TR2021018876A2 - TOFASITINIB FILM-COATED TABLET FORMULATIONS WITH IMPROVED DISSOLVING SPEED - Google Patents
TOFASITINIB FILM-COATED TABLET FORMULATIONS WITH IMPROVED DISSOLVING SPEEDInfo
- Publication number
- TR2021018876A2 TR2021018876A2 TR2021/018876A TR2021018876A TR2021018876A2 TR 2021018876 A2 TR2021018876 A2 TR 2021018876A2 TR 2021/018876 A TR2021/018876 A TR 2021/018876A TR 2021018876 A TR2021018876 A TR 2021018876A TR 2021018876 A2 TR2021018876 A2 TR 2021018876A2
- Authority
- TR
- Turkey
- Prior art keywords
- tofacitinib
- film
- weight
- formulations
- coated tablet
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 55
- 239000007941 film coated tablet Substances 0.000 title claims abstract description 23
- 238000009472 formulation Methods 0.000 claims abstract description 47
- 238000004519 manufacturing process Methods 0.000 claims abstract description 31
- 239000004012 Tofacitinib Substances 0.000 claims abstract description 20
- 229960001350 tofacitinib Drugs 0.000 claims abstract description 19
- 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 abstract description 19
- 239000003085 diluting agent Substances 0.000 claims abstract description 18
- 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 claims abstract description 17
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 14
- 239000002270 dispersing agent Substances 0.000 claims abstract description 14
- 239000000945 filler Substances 0.000 claims abstract description 14
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 14
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 14
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 14
- 229960004247 tofacitinib citrate Drugs 0.000 claims abstract description 14
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims abstract description 13
- 229920002785 Croscarmellose sodium Polymers 0.000 claims abstract description 13
- 229960001021 lactose monohydrate Drugs 0.000 claims abstract description 13
- 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 abstract description 12
- 229960001681 croscarmellose sodium Drugs 0.000 claims abstract description 12
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims abstract description 12
- 239000004480 active ingredient Substances 0.000 claims abstract description 11
- 238000007907 direct compression Methods 0.000 claims description 6
- 238000010017 direct printing Methods 0.000 abstract description 15
- 238000000034 method Methods 0.000 description 34
- 238000004090 dissolution Methods 0.000 description 26
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 20
- 239000003826 tablet Substances 0.000 description 16
- 239000013543 active substance Substances 0.000 description 14
- 238000005469 granulation Methods 0.000 description 11
- 230000003179 granulation Effects 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- 235000019359 magnesium stearate Nutrition 0.000 description 10
- 239000000546 pharmaceutical excipient Substances 0.000 description 9
- 229940039887 tofacitinib 5 mg Drugs 0.000 description 8
- 230000008569 process Effects 0.000 description 7
- 239000007916 tablet composition Substances 0.000 description 6
- 238000007908 dry granulation Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 238000005550 wet granulation Methods 0.000 description 5
- 102000015617 Janus Kinases Human genes 0.000 description 4
- 108010024121 Janus Kinases Proteins 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000003204 osmotic effect Effects 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 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 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000000428 dust Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 238000007639 printing Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 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-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 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
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 2
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000001125 extrusion Methods 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 239000007888 film coating Substances 0.000 description 2
- 238000009501 film coating Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 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 description 2
- 229960001375 lactose Drugs 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- 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
- 239000005711 Benzoic acid Substances 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000003951 Erythropoietin Human genes 0.000 description 1
- 108090000394 Erythropoietin Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 229920003091 Methocel™ Polymers 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000003915 air pollution Methods 0.000 description 1
- 229960004977 anhydrous lactose Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 229960003563 calcium carbonate Drugs 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 229920002678 cellulose Chemical class 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 229960005168 croscarmellose Drugs 0.000 description 1
- 238000012864 cross contamination Methods 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 229940095079 dicalcium phosphate anhydrous Drugs 0.000 description 1
- 238000010410 dusting Methods 0.000 description 1
- 229940105423 erythropoietin Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229960002900 methylcellulose Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
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- 150000002894 organic compounds Chemical class 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- -1 polyethylene Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- 229920003124 powdered cellulose Polymers 0.000 description 1
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- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229920003176 water-insoluble polymer Polymers 0.000 description 1
- 229940039916 xeljanz Drugs 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
Mevcut buluş, tofasitinib film kaplı tablet formülasyonu olup, özelliği; etkin madde olarak 5 ağırlıkça % 1-15 oranında tofasitinib sitrat, dolgu maddesi olarak ağırlıkça % 25 - 35 oranında laktoz monohidrat, seyreltici madde olarak ağırlıkça % 40 - 60 oranında mikrokristalin selüloz, dağıtıcı madde olarak ağırlıkça % 1- 4 oranında kroskarmelloz sodyum içermesi ve direkt basım üretim yönteminin kullanılması ile karakterize edilmesidir.The present invention is tofacitinib film-coated tablet formulation and its feature is; It contains 1-15% by weight of tofacitinib citrate as active ingredient, 25-35% by weight of lactose monohydrate as a filler, microcrystalline cellulose 40-60% by weight as a diluent, 1-4% by weight of croscarmellose sodium as a dispersing agent and It is characterized by the use of the direct printing production method.
