EP4251271A1 - Direct compression method for non-micronised apixaban formulations - Google Patents
Direct compression method for non-micronised apixaban formulationsInfo
- Publication number
- EP4251271A1 EP4251271A1 EP20963793.3A EP20963793A EP4251271A1 EP 4251271 A1 EP4251271 A1 EP 4251271A1 EP 20963793 A EP20963793 A EP 20963793A EP 4251271 A1 EP4251271 A1 EP 4251271A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- pharmaceutical composition
- solid oral
- oral pharmaceutical
- composition according
- apixaban
- 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
- QNZCBYKSOIHPEH-UHFFFAOYSA-N Apixaban Chemical compound C1=CC(OC)=CC=C1N1C(C(=O)N(CC2)C=3C=CC(=CC=3)N3C(CCCC3)=O)=C2C(C(N)=O)=N1 QNZCBYKSOIHPEH-UHFFFAOYSA-N 0.000 title claims abstract description 81
- 229960003886 apixaban Drugs 0.000 title claims abstract description 79
- 238000000034 method Methods 0.000 title claims abstract description 31
- 238000007907 direct compression Methods 0.000 title claims abstract description 22
- 239000000203 mixture Substances 0.000 title claims description 47
- 238000009472 formulation Methods 0.000 title description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 24
- 239000002245 particle Substances 0.000 claims abstract description 23
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 239000007787 solid Substances 0.000 claims description 29
- 239000008203 oral pharmaceutical composition Substances 0.000 claims description 25
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 16
- 239000000843 powder Substances 0.000 claims description 15
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 14
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 14
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 13
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 13
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 13
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 13
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 claims description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- 239000000314 lubricant Substances 0.000 claims description 9
- 239000004094 surface-active agent Substances 0.000 claims description 9
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 8
- 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 8
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 8
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 8
- 239000007884 disintegrant Substances 0.000 claims description 8
- 235000019359 magnesium stearate Nutrition 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- 239000000945 filler Substances 0.000 claims description 7
- -1 glidant Substances 0.000 claims description 7
- 238000007906 compression Methods 0.000 claims description 5
- 230000006835 compression Effects 0.000 claims description 5
- 239000008363 phosphate buffer Substances 0.000 claims description 5
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 4
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 claims description 4
- 206010003658 Atrial Fibrillation Diseases 0.000 claims description 3
- 208000005189 Embolism Diseases 0.000 claims description 3
- 206010014522 Embolism venous Diseases 0.000 claims description 3
- 208000006011 Stroke Diseases 0.000 claims description 3
- 238000011540 hip replacement Methods 0.000 claims description 3
- 210000003127 knee Anatomy 0.000 claims description 3
- 238000013150 knee replacement Methods 0.000 claims description 3
- 239000000377 silicon dioxide Substances 0.000 claims description 3
- 235000012239 silicon dioxide Nutrition 0.000 claims description 3
- 238000001356 surgical procedure Methods 0.000 claims description 3
- 230000009885 systemic effect Effects 0.000 claims description 3
- 239000000454 talc Substances 0.000 claims description 3
- 229910052623 talc Inorganic materials 0.000 claims description 3
- 235000012222 talc Nutrition 0.000 claims description 3
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 3
- 208000004043 venous thromboembolism Diseases 0.000 claims description 3
- 229920002261 Corn starch Polymers 0.000 claims 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 claims 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 claims 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 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 229920000881 Modified starch Polymers 0.000 claims description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- 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 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 2
- 159000000007 calcium salts Chemical class 0.000 claims description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 2
- 235000013539 calcium stearate Nutrition 0.000 claims description 2
- 239000008116 calcium stearate Substances 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 239000008120 corn starch Substances 0.000 claims description 2
- 229960000913 crospovidone Drugs 0.000 claims description 2
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000000194 fatty acid Substances 0.000 claims description 2
- 229930195729 fatty acid Natural products 0.000 claims description 2
- 150000004676 glycans Chemical class 0.000 claims description 2
- 238000005469 granulation Methods 0.000 claims description 2
- 230000003179 granulation Effects 0.000 claims description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 229920001983 poloxamer Polymers 0.000 claims description 2
- 229920001282 polysaccharide Polymers 0.000 claims description 2
