparation method thereof |
| CN111184696A (en) * | 2020-02-26 | 2020-05-22 | 江苏艾立康药业股份有限公司 | Tofacitinib citrate sustained-release tablet and preparation method thereof |
| CN112007004A (en) * | 2020-09-17 | 2020-12-01 | 山东鲁抗医药股份有限公司 | Tofacitinib citrate tablet and preparation method thereof |
| CN112587492A (en) * | 2020-12-20 | 2021-04-02 | 武汉中点医药科技有限公司 | Tofacitinib citrate sustained-release tablet with membrane control and framework dual sustained release |
| CN112755000A (en) * | 2021-01-21 | 2021-05-07 | 石药集团欧意药业有限公司 | Tofacitinib citrate sustained-release tablet |
| CN113018273A (en) * | 2019-12-25 | 2021-06-25 | 上海宣泰医药科技股份有限公司 | Solid preparation and preparation method and application thereof |
| CN113069434A (en) * | 2021-03-11 | 2021-07-06 | 绍兴文理学院元培学院 | Tofacitinib citrate controlled-release capsule and preparation method thereof |
| CN113712932A (en) * | 2020-05-25 | 2021-11-30 | 南京帝昌医药科技有限公司 | Tofacitinib citrate osmotic pump tablet and preparation method thereof |
| WO2022022369A1 (en) * | 2020-07-29 | 2022-02-03 | 中国科学院上海药物研究所 | Sustained-release formulation of tofacitinib or salt thereof and preparation method therefor |
| CN114642639A (en) * | 2020-12-18 | 2022-06-21 | 南京佰麦生物技术有限公司 | Tofacitinib citrate sustained-release composition and preparation method thereof |
-
2022
- 2022-08-02 CN CN202210921132.2A patent/CN115068432A/en active Pending
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110787145A (en) * | 2019-12-17 | 2020-02-14 | 南京康川济医药科技有限公司 | Tofacitinib citrate sustained-release tablet and preparation method thereof |
| CN113018273A (en) * | 2019-12-25 | 2021-06-25 | 上海宣泰医药科技股份有限公司 | Solid preparation and preparation method and application thereof |
| CN111184696A (en) * | 2020-02-26 | 2020-05-22 | 江苏艾立康药业股份有限公司 | Tofacitinib citrate sustained-release tablet and preparation method thereof |
| CN113712932A (en) * | 2020-05-25 | 2021-11-30 | 南京帝昌医药科技有限公司 | Tofacitinib citrate osmotic pump tablet and preparation method thereof |
| WO2022022369A1 (en) * | 2020-07-29 | 2022-02-03 | 中国科学院上海药物研究所 | Sustained-release formulation of tofacitinib or salt thereof and preparation method therefor |
| CN112007004A (en) * | 2020-09-17 | 2020-12-01 | 山东鲁抗医药股份有限公司 | Tofacitinib citrate tablet and preparation method thereof |
| CN114642639A (en) * | 2020-12-18 | 2022-06-21 | 南京佰麦生物技术有限公司 | Tofacitinib citrate sustained-release composition and preparation method thereof |
| CN112587492A (en) * | 2020-12-20 | 2021-04-02 | 武汉中点医药科技有限公司 | Tofacitinib citrate sustained-release tablet with membrane control and framework dual sustained release |
| CN112755000A (en) * | 2021-01-21 | 2021-05-07 | 石药集团欧意药业有限公司 | Tofacitinib citrate sustained-release tablet |
| CN113069434A (en) * | 2021-03-11 | 2021-07-06 | 绍兴文理学院元培学院 | Tofacitinib citrate controlled-release capsule and preparation method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115887408A (en) * | 2022-11-29 | 2023-04-04 | 江苏慧聚药业股份有限公司 | Pharmaceutical composition and pharmaceutical preparation comprising tofacitinib |
| CN115887408B (en) * | 2022-11-29 | 2024-05-24 | 江苏慧聚药业股份有限公司 | Pharmaceutical compositions and pharmaceutical formulations comprising tofacitinib |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10912781B2 (en) | Pharmaceutical composition comprising licarbazepine acetate | |
| IL207400A (en) | Composition comprising degarelix for use in the treatment of prostate cancer | |
| KR101853347B1 (en) | Choline alfoscerate-containing tablet and process for preparing the same | |
| CN115068432A (en) | Tofacitinib citrate pressed coating sustained release tablet and preparation method thereof | |
| WO2011005250A1 (en) | Formulations of 6- (5-chloro-2-pyridyl) - 5- [ (4-methyl-1-piperazinyl) carbonyloxy] - 7-0x0-6, 7- dihydro- 5h- phyrrolo [3, 4-b] pyrazine | |
| KR101823071B1 (en) | Process for preparing telmisartan-containing tablets | |
| US20060204571A1 (en) | Stable compositions of bupropion or its pharmaceutically acceptable salts | |
| CN110279666B (en) | Trimetazidine dihydrochloride tablet and preparation method thereof | |
| KR20070002702A (en) | Composition containing clopidogrel free base | |
| EP3603643B1 (en) | Tableted medicinal composition comprising nalfurafine | |
| WO2020111089A1 (en) | Pharmaceutical composition | |
| CN107753446B (en) | Rasagiline tablet and preparation method thereof | |
| US20210346392A1 (en) | Pharmaceutical composition for oral administration | |
| CN113893222B (en) | Pharmaceutical composition and preparation method and application thereof | |
| RU2663691C2 (en) | Pharmaceutical composition of n-(6-phenylhexanoyl)glycyl-l-tryptophan amide with film coating and the method of its production | |
| KR100715354B1 (en) | A stable gabapentin formulation suppressing production of impurities and preparation process thereof | |
| CN101590058B (en) | Medicinal composition containing dihydroergocryptine A mesylate | |
| WO2022155507A1 (en) | Transmucosal dosage forms of brexanolone | |
| CN113440484A (en) | Preparation method of edaravone solid dispersion | |
| WO2019230017A1 (en) | Tablet and production method therefor |
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 |