Description
TARIFNAME GELISTIRILMIS ÇÖZÜNME HIZINA SAHIP TOFASITINIB FILM KAPLI TABLET FORMÜLASYONLARI Teknik Alan Mevcut bulus farmasötik teknoloji alani ile ilgilidir ve gelistirilmis çözünme hizina sahip tofasitinib etkin maddesini içeren film kapli tablet formundaki farmasötik forrnülasyonlari ve üretim teknolojisini tarif etmektedir. Önceki Teknik Tofasitinib etkin maddesi ilk olarak Pfizer firmasina ait EP123583OBI numarali Avrupa patentinde tarif edilmistir. Tofasitinib sitrat tuzunun kimyasal ismi 2-hidr0ksipropan-1,2,3- 1-iIi-3-oksopropionnitrildir. Tofasitinib sitrat tuzunun kimyasal yapisi asagida verilmistir. DESCRIPTION TOFASITINIB FILM COATED WITH IMPROVED DISSOLVING SPEED TABLET FORMULATIONS Technical Area The present invention relates to the field of pharmaceutical technology and has an improved dissolution rate. Pharmaceutical formulations in the form of film-coated tablets containing the active ingredient tofacitinib and describes the production technology. Prior Art The active substance of tofacitinib was first published in Europe with the number EP123583OBI from Pfizer. described in the patent. Chemical name of Tofacitinib citrate salt 2-hydroxypropane-1,2,3- It is 1-yli-3-oxopropionnitrile. The chemical structure of Tofacitinib citrate salt is given below.
Tofasitinib oral bir Janus kinaz (JAK) inhibitörüdür. Günümüzde tofasitinib etkin maddeli ilaçlar romatoit artrit (RA), psöriatik artrit (PSA) ve benzeri romatizmal hastaliklarin tedavisinde kullanilmaktadir. Janus kinazlar (JAKs) hücre membrani üzerinde interferonlar, interlökinler ve eritropoetin gibi sitokin veya büyüme faktörlerinin immun hücre fonksiyonundaki ligand-reseptör etkilesmelerinden dogan sinyalleri ileten hücre içi enzimlerdir. Tofacitinib is an oral Janus kinase (JAK) inhibitor. Today, tofacitinib with active ingredient drugs for rheumatoid arthritis (RA), psoriatic arthritis (PSA) and similar rheumatic diseases used in the treatment. Janus kinases (JAKs) are interferons on the cell membrane, cytokines or growth factors such as interleukins and erythropoietin intracellular that transmits signals arising from ligand-receptor interactions in the are enzymes.
Tofasitinib etkin maddesi uygulama formlarina göre geleneksel fanriasötik uygulamalar ile uyumlu eksipiyanlar ile karisim halinde formüle edilir. Tofasitinib sitrat çözünürlügü yüksek, geçirgenligi düsük olan ve higroskopik olmayan bir moleküldür. Etkin madde konsantrasyonu agirlikça %5 seviyesinde bulunan toz karisima ait çözünme hizi ve final karisim içerik tekdüzeligi sonuçlari; optimize edilmis fonksiyonel kullanim araliklarina bagimliligi yüksek ve riskli olarak degerlendirilmektedir. Bu optimizasyon, uygulanan üretim prosesine ve kullanilan yardimci maddelere aittir. Piyasada halihazirda 5 mg dozunda film kapli tablet formunda Pfizer firmasina ait Xeljanz ismi altinda ürün bulunmaktadir. Bu üründe üretim yöntemi olarak kuru granülasyon yöntemi kullanilmistir. According to the application forms of tofacitinib active substance, with traditional pharmaceutical applications Formulated as a mixture with compatible excipients. Tofacitinib citrate has high solubility, It is a low permeability and non-hygroscopic molecule. Active ingredient concentration Dissolution rate and final mixture content of the powder mixture at the level of 5% by weight uniformity results; highly dependent on optimized functional usage ranges and is considered risky. This optimization depends on the applied production process and the used belong to auxiliary materials. Pfizer is currently available in the form of 5 mg film-coated tablets. There is a product under the name Xeljanz belonging to the company. Dry as a production method for this product The granulation method was used.
Film kapli tablet dozaj formunun hazirlanmasinda kullanilan üretim yöntemi çesitli faktörlere bagli olarak seçilmektedir. Ilaç endüstrisinde en çok kullanilan üretim yöntemleri; direkt baski, yas granülasyon, kuru granülasyon ve eriyik ekstrüsyonu granülasyonudur. Kuru ve yas granülasyonun amaci karisimin akisini iyilestirmek veya basilabilirligini arttirmaktir. Kuru granülasyonla üretimde, baglayici solüsyon veya granülasyon solüsyonu eklenmeden granülasyon ürettiginden asiri tozlanma sonucunda hava kirliligi olasiligi ve toz ile yüksek düzeyde çapraz bulasma olasiligi vardir. Kuru granülasyonun üretim kapasitesinin düsük olmasi, depo alani gerekliligi ve asiri gürültü olusmasi gibi dezavantajlari da mevcuttur. Bir diger sinirlayici faktör ise, içerik tekdüzeligidir; içerik tekdüzeligi olmasa dahi homojen olmayan bilesimler her bir dozaj formunda farkli miktarda etkin madde bulunmasiyla sonuçlanabilmektedir. Yas granülasyon yöntemi ile üretim prosesi granüller basilmadan önce mutlaka kurutma basamagi içermelidir. Kurutma islemi ekonomik açidan maliyetli olmakla beraber, kurutma süresi ve kurutma sicakligi bakimindan oldukça zahmetli bir süreçtir. Bu üretimde kullanilan baglayici madde çözeltisinin viskozitesi, sicakligi, ilave edilme hizi, granülün yapisini ve özelliklerini etkilerken; kurutma süresi ve nem orani da ürün kalitesini etkileyebilmektedir. Eriyik ekstrüsyonu granülasyonu yöntemi de üretim prosesi açisindan fazla basamak içermektedir ve yüksek maliyetlidir. The production method used in the preparation of the film-coated tablet dosage form depends on various factors. is selected accordingly. The most used production methods in the pharmaceutical industry; direct print, wet granulation, dry granulation and melt extrusion granulation. dry and wet The purpose of granulation is to improve the flow of the mixture or to increase its compressibility. Dry in production by granulation, without adding binder solution or granulation solution Since it produces granulation, the possibility of air pollution as a result of excessive dusting and high dust There is a high probability of cross-contamination. Low production capacity of dry granulation It also has disadvantages such as the need for storage space and excessive noise. One the other limiting factor is content uniformity; homogeneous even without content uniformity non-compounds with different amounts of active ingredient in each dosage form. can result. The production process with the wet granulation method is before the granules are printed. must necessarily include a drying step. While the drying process is economically costly, However, it is a very laborious process in terms of drying time and drying temperature. This viscosity, temperature, addition speed of the binder solution used in production, while affecting the structure and properties of the granule; drying time and humidity rate also affect the product quality. can affect. The melt extrusion granulation method is also important in terms of the production process. involves many steps and is costly.