- 239000005017 polysaccharide Substances 0.000 claims description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 229920003124 powdered cellulose Polymers 0.000 claims description 2
- 235000019814 powdered cellulose Nutrition 0.000 claims description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 235000010356 sorbitol Nutrition 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 235000000346 sugar Nutrition 0.000 claims description 2
- 235000019731 tricalcium phosphate Nutrition 0.000 claims description 2
- 239000001506 calcium phosphate Substances 0.000 claims 1
- 229910000389 calcium phosphate Inorganic materials 0.000 claims 1
- 235000011010 calcium phosphates Nutrition 0.000 claims 1
- 229940080313 sodium starch Drugs 0.000 claims 1
- 150000008163 sugars Chemical class 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 34
- 238000004090 dissolution Methods 0.000 abstract description 20
- 239000003826 tablet Substances 0.000 description 13
- 238000004519 manufacturing process Methods 0.000 description 8
- 239000003085 diluting agent Substances 0.000 description 7
- 239000003814 drug Substances 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000007908 dry granulation Methods 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 229920000642 polymer Polymers 0.000 description 5
- 238000005550 wet granulation Methods 0.000 description 5
- 108010074860 Factor Xa Proteins 0.000 description 4
- 108090000190 Thrombin Proteins 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 229940126534 drug product Drugs 0.000 description 4
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- 229960004072 thrombin Drugs 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 102000009123 Fibrin Human genes 0.000 description 3
- 108010073385 Fibrin Proteins 0.000 description 3
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 3
- 238000007922 dissolution test Methods 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 229950003499 fibrin Drugs 0.000 description 3
- 229940127021 low-dose drug Drugs 0.000 description 3
- 239000006186 oral dosage form Substances 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 108010094028 Prothrombin Proteins 0.000 description 2
- 102100027378 Prothrombin Human genes 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 229940047562 eliquis Drugs 0.000 description 2
- JBKVHLHDHHXQEQ-UHFFFAOYSA-N epsilon-caprolactam Chemical compound O=C1CCCCCN1 JBKVHLHDHHXQEQ-UHFFFAOYSA-N 0.000 description 2
- 239000007941 film coated tablet Substances 0.000 description 2
- 239000010419 fine particle Substances 0.000 description 2
- 229920000578 graft copolymer Polymers 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 229960003943 hypromellose Drugs 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 229940069328 povidone Drugs 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 229940039716 prothrombin Drugs 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- 102000003847 Carboxypeptidase B2 Human genes 0.000 description 1
- 108090000201 Carboxypeptidase B2 Proteins 0.000 description 1
- 206010053567 Coagulopathies Diseases 0.000 description 1
- 206010051055 Deep vein thrombosis Diseases 0.000 description 1
- 108010071289 Factor XIII Proteins 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 208000010378 Pulmonary Embolism Diseases 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 229960004977 anhydrous lactose Drugs 0.000 description 1
- 229940127090 anticoagulant agent Drugs 0.000 description 1
- 229960004676 antithrombotic agent Drugs 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 210000001815 ascending colon Anatomy 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- XAAHAAMILDNBPS-UHFFFAOYSA-L calcium hydrogenphosphate dihydrate Chemical compound O.O.[Ca+2].OP([O-])([O-])=O XAAHAAMILDNBPS-UHFFFAOYSA-L 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000035602 clotting Effects 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 229920001531 copovidone Polymers 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 229940095079 dicalcium phosphate anhydrous Drugs 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229940012444 factor xiii Drugs 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000012943 hotmelt Substances 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 238000010902 jet-milling Methods 0.000 description 1
- 238000004898 kneading Methods 0.000 description 1
- 229960001021 lactose monohydrate Drugs 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000008180 pharmaceutical surfactant Substances 0.000 description 1
- 230000010118 platelet activation Effects 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229940068984 polyvinyl alcohol Drugs 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 239000012254 powdered material Substances 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 229960005196 titanium dioxide Drugs 0.000 description 1
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- 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
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- 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
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
Definitions
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising Apixaban or one of its pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient manufactured by using direct compression method to get desired dissolution profile wherein Apixaban particle size D90 value is more than 89 microns.
- Apixaban is orally active, direct, selective inhibitor of the coagulation Factor Xa (FXa) which occupies a pivotal role in the clotting cascade when there is occurring to conversion from prothrombin to thrombin.
- FXa coagulation Factor Xa
- Thrombin is a powerful platelet agonist and has multiple functions such as, converting fibrinogen to fibrin, promoting fibrin cross-linking by activating factor XIII, or activating thrombin-activatable fibrinolysis inhibitor to protect the clot from premature degradation.
- thrombin is central to the process of blood clotting and that includes both deep vein thrombosis and pulmonary embolism.
- Factor Xa causes to decrease the conversion of prothrombin to active thrombin.
- Apixaban is being co-developed by Bristol-Myers Squibb (BMS) and Pfizer as an anticoagulant and antithrombotic agent for the prevention and treatment of a wide range of thrombotic diseases.
- Apixaban is a pyrazole derivative, is chemically described as l-(4-methoxyphenyl)-7-oxo-6- [4-(2-oxo-l-piperidinyl) phenyl]-4, 5, 6, 7-tetrahydro-lH-pyrazolo [3, 4-c] pyridine-3- carboxamide.
- the molecular formula of which is C25H25N5O4, its relative molecular mass 459.50 and its structural formula is shown in the Formula I.
- Formula I Apixaban appears as a white to pale yellow, non-hygroscopic crystalline powder, with an aqueous solubility of 0.028 mg/ml at 24°C.
- the molecule has no chiral central, therefore, no stereoisomers exist. It shows polymorphism and a number of hydrates and solvates were identified. However, only one form is consistently produced by the proposed synthetic process.
- Apixaban was firstly commercially authorized by the European Medicines Agency on May 2011. The medicinal product of it been launched in the film-coated tablet form under the name of the ELIQUIS ® which is used for the treatment for preventing Venous thromboembolism in adults following elective knee or hip replacement surgery and for reducing the risk of stroke or systemic embolism in adults with non-valvular Atrial fibrillation.
- ELIQUIS ® film coated tablets are available for oral administration in strengths of 2.5 mg and 5 mg of Apixaban with the following inactive ingredients: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate.
- the film coating contains lactose monohydrate, hypromellose, titanium dioxide, triacetine, and yellow iron oxide for 2.5 mg tablets or red iron oxide for 5 mg tablets.
- Apixaban is known to be a non-ionizable compound.
- the aqueous solubility of Apixaban is 0.04 mg/ml at 37°C over a pH range of 1.2 to 6.8. It is also classified as highly soluble for doses up to 10 mg in 250 ml. of physiological buffer.
- the absolute bioavailability of apixaban is approximately 50% for doses up to 10 mg. Food does not affect the bioavailability of apixaban. Maximum concentrations (C m ax) of apixaban appear 3 to 4 hours after oral administration. Apixaban is absorbed throughout the gastrointestinal tract with the distal small bowel and ascending colon contributing about 55% of apixaban absorption. Apixaban demonstrates linear pharmacokinetics with dose- proportional increases in exposure for oral doses up to 10 mg. At doses more than 25 mg, apixaban displays dissolution-limited absorption with decreased bioavailability.
- Apixaban base and its pharmaceutically acceptable salts first have been declared in EP 1427415 by Bristol-Myers Squibb.
- Example 18 at the EP1427415 discloses the preparation of Apixaban base.
- EP2538925 relates to a pharmaceutical composition
- a pharmaceutical composition comprising crystalline Apixaban particles having a D90 equal to or less than 89 pm and a pharmaceutically acceptable diluent or carrier excipients wherein the prepared composition is manufactured by using a dry granulation process.