Tablet üretim yönteminde, üretim öncesinde uygulanan granülasyon islemleri, tablet formülasyonunda kullanilan en yaygin tekniklerden biri olmasina karsin bu teknikte, basilaeak olan toz kümesinin partikül özelliklerinin olabildigince yakin duruma getirilmesi gerekmektedir. Heterojen partikül büyüklügünü ve dagilimini engellemek için granülasyonun her asamasinda islem akisinin kontrol altinda tutulmasi islem süresini uzatmakta ve enerji kayiplarina neden olmaktadir. Direkt basim, isiya, neme hassas ve uçuculuk gösteren maddelerin kuru ve yas granülasyonda açiga çikan problemlerini engelleyebilir. In the tablet production method, the granulation processes applied before the production Although it is one of the most common techniques used in the formulation of Bringing the particle properties of the dust cluster to the closest possible required. Granulation to prevent heterogeneous particle size and dispersion. Keeping the process flow under control at every stage prolongs the process time and saves energy. causes losses. Sensitive to direct compression, heat, humidity and volatile It can prevent the problems of substances in dry and wet granulation.
Mevcut bulusun bir unsuru olarak formülasyon direkt basim yöntemi ile hazirlanmistir. Direkt basim uygulamasi, yas granülasyon yönteminde oldugu gibi nemlendirme, isi ve yüksek basinç gibi islemleri gerektirmez. Yas granülasyonda tabletlemede uygulanan nem ve isi etkin maddelerin stabilitesi için uygun olmamakta ve tabletlerin hazirlanmasinda islem basamaklarinin çok olmasi, tablet özelliklerinin seriden seriye degisiklik göstermesi olasiligini arttirmaktadir. Direkt basim yöntemiyle, daha az ekipman kullanilarak ve daha az enerji harcanarak, diger yöntemlere göre daha kisa sürede tablet üretimi yapilabilmektedir. Maliyeti düsük ve uygulamasi kolay bir yöntem olan direkt basim yöntemi ile üretim ve ambalajlamaya dayanikli, yeterli sertlige sahip formülasyonlar elde edilmektedir. Ayrica, granülasyon yönteminde karsilasilan bir sorun olan impürite olusumu, dissolüsyon hizlarinda düsüse neden olmaktadir. Direkt basim yöntemiyle hazirlanan formülasyonlar ile, stabilite testlerinde daha iyi dagilma zamani ve dissolüsyon profilleri gösteren gelistirilmis çözünme hizina sahip tofasitinib film kapli tablet forrnülasyonlari elde edilmistir. As an element of the present invention, the formulation was prepared by the direct compression method. Direct compression application, moistening, heat and high pressure as in the wet granulation method does not require such actions. Moisture and heat applied in tableting in wet granulation are effective. not suitable for the stability of substances and the process in the preparation of tablets The fact that there are many steps indicates that the tablet features may vary from series to series. is increasing. With the direct printing method, using less equipment and less energy tablet production can be done in a shorter time compared to other methods. cost production and packaging with the direct printing method, which is a low and easy-to-apply method. durable, adequate hardness formulations are obtained. Also, granulation Impurity formation, which is a problem encountered in the method, causes a decrease in dissolution rates. is happening. With formulations prepared by direct compression method, stability tests are more with improved dissolution rate showing good disintegration time and dissolution profiles Tofacitinib film-coated tablet formulations were obtained.
Direkt baski yöntemi, üretim yönteminin basit ve ekonomik olmasindan dolayi en sik tercih edilen tablet üretim yöntemlerinden biridir. Direkt baski yöntemi, formülasyona giren etkin madde ve yardimci maddelerin karistirilip dogrudan tablet sekline getirilmesi esasina dayanmaktadir. Isiya, neme hassas maddeler ile uçucu özellik gösteren maddeler için en uygun tablet hazirlama yöntemidir. Direkt basimda kullanilan yardimci maddeler, istenen akis ve basilabilirligi saglar. En yaygin kullanilan dolgu maddeleri ve seyrelticiler; SUSUZ laktOZ, laktoz, sorbitol, mannitol, modifiye nisastalar, mikrokristalin selüloz. toz edilmis selüloz, dibazik kalsiyum fosfat, laktoz monohidrat ve kalsiyum karbonattir. Mevcut bulusta dolgu maddesi olarak laktoz monohidrat kullanilirken seyreltici olarak mikrokristalin selüloz kullanilmistir. The direct printing method is the most common choice because the production method is simple and economical. It is one of the tablet production methods. The direct printing method is the active ingredient entering the formulation. on the basis of mixing substances and auxiliary substances and bringing them directly into tablets. is based on. It is most suitable for heat, moisture sensitive substances and volatile substances. tablet preparation method. Excipients used in direct printing, desired flow and provides printability. The most commonly used fillers and diluents; Anhydrous lactose, lactose, sorbitol, mannitol, modified starches, microcrystalline cellulose. powdered cellulose, dibasic calcium phosphate, lactose monohydrate and calcium carbonate. filler in the present invention While lactose monohydrate was used as the diluent, microcrystalline cellulose was used.