- EP2538925 patent document has many divisional applications.
- One of the divisional application EP3017811 discloses to the dry granulation process steps of the prepared pharmaceutical formulations comprising Apixaban and a pharmaceutically acceptable diluent or carrier excipients.
- EP3251660 discloses to a pharmaceutical composition
- a pharmaceutical composition comprising crystalline Apixaban particles having a D90 less than 50 pm and a pharmaceutically acceptable diluent or carrier excipients.
- Another divisional application EP3246021 discloses to a pharmaceutical composition exhibits dissolution properties such that an amount of the drug equivalent to at least 77% dissolves within 30 minutes, wherein the dissolution test is performed in an aqueous media buffered to a pH range 1 to 7.4 and controlled at 37° C.
- Another divisional application EP3257500 discloses to a pharmaceutical composition
- a pharmaceutical composition comprising crystalline Apixaban particles and a pharmaceutically acceptable diluent or carrier and a surfactant, wherein the surfactant is present in a concentration of 0.25% to 2% by weight, also wherein the composition is manufactured by using an air-jet milling process to reduce Apixaban particle size to the desired size and dry granulation.
- Another divisional application EP3643301 discloses to a pharmaceutical composition exhibits dissolution properties such that an amount of the drug equivalent to at least 77% dissolves within 30 minutes, wherein the dissolution test is performed in 900 mL of dissolution medium containing 0.05 M sodium phosphate at pH 6.8 with 0.05% SDS at 37°C using USP Apparatus 2 (paddle) at a rotation speed of 50-75 rpm.
- EP3662899 is rather close with the EP3643301 patent document wherein EP3662899 patent document discloses to the dose/solubility ratio of the Apixaban in the tablet which is less than 250 mL.
- the given dissolution properties are same with the EP3643301 patent document.
- WO2018150286 relates to a pharmaceutical composition
- a pharmaceutical composition comprising Apixaban having a D90 more than 100 microns, a diluent, a surfactant, a disintegrant and a lubricant wherein the prepared composition is manufactured by using a wet granulation process.
- EP3405195 relates to a pharmaceutical composition comprising Apixaban or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable polymer wherein the polymer is graft copolymer of polyvinyl caprolactam, polyvinyl acetate and polyethylene glycol obtained by using of hot-melt method.
- WO2019177318 relates to a pharmaceutical composition
- a pharmaceutical composition comprising Apixaban was prepared according to a preparation method comprising the steps of; mixing Apixaban and a water- soluble polymer to prepare a mixture; and wet kneading and vacuum drying of the mixture.
- WO2017221209 relates to a pharmaceutical composition
- a pharmaceutical composition comprising the crystalline Apixaban particles having a D90 more than 100 microns and a pharmaceutically acceptable carrier wherein the crystalline Apixaban is Form M.
- EP3243505 relates to a pharmaceutical composition
- a pharmaceutical composition comprising amorphous Apixaban or a salt thereof together with one or more pharmaceutically acceptable excipients or carriers, wherein the composition exhibits an in vitro dissolution profile measured in phosphate buffer at pH 6.8 containing 0.05 % weight/volume of sodium lauryl sulfate according to which: at least 30% of Apixaban is dissolved after 5 minutes and at least 60% of Apixaban is dissolved after 10 minutes.
- EP2907507 relates to a pharmaceutical composition
- a pharmaceutical composition comprising Apixaban and a particularly selected polymer having low viscosity as binder.
- W02017163170 relates to a pharmaceutical composition
- a pharmaceutical composition comprising Apixaban prepared by a non-aqueous wet granulation process wherein the composition releases at least 80% of Apixaban in 30 minutes.
- EP3107530 relates to a pharmaceutical composition
- a pharmaceutical composition comprising Apixaban and a polymer having low viscosity as binder wherein the polymer is selected from the group consisting of povidone, hypromellose, hydroxypropyl cellulose, polyvinyl alcohol, copovidone, polyvinyl alcohol-polyethylene glycol graft copolymer, respectively having low viscosity, and a mixture thereof and wherein the composition prepared by wet granulation process.