Yapilan denemelerde, laktoz monohidrat ve mikrokristalin selüloz kullanimi ile diger dolgu maddelerine ve seyrelticilere kiyasla daha kisa bir dagilma süresine sahip gelistirilmis çözünme hizina sahip film kapli tablet formülasyonlari elde edilmistir. In the experiments, lactose monohydrate and microcrystalline cellulose were used and other filling materials were used. Improved dissolution with a shorter dispersion time compared to solvents and diluents Film-coated tablet formulations with high speed were obtained.
Bir diger yardimci madde dagiticilardir. Dagiticilar, mide-barsak kanalinda tabletin dagilmasim ve ilacin salimini kolaylastirmak amaciyla formülasyona ilave edilen maddelerdir. Örnek olarak, misir ve patates nisastasi, kroskarmelloz sodyum, sodyum aljinat, metil selüloz ve hidroksipropil metil selüloz verilebilir. Mevcut bulusta dagitici madde olarak kroskarmelloz sodyum kullanilmistir. Formülasyona roskarmelloz sodyum ilavesiyle, en uygun dissolüsyon sonucunu veren fiilm kapli tablet ürünleri elde edilmistir. Another auxiliary substance is dispersants. Distributors, disintegration of the tablet in the gastrointestinal tract and substances added to the formulation to facilitate the release of the drug. Example as corn and potato starch, croscarmellose sodium, sodium alginate, methyl cellulose and hydroxypropyl methyl cellulose can be given. Croscarmellose as dispersant in the present invention sodium is used. By adding roscarmellose sodium to the formulation, optimal dissolution Film-coated tablet products giving the result were obtained.
Kaydirici madde olarak lubrikantlar ise, yapismayi önleyici özellik göstererek, toz partikülleri arasindaki sürtünmeyi azaltmak, tabletin basimini ve kaliptan atilmasini kolaylastirmak amaciyla ilave edilir. Talk, magnezyum stearat, stearik asit, hidroj ene bitkisel yaglar, polietilen gIIkOI ve magnezyum stearat yaygin olarak kullanilan kaydiricilar arasinda yer alir. Mevcut bulusa konu lubrikant olarak magnezyum stearat kullanilip, üretim esnasinda karsilasilan önemli bir problem olan aktif madde partiküllerinin birbirine yapismasi gibi sorunlarin yasanmadigi gelistirilmis çözünme hizina sahip tablet formülasyonlari elde edilmistir. Lubricants as a lubricant, by showing anti-adhesion properties, reduce dust particles. to reduce the friction between is added for the purpose. Talc, magnesium stearate, stearic acid, hydrogenated vegetable oils, polyethylene gIIkOI and magnesium stearate are among the widely used lubricants. Available Magnesium stearate is used as the lubricant, which is the subject of the invention, and problems such as sticking of active substance particles to each other, which is an important problem. Tablet formulations with improved dissolution rate were obtained.
Teknikte bilinen, etkin madde olarak tofasitinib içeren film kapli tablet formülasyonlari asagida verilmistir. Belirtilen patentler ve piyasada bulunun ürünler göz önüne alindiginda, gelistirilmis çözünme hizina sahip film kapli tablet formülasyonlarina ihtiyaç oldugu görülmektedir. Below are the film-coated tablet formulations known in the art containing tofacitinib as an active ingredient. given. Considering the patents mentioned and products available on the market, the developed It is seen that there is a need for film-coated tablet formulations with dissolution speed.
E P2968155 B 1 numarali Pfizer firmasina ait patentte, günde bir kez alinan farmasötik bir dozaj formu tarif edilmistir. Patentte, tofasitinib ya da farmasötik olarak esdeger tuzu ve tasiyici içeren, uygun osmotik basinç kosullari altinda hazirlanan sürekli salimli bir tablet forrnülasyonu açiklanmaktadir. Forrnülasyon çekirdek kisminda yer alan tofasitinib ve selüloz türevi içeren suda çözünmeyen polimerle kapli yari geçirgen bir zar içeren sürekli salimli bir dozaj fomudur. E P2968155 B Pfizer patent 1 describes a pharmaceutical dosage taken once a day. form is described. In the patent, tofacitinib or its pharmaceutically equivalent salt and carrier A sustained-release tablet formulation prepared under favorable conditions of osmotic pressure containing is explained. Containing tofacitinib and cellulose derivative in the formulation core It is a sustained release dosage form containing a semipermeable membrane coated with a water-insoluble polymer.