- W02017121340 relates to a pharmaceutical composition
- a pharmaceutical composition comprising non-micronized Apixaban and pharmaceutically acceptable excipients wherein the povidone is selected as binder as is dissolved in DMSO.
- EP2554159 relates to a pharmaceutical composition comprising micronized Apixaban and a content uniformity enhancer manufactured by using direct compression.
- WO2017182908 relates to a pharmaceutical composition comprising micronized Apixaban and pharmaceutically acceptable excipients manufactured by using direct compression wherein the amount of the micronized Apixaban is present up to 20% of the total weight.
- TR2017/17703 relates to a pharmaceutical composition
- a pharmaceutical composition comprising Apixaban or a pharmaceutically acceptable salt thereof manufactured by using wet granulation method wherein Apixaban is dispersed into the solvent or solvent mixture to prepare the granulating fluid.
- the particle size of Apixaban effects on the dissolution and absorption rate.
- it is often formulated in a composition having a reasonable particle size using proper manufacturing process, to achieve and maintain relatively fine particles to obtain proper in vitro dissolution profiles.
- a pharmaceutical composition comprising crystalline Apixaban particles having a D90 value more than 89 microns and at least one pharmaceutically acceptable excipient manufactured by using direct compression method and at least 85% of Apixaban is dissolved in 30 minutes when measured by using USP Apparatus 2 (paddle) method at a rotation speed of 75 rpm in 900 mL pH 6.8 phosphate buffer at 37°C temperature containing 0.05% weight/volume of sodium lauryl sulfate.
- the object of this invention is to develop a solid oral pharmaceutical composition
- a solid oral pharmaceutical composition comprising a therapeutically effective amount of Apixaban or one of its pharmaceutically acceptable salts, and at least one pharmaceutically acceptable excipients.
- It is an object of the present invention is to develop a solid oral pharmaceutical composition
- a solid oral pharmaceutical composition comprising Apixaban or one of its pharmaceutically acceptable salts, which is used for the treatment for preventing venous thromboembolism in adults following elective knee or hip replacement surgery and for reducing the risk of stroke or systemic embolism in adults with non-valvular atrial fibrillation.
- the object of the present invention is to provide the pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and Apixaban that has a D90 value more than 89 microns either in particulate or crystalline form.
- Another object of the present invention is to provide a pharmaceutical composition comprising Apixaban which can be manufactured as solid oral dosage forms, such as tablets having desired dissolution profiles.
- Another object of the present invention is to provide a solid oral pharmaceutical composition comprising crystalline Apixaban and one or more pharmaceutically acceptable excipients manufactured by using direct compression method.
- Another object of the present invention is to provide a solid oral pharmaceutical composition comprising Apixaban manufactured by using direct compression method wherein provided for the manufacture of tablets containing the active ingredient, filler, disintegrant, lubricant, glidant and surfactant selected as to be the most suitable ones with respect to the targeted form of administration.
- Another object of the present invention relates to provide direct compression method for preparing a solid oral pharmaceutical composition, direct compression method comprising the steps: i. Apixaban and Sodium lauryl sulfate are screened through a proper sieve and stirred, ii. Silicon dioxide and specified amount of Lactose anhydrous are screened through a proper sieve and then added to the powder blend prepared in Step i and stirred, iii. Croscarmellose sodium and specified amount of Microcrystalline cellulose are screened through a proper sieve and then added to the powder blend prepared in Step ii and stirred, iv.
- Another object of the present invention is to provide a solid oral pharmaceutical composition
- a solid oral pharmaceutical composition comprising Apixaban particles having a D90 value more than 89 microns and at least one pharmaceutically acceptable excipients manufactured by using direct compression method and at least 85% of Apixaban is dissolved in 30 minutes when measured by using USP Apparatus 2 (paddle) method at a rotation speed of 75 rpm in 900 mL pH 6.8 phosphate buffer at 37°C temperature containing 0.05% weight/volume of sodium lauryl sulfate.
- the present invention provides a solid oral pharmaceutical composition comprising an Apixaban and at least one pharmaceutically acceptable excipient is developed in the immediate release dosage form wherein the prepared composition is manufactured by using direct compression method to get desired dissolution profile.
- immediate release tablet refers to dosage forms undergo rapid disintegration to smaller granules and subsequent degradation to fine particles to release the medicaments.
- immediate release may be provided of an appropriate pharmaceutically acceptable diluent or carrier, which diluent or carrier does not delay the rate of drug release and/or absorption.
- Suitable solid oral dosage forms are selected from the group comprising tablets, capsules, granules, powders, and pellet or unit dose packets, preferably the solid oral dosage form is tablet.
- apixaban refers to apixaban in the form of free base or in the form of pharmaceutically acceptable salts, crystalline polymorph, solvates, hydrates, esters or in an amorphous form or mixtures thereof.
- Apixaban is known to be highly water-soluble and relatively low oral bioavailability (about 50% for a single 10 mg dose) compound.
- EP2538925 discloses a pharmaceutical composition comprising Apixaban lead to consistent in-vivo dissolution profiles which means that the particle size has an impact on Apixaban absorption rate when it has a D90 value equal or less than 89 microns.
- a prepared composition having a reasonable particle size of Apixaban using dry granulation process to facilitate consistent in vitro dissolution.
- the prepared pharmaceutical composition comprising Apixaban particles more than 89 microns exhibits a proper dissolution profile.
- the pharmaceutical composition comprising Apixaban particles having a D90 more than 89 microns and at least one pharmaceutical acceptable excipient.
- the ranges of particle size preferred for use in the present invention is more than 89 microns, preferably D90 value more than 100 microns, more preferably D90 value is 139.6 microns.
- the particle size distribution of apixaban particles as described in the specification is characterized by D90 values.
- D90 is defined as 90% of the volume of particles having a diameter less than a specified diameter.
- Apixaban is a low dose drug which is constituted less than 5% weight by the total weight of the composition.
- the mixing and formulation of low dose drugs can be difficult due to problem related to content uniformity.
- selection of proper manufacturing step is critical to develop a homogenous low dose drug.
- the manufacturing may be performed by the methods like direct compression, dry granulation or wet-granulation before tableting.
- the manufacturing method is selected as direct compression method.
- direct compression refers to being a relatively quick process where the powdered materials are compressed directly without changing the physical and chemical properties of the drug.
- the active ingredient(s), direct compression excipients and other auxiliary substances, such as a glidant and lubricant are blended in a twin shell blender or similar low shear apparatus before being compressed into tablets. This type of mixing is believed to be essential in order to prepare “pharmaceutically acceptable” dosage forms.
- the advantages of direct compression include uniformity of blend; few manufacturing steps, i.e., the overall process involves weighing of powders, blending and compression, hence less cost; elimination of heat and moisture, prime particle dissociation and physical stability.
- a solid oral pharmaceutical composition comprising Apixaban having a D90 value more than 89 microns by using direct compression method which involves blending and compression.
- the prepared pharmaceutically composition is also provided for the manufacture of tablets containing at least one pharmaceutically acceptable excipient is selected from fillers, disintegrants, binders, lubricants, surfactants and mixtures thereof.
- the pharmaceutical composition comprising at least one pharmaceutically acceptable filler, preferably selected from which can be selected from dibasic calcium phosphate dehydrate, polysaccharides, primarily microcrystalline cellulose, lactose anhydrous, mannitol, sugar's, sorbitol, sucrose, inorganic salts, primarily calcium salts and the like and mixtures thereof.
- filler is a combination of lactose anhydrous and microcrystalline cellulose.
- the pharmaceutical composition comprising at least one pharmaceutically acceptable disintegrant preferably selected from croscarmellose sodium, sodium starch glycolate, crospovidone, corn starch, pregelatinized starch, low-substituted hydroxypropyl cellulose and microcrystalline cellulose.
- the disintegrant is croscarmellose sodium.