Söz konusu dozaj formu, ozmotik basinç ile öncelikli olarak tofasitinib salinimini saglayan ekstrüde edilebilir çekirdek sistemi olan tablet veya kapsüldür. Tofasitinib içeren bilesim, agirlikça %2 - 20'si arasinda degisen miktarda Viskozlastirici polimerleri ve agirlikça %60 - 85 arasinda degisen ozmotik olarak aktif ajanlari içermektedir. Elde edilen Tofasitinib tablet ürünlerinda; 1 saatte tofasitinibin en fazla %30'u çözünürken, 2.5 saatte % 35'inden daha fazla tarif edilen formülasyonda tofasitinib veya bunun farmasötik olarak kabul edilebilir bir tuzu kullanilarak %2 ile %20 oraninda polietilen oksit (PEOl ve hidroksietil selüloz (HECl gibi viskozlastirici polimerler; %60 ile %85 araliginda ozmotik olarak aktif ajanlar kullanilmistir. The dosage form in question provides a primary release of tofacitinib by osmotic pressure. It is a tablet or capsule with an extrudable core system. Composition containing tofacitinib, Viscosifier polymers in varying amounts between 2 - 20% by weight and 60 - 85% by weight It contains osmotically active agents ranging from The resulting Tofacitinib tablet in its products; Up to 30% of tofacitinib dissolves in 1 hour, while more than 35% in 2.5 hours tofacitinib or a pharmaceutically acceptable salt thereof in the formulation described 2% to 20% polyethylene oxide (PEOl and hydroxyethyl cellulose (such as HECl) viscosifying polymers; Between 60% and 85% of osmotically active agents have been used.
Ozmotik olarak aktif ajanlar sodyum klorür, potasyum klorür gibi suda çözünür tuzlari; laktoz, mannitol ve sorbitol gibi sekerleri; askorbik asit, benzoik asit ve sitrik asit gibi organik asitleri ve düsük molekül agirlikli organik bilesikleri içermektedir. Söz konusu patentte, kontrollü salim yapabilen çift katmanli ozmotik tablet formülasyonlari açiklanmistir. Çift katmanli Ozmotik tabletler, çift fazli bir üretim yöntemi ve direkt baski teknolojisi ile üretilir. B urada çift fazli olarak belirtilen tablette, aktif tabaka olan birinci katmanda tofasitinib sitrat etkin maddesi, polietilen oksit ve magnezyum stearat; ikinci katmanda polietilen oksit, sodyum klorür, boyar madde ve magnezyum stearat kullanilmistir. Kaplama içeriginde selüloz asetat, hidroksipropil selüloZ, aseton ve saf su mevcuttur. Patentte açiklanan hidrofilik matriks kontrollü salim tablet formülasyonlarinda ise tofasitinib sitrat etkin maddesi agirlikça %7.1 oraninda kullanilirken, kontrollü salimi saglamak için hidroksipropil metilselüloz türevlerinden olan Methocel polimer maddesi agirlikça %30 oraninda, dolgu maddesi olarak kullanilan laktoz monohidrat agirlikça üzere formülasyon içerisinde iki kez kullanilmistir. Patentte verilen formülasyon örneklerinde, kuru granülasyon yöntemi kullanilarak üretim yapildigi açiklanmistir, Verilen örnekler dikkate alindiginda tofasitinib sitrat etkin maddesi içeren formülasyonlarin kuru granülasyonla üretimi gerek zaman gerek kullanilan ekipman ve yardimci maddelerin maliyeti açisindan üretimi daha zor görünmekte ve ürün stabilitelerinde sikintilar yasanmaktadir. Belirtilen patentler ve piyasada bulunun ürünler göz önüne alindiginda, gelistirilmis çözünme hizina sahip film kapli tablet formülasyonlarina ihtiyaç oldugu görülmektedir. Direkt salimli tablet formülasyonlarinin en eski ve en sik kullanilan ilaç salim mekanizmasi oldugu bilinmekle beraber, hasta uyuncu açisindan da en etkili ilaç salimi oldugu bilinmektedir. Bu nedenle mevcut bulusta, direkt salim etkili tablet formülasyonlari direkt basim yöntemi ile üretilmistir. Mevcut bulusta, uygulanan direkt basim yöntemi, kuru granülasyon yöntemine kiyasla etkin madde ve yardimci maddenin kati partiküllere ait yüzey spesifik özelliklerinin degismemesi nedeni ile proses tekrarlanabilirligi yönünden daha avantajli ve daha az zaman gerektiren bir üretim metodudur. Direkt basim yöntemi ile hedeflenen, gelistirilmis partiküler akis özelligine, optimize edilmis yardimci madde kon santrasyonuna, karisim tekdüzeligi özelligine ve referans ürüne benzer çözünme hizi profili sahip ürün eldesidir. Piyasada hali hazirda bulunan tablet forrnülasyonlarinin dissolüsyon profilindeki çözünmeyi arttirmak, ayni zamanda baski esnasinda yasanan çekirdek tablet yüzeyinde matlasma ve kopmayi engellemek amaciyla önceki teknikte bilinen formülasyonlar yerine yenilikçi formülasyonlara ihtiyaç duyulmustur. Bu baglamda direkt basim yöntemi kullanilarak hazirlanan mevcut bulusumuzda film kaplama islemi yapilmasiyla hem ürünün stabilitesi arttirilmis hem de nemden korumasi gerçeklestirilmistir Çalismalarimiz sonucu, sasirtici bir sekilde, direkt basim yöntemiyle hazirlanan ve etkin madde olarak agirlikça % 1-15 oraninda tofasitinib Sitrat, dolgu maddesi olarak agirlikça % 25 - 35 oraninda laktoz monohidrat, seyreltici madde olarak agirlikça % 40 - 60 oraninda mikrokristalin selüloz, dagitici olarak agirlikça % 1 - 4 oraninda kroskarmelloz sodyum içeren formülasyonlar ile en uygun dissolüsyon profiline sahip tofasitinib film kapli tablet ürünlerinin elde edildigi bulunmustur. Osmotically active agents include water-soluble salts such as sodium chloride, potassium chloride; lactose, sugars such as mannitol and sorbitol; organic acids such as ascorbic acid, benzoic acid and citric acid and low molecular weight organic compounds. In the patent in question, controlled Two-layer osmotic tablet formulations capable of releasing have been described. double layer Osmotic tablets are produced with a dual-phase production method and direct printing technology. couple here In the tablet indicated as phased, the active substance of tofacitinib citrate in the first layer, which is the active layer, polyethylene oxide and magnesium stearate; polyethylene oxide, sodium chloride, dye in the second layer substance and magnesium stearate were used. Coating content of cellulose acetate, hydroxypropyl Cellulose, acetone and pure water are available. Hydrophilic matrix controlled release tablet described in the patent In its formulations, the active ingredient of tofacitinib citrate is used at a rate of 7.1% by weight, Methocel polymer from hydroxypropyl methylcellulose derivatives to provide controlled release lactose monohydrate used as filler, 30% by weight It was used twice in the formulation. In the formulation examples given in the patent, It is explained that the production is made using the dry granulation method, Considering the examples given, formulations containing the active ingredient tofacitinib citrate The production of dry granulation requires both time and equipment and auxiliary materials. It seems more difficult to produce in terms of cost and problems in product stability is being made. Considering the patents mentioned and products available on the market, There is a need for film-coated tablet formulations with improved dissolution rates. is seen. The oldest and most commonly used drug release formulations of direct-release tablet formulations Although it is known that it has a mechanism of action, it is also the most effective drug release in terms of patient compliance. known. Therefore, in the present invention, direct-release tablet formulations It is produced by the printing method. In the present invention, the applied direct printing method is dry. the surface of the solid particles of the active substance and excipient compared to the granulation method more in terms of process reproducibility due to the fact that its specific properties do not change. It is an advantageous and less time-consuming production method. By direct printing method targeted, improved particulate flow, optimized excipient concentration, mixture uniformity, and dissolution rate profile similar to the reference product product is obtained. Dissolution of tablet formulations currently available in the market to increase the dissolution in the profile, at the same time, the core tablet experienced during printing formulations known in the prior art to prevent matting and breaking on the surface. Instead, innovative formulations are needed. In this context, the direct printing method In our present invention, which is prepared by using the film coating process, both the product its stability has been increased and its protection from moisture has been realized. Surprisingly, as a result of our studies, the active substance prepared by the direct printing method and 1-15% by weight tofacitinib Citrate, 25-35% by weight as filler lactose monohydrate, 40-60% by weight as diluent microcrystalline cellulose, containing 1 - 4% by weight croscarmellose sodium as a dispersant formulations and tofacitinib film-coated tablet products with the most suitable dissolution profile. has been found to be obtained.
Bulusun detayli olarak açiklanmasi Mevcut bulus, tofasitinib film kapli tablet formülasyonu olup, özelligi; etkin madde olarak agirlikça % 1-15 oraninda tofasitinib sitrat, dolgu maddesi olarak agirlikça % 25 - 35 oraninda dagitici madde olarak agirlikça % 1- 4 Oraninda kroskarmelloz sodyum içermesi ve direkt basim üretim yönteminin kullanilmasi ile karakterize edilmesidir. Detailed description of the invention The present invention is a film-coated tablet formulation of tofacitinib, and its feature is; as active ingredient 1-15% by weight tofacitinib citrate, 25-35% by weight as filler Containing 1-4% croscarmellose sodium by weight as a dispersant and direct compression characterized by the use of the production method.
Tablo 1,de verilen örnekler mevcut bulusu detayli olarak açiklamak üzere verilmistir, ancak bulusun kapsami bu örneklerle sinirli degildir. The examples given in Table 1 are given to illustrate the present invention in detail, but The scope of the invention is not limited to these examples.
Mevcut bulusa uygun tofasitinib 5 mg film kapli tablet fonnülasyonuna ait etkin madde ve yardimci maddelerin miktarlari Tablo 1” de verilmistir. Formülasyonun üretim yöntemi olarak direkt basim yöntemi uygulanmistir. The active substance of the formulation of tofacitinib 5 mg film-coated tablets according to the present invention and The amounts of excipients are given in Table 1. As the production method of the formulation Direct printing method was used.
Tablo 1. Bulusa uygun Tofasitinib 5 mg film kapli tablet formülasyonlari Bilesenler Birim formül (% } Etkin madde Örnek 1 Tofasitinib sitrat % 1- 15 Yardimci maddeler Laktoz monohidrat % 25 - 35 Mikrokristalin Selüloz % 40 - 60 Kroskarmelloz sodyum % 1 - 4 Magnezyum stearat % 0.5 - 2.5 Opadry Beyaz % 2 -5 Saf Su y.m. Table 1. Tofacitinib 5 mg film-coated tablet formulations according to the invention Components Unit formula (% } Active substance Example 1 Tofacitinib citrate 1% to 15% Excipients Lactose monohydrate 25 - 35% Microcrystalline Cellulose % 40 - 60 Croscarmellose sodium 1% - 4% Magnesium stearate 0.5 - 2.5% Opadry White 2 -5 % Pure Water y.m.
Mevcut bulusa uygun film kapli tablet formülasyonunun hazirlanmasinda kullanilan üretim yöntemi asagidaki basamaklari içermektedir; l. Tofasitinib Sitrat, mikrokristalin selüloz, laktoz monohidrat ve kroskarmelloz sodyum ile beraber elenip homojen olarak karistirilir. 2. Hazirlanan bulk`in üzerine magnezyum stearat eklenir ve karistilir. 3. Hazirlanan toz karisim tablet baski makinesinde spesifikasyonlara uygun olarak basilir. 4. Basilan tabletler film kaplama makinesinde spesifikasyonlara uygun olarak kaplanir. Örnek 1`den farkli olarak formülasyonda dolgu maddesi ve seyreltici miktarlari farkli yüzde araliklarinda kullanilmistir. Dolgu maddesi olarak laktoz monohidrat orani % 10 - 20, seyreltici olarak mikrokristalin selüloz orani % 60 - 90 olarak gelistirilen Örnek 2 formülasyonlarinda üretim yöntemi olarak direkt basim üretim yöntemi kullanilmistir. Tablo 2.”de dolgu maddesi ve seyreltici miktarlari Örnek l.°den farkli olarak kullanilan tofasitinib 5 mg film kapli tablet formülasyonlari verilmistir. Production used in the preparation of the film-coated tablet formulation according to the present invention method includes the following steps; l. Tofacitinib Citrate, microcrystalline cellulose, lactose monohydrate and croscarmellose sodium It is sieved together and mixed homogeneously. 2. Magnesium stearate is added to the prepared bulk and mixed. 3. The powder mixture prepared is printed on the tablet printing machine in accordance with the specifications. 4. The printed tablets are coated in the film coating machine in accordance with the specifications. Unlike Example 1, the amount of filler and diluent in the formulation is different. used in the range. The ratio of lactose monohydrate as a filler is 10 - 20%, diluent In Example 2 formulations developed as a microcrystalline cellulose ratio of 60 - 90 % The direct printing production method was used as the production method. Filling material in Table 2. and diluent amounts Tofacitinib 5 mg film-coated tablet used different from Example 1. formulations are given.
Tablo 2. Dolgu maddesi ve seyreltici miktarlari Örnek lIden farkli olarak kullanilan Tofasitinib 5 mg film kapli tablet formülasyonu Bilesenler Birim formül (% ] Etkin madde Örnek 1 Tofasitinib sitrat % 1- 15 Yardimci maddeler Laktoz monohidrat % 10 - 20 Mikrokristalin Selüloz % 60 - 90 Kroskarmelloz sodyum % 1 - 4 Magnezyum stearat % 0.5 , 2.5 Opadry Beyaz % 2 -5 Saf Su y.m. Örnek 1`den farkli olarak, seyreltici ve dagitici miktarlari degistirilmistir. Seyreltici olarak mikrokristalin selüloz orani % 60 - 90 ve dagitici olarak kroskarmelloz sodyum orani % 4 - 9 olarak gelistirilen Örnek 3 formülasyonlarinda üretim yöntemi olarak direkt basim üretim yöntemi kullanilmistir. Tablo 3.”te seyreltici ve dagitici miktarlari Örnek 1.7den farkli olarak kullanilan tofasitinib 5 mg film kapli tablet formülasyonlari verilmistir. Table 2. Amounts of filler and diluent. Tofacitinib 5 mg film-coated tablet formulation Components Unit formula (%] Active substance Example 1 Tofacitinib citrate 1% to 15% Excipients Lactose monohydrate 10 - 20% Microcrystalline Cellulose 60 - 90 % Croscarmellose sodium 1% - 4% Magnesium stearate 0.5% , 2.5 Opadry White 2 -5 % Pure Water y.m. Unlike Example 1, the diluent and dispersant amounts were changed. As a diluent microcrystalline cellulose 60 - 90% and croscarmellose sodium 4 - 9% as dispersant Direct printing production as a production method in Example 3 formulations developed as method has been used. In Table 3, the diluent and dispersant amounts are different from Example 1.7. Tofacitinib 5 mg film-coated tablet formulations used were given.
Tablo 3. Seyreltici ve dagitici miktarlari Örnek lfden farkli olarak kullanilan Tofasitinib 5 mg Bilesenler Birim formül (% ] Etkin madde Örnek 1 Tofasitinib sitrat % 1- 15 Yardimci maddeler Laktoz monohidrat % 25 - 35 Mikrokristalin Selüloz % 60 - 90 Kroskarmelloz sodyum % 4 - 9 Magnezyum stearat % 0.5 - 2.5 Opadry Beyaz % 2 - 5 Saf Su y.m. Örnek l”den farkli olarak formülasyonda farkli oranlarda dolgu maddesi, seyreltici ve dagitici kullanilmistir. Dolgu maddesi olarak Iaktoz monohidrat % 10-20, seyreltici olarak mikrokristalin selüloz orani % 60-90 ve dagitici olarak kroskarmelloz sodyum orani % 4-9 olarak gelistirilen Örnek 4 formülasyonlarinda üretim yöntemi olarak direkt basim üretim yöntemi kullanilmistir. Tablo 3.”te dolgu maddesi, seyreltici ve dagitici miktarlari Ömek1.°den farkli olarak kullanilan Tofasitinib 5 mg film kapli tablet formülasyonlari verilmistir. Table 3. Amounts of diluent and dispersant Tofacitinib 5 mg used different from Example l Components Unit formula (%] Active substance Example 1 Tofacitinib citrate 1% to 15% Excipients Lactose monohydrate 25 - 35% Microcrystalline Cellulose 60 - 90 % Croscarmellose sodium 4 - 9% Magnesium stearate 0.5 - 2.5% Opadry White 2 - 5 % Pure Water y.m. Different from Example 1, different ratios of filler, diluent and dispersant in the formulation used. Iactose monohydrate 10-20% as a filler, as a diluent microcrystalline cellulose 60-90% and croscarmellose sodium 4-9% as dispersant Direct printing production as a production method in Example 4 formulations developed as method has been used. The amounts of filler, diluent and dispersant in Table 3 are from Example1. Tofacitinib 5 mg film-coated tablet formulations used differently were given.
Tablo 4. Dolgu maddesi, seyreltici ve dagitici miktarlari Örneklfden farkli olarak kullanilan Tofasitinib 5 mg film kapli tablet formülasyonu Bilesenler Birim formül (% l Etkin madde Örnek 1 Tofasitinib sitrat % 1- 15 Yardimci maddeler Laktoz monohidrat % 10 - 20 Mikrokristalin Selüloz % 60 - 90 Kroskarmelloz sodyum % 4 - 9 Magnezyum stearat % 0.5 , 2.5 Opadry Beyaz % 2 -5 Saf Su y.m. Table 4. Amounts of filler, diluent and dispersant Used different from the example Tofacitinib 5 mg film-coated tablet formulation Components Unit formula (% l Active substance Example 1 Tofacitinib citrate 1% to 15% Excipients Lactose monohydrate 10 - 20% Microcrystalline Cellulose 60 - 90 % Croscarmellose sodium 4 - 9% Magnesium stearate 0.5% , 2.5 Opadry White 2 -5 % Pure Water y.m.
Yapilan çalismalar sonucunda gelistirilen tüm örneklerin dissolüsyon analizleri ve fl-f2 analizleri gerçeklestirilmistir. Tablo 5.°de deneme ürünlerine ait dissolüsyon analizi ve fl-f2 analiz sonuçlari verilmistir. Dissolution analyzes of all samples developed as a result of the studies and fl-f2 analyzes were carried out. Dissolution analysis of the trial products and fl-f2 in Table 5. analysis results are given.
Tablo 5: Tofasitinib film kapli tablet fonnülasyonu örnekleri için dissolüsyon ve fl-f2 analiz sonuçlari Tofasitinib Sitrat Dissolüsyon % Örnekler pH 6.8 fosfat USP , 900 RPM, 100 ml. pedal *Avrupa Farmakopesinde dissolüsyön spesitîkasyonu “30 dakika sonunda en az % ” Olarak belirtilmistir. Table 5: Dissolution and fl-f2 analysis for Tofacitinib film-coated tablet formulation samples results Tofacitinib Citrate Dissolution % Examples pH 6.8 phosphate USP, 900 RPM, 100 ml. pedal *The dissolution specification in the European Pharmacopoeia is “at least % after 30 minutes” specified.
Fark Etkeni (Difference Factor): Test ürünü ile referans ürün arasindaki farkliligi belirtir. Difference Factor: It indicates the difference between the test product and the reference product.
Asagidaki yöntemle hesaplanan parametre. fl ile gösterilmektedir: 1 Z ::IR' Benzerlik Etkeni (Similarity factor): Test ürünü ile referans ürün arasindaki benzerligi belirtir. Parameter calculated by the following method. denoted by fl: 1 Z ::IR' Similarity Factor: It indicates the similarity between the test product and the reference product.
Asagidaki yöntemle hesaplanan parametre, f2 ile gösterilmektedir: f2 :50 log i 1+;Z:i(Ri _Tir Iki formülasyonun çözünme oranlari arasinda benzerlikten bahsedebilmek için fl degerinin O'a; f2 degerinin de lOO'e yakin olmasi gerekmektedir. Genellikle fl 'in 15'den küçük (0-15] ve f2' nin de 50'den büyük (50-100) olmasi yeterli görülmektedir. The parameter calculated by the following method is denoted by f2: f2 : 50 logi 1+;Z:i(Ri _Tir In order to talk about the similarity between the dissolution rates of the two formulations, the value of fl should be 0; The f2 value should also be close to 100. Usually fl 's less than 15 (0-15] and f2's It is considered sufficient to be greater than 50 (50-100).
Dissolüsyon analiz sonuçlari ve fl-I2 degerleri incelendiginde; en uygun dissolüsyon sonucunu ve fl-f2 degerlerini veren formülasyonlarin Örnek 1 formülasyonlari oldugu görülmektedir. Örnek 2 formülasyonunda dissolüsyon sonuçlari yüksek çikmasina ragmen fl-I2 degerleri uygun çikmamistir. Örnek 3 formülasyonlarinin dissolüsyon ve f1-f2 sonuçlari gerekli spesifikasyonlari saglamasina ragmen Örnek l'e kiyasla daha düsük sonuçlar vermistir. Örnek 4 formülasyonlari Avrupa Farmakopesi dissolüsyon spesifikasyonu olarak belirtilen kriterlere göre, 30 dakika sonunda en az % 80.0 dissolüsyon kriterini saglamamistir. When dissolution analysis results and fl-I2 values are examined; best dissolution result It is seen that the formulations giving the values of and fl-f2 are Example 1 formulations. Although dissolution results were high in Example 2 formulation, fl-I2 values were appropriate. it didn't come out. Dissolution and f1-f2 results required specifications of Example 3 formulations However, it gave lower results compared to Example 1. Example 4 formulations 30 minutes, according to the criteria specified as the European Pharmacopoeia dissolution specification. did not meet the dissolution criteria of at least 80.0% at the end.
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