- the pharmaceutical composition comprising at least one pharmaceutically acceptable glidant preferably selected from colloidal silicon dioxide, powdered cellulose, talc, tribasic calcium phosphate.
- the glidant is colloidal silicon dioxide.
- the pharmaceutical composition comprising at least one pharmaceutically acceptable lubricant preferably selected from sodium stearyl fumarate, magnesium stearate, calcium stearate tale, stearic acid and mixtures thereof.
- the lubricant is magnesium stearate.
- the pharmaceutical composition comprising at least one pharmaceutically acceptable surfactant preferably selected from polyoxyethylene fatty alcohol ethers, sorbitan fatty acid esters, stearyl alcohol, poloxamers, potassium laureate, sodium lauryl sulfate, benzalkonium chloride and mixtures thereof.
- the surfactant is sodium lauryl sulfate.
- the embodiment in accordance with the present invention was designed with adjusted quantitative composition composed of pharmaceutically acceptable ingredients mentioned above by using direct compression method.
- Example 1 is given in the below.
- Example 1 Unit Formula in this embodiment of the present invention, detailed manufacturing steps of a solid dosage form are presented below: i. Apixaban and Sodium lauryl sulfate are screened through a proper sieve and stirred, ii. Silicon dioxide and specified amount of Lactose anhydrous are screened through a proper sieve and then added to the powder blend prepared in Step i and stirred, iii. Croscarmellose sodium and specified amount of Microcrystalline cellulose were screened through a proper sieve and then added to the powder blend prepared in Step ii and stirred, iv.
- the obtained tablets were subjected to in vitro dissolution study and the dissolution conditions were designated considering the gastrointestinal pathway of orally applied solid dosage forms.
- the dissolution test is carried out in pH 6.8 phosphate buffer medium containing sodium lauryl sulfate. Other conditions are defined as; volume of dissolution medium is 900 ml, temperature of study is 37°C ⁇ 0.5, rotation speed is 75 rpm, apparatus is paddle and the duration of dissolution study is 60 minutes. Table 1: The results of dissolution study belongs to Example 1
- Example 1 Based on the results presented in Table 1 above, the in-vitro dissolution results of Example 1 were similar with the Reference drug product. In accordance with FDA regulations, similarity of two drug products can be compared based on the results of in vitro dissolution profile studies of these drug products by using a similarity factor f 2 .
- the similarity factor ⁇ 2 is the most common comparison index and if the estimated value is between 50 -100, the dissolution profiles of two drug products in comparison are concluded as similar.
- the similarity factor ⁇ 2 of Example 1 was calculated as 55.0 which means the developed formulation was suitable and the prepared pharmaceutical composition is proper as it was intended.
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Abstract
The present invention relates to a pharmaceutical composition comprising Apixaban or one of its pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient manufactured by using direct compression method to get desired dissolution profile wherein Apixaban particle size D90 value is more than 89 microns.
Description
DIRECT COMPRESSION METHOD FOR NON-MICRONISED APIXABAN
FORMULATIONS
FIELD OF INVENTION The present invention relates to a pharmaceutical composition comprising Apixaban or one of its pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient manufactured by using direct compression method to get desired dissolution profile wherein Apixaban particle size D90 value is more than 89 microns. STATE OF ART
Apixaban is orally active, direct, selective inhibitor of the coagulation Factor Xa (FXa) which occupies a pivotal role in the clotting cascade when there is occurring to conversion from prothrombin to thrombin. Thrombin is a powerful platelet agonist and has multiple functions such as, converting fibrinogen to fibrin, promoting fibrin cross-linking by activating factor XIII, or activating thrombin-activatable fibrinolysis inhibitor to protect the clot from premature degradation. In other way, thrombin is central to the process of blood clotting and that includes both deep vein thrombosis and pulmonary embolism.
To diminish fibrin formation, and reduce coagulation and platelet activation, Factor Xa is blocked. Factor Xa causes to decrease the conversion of prothrombin to active thrombin. Thus, Apixaban is being co-developed by Bristol-Myers Squibb (BMS) and Pfizer as an anticoagulant and antithrombotic agent for the prevention and treatment of a wide range of thrombotic diseases.
Apixaban is a pyrazole derivative, is chemically described as l-(4-methoxyphenyl)-7-oxo-6- [4-(2-oxo-l-piperidinyl) phenyl]-4, 5, 6, 7-tetrahydro-lH-pyrazolo [3, 4-c] pyridine-3- carboxamide. The molecular formula of which is C25H25N5O4, its relative molecular mass 459.50 and its structural formula is shown in the Formula I.
Formula I
Apixaban appears as a white to pale yellow, non-hygroscopic crystalline powder, with an aqueous solubility of 0.028 mg/ml at 24°C.
The molecule has no chiral central, therefore, no stereoisomers exist. It shows polymorphism and a number of hydrates and solvates were identified. However, only one form is consistently produced by the proposed synthetic process.
Apixaban was firstly commercially authorized by the European Medicines Agency on May 2011. The medicinal product of it been launched in the film-coated tablet form under the name of the ELIQUIS® which is used for the treatment for preventing Venous thromboembolism in adults following elective knee or hip replacement surgery and for reducing the risk of stroke or systemic embolism in adults with non-valvular Atrial fibrillation.
ELIQUIS® film coated tablets are available for oral administration in strengths of 2.5 mg and 5 mg of Apixaban with the following inactive ingredients: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate. The film coating contains lactose monohydrate, hypromellose, titanium dioxide, triacetine, and yellow iron oxide for 2.5 mg tablets or red iron oxide for 5 mg tablets.
Apixaban is known to be a non-ionizable compound. The aqueous solubility of Apixaban is 0.04 mg/ml at 37°C over a pH range of 1.2 to 6.8. It is also classified as highly soluble for doses up to 10 mg in 250 ml. of physiological buffer.
The absolute bioavailability of apixaban is approximately 50% for doses up to 10 mg. Food does not affect the bioavailability of apixaban. Maximum concentrations (Cmax) of apixaban appear 3 to 4 hours after oral administration. Apixaban is absorbed throughout the gastrointestinal tract with the distal small bowel and ascending colon contributing about 55% of apixaban absorption. Apixaban demonstrates linear pharmacokinetics with dose- proportional increases in exposure for oral doses up to 10 mg. At doses more than 25 mg, apixaban displays dissolution-limited absorption with decreased bioavailability.
Apixaban base and its pharmaceutically acceptable salts first have been declared in EP 1427415 by Bristol-Myers Squibb. In particular, Example 18 at the EP1427415 discloses the preparation of Apixaban base.
In the state of art there are many patents/patent applications which are summarized below.
EP2538925 relates to a pharmaceutical composition comprising crystalline Apixaban particles having a D90 equal to or less than 89 pm and a pharmaceutically acceptable diluent or carrier
excipients wherein the prepared composition is manufactured by using a dry granulation process.
EP2538925 patent document has many divisional applications.
One of the divisional application EP3017811 discloses to the dry granulation process steps of the prepared pharmaceutical formulations comprising Apixaban and a pharmaceutically acceptable diluent or carrier excipients.
Another divisional application EP3251660 discloses to a pharmaceutical composition comprising crystalline Apixaban particles having a D90 less than 50 pm and a pharmaceutically acceptable diluent or carrier excipients.
Another divisional application EP3246021 discloses to a pharmaceutical composition exhibits dissolution properties such that an amount of the drug equivalent to at least 77% dissolves within 30 minutes, wherein the dissolution test is performed in an aqueous media buffered to a pH range 1 to 7.4 and controlled at 37° C.
Another divisional application EP3257500 discloses to a pharmaceutical composition comprising crystalline Apixaban particles and a pharmaceutically acceptable diluent or carrier and a surfactant, wherein the surfactant is present in a concentration of 0.25% to 2% by weight, also wherein the composition is manufactured by using an air-jet milling process to reduce Apixaban particle size to the desired size and dry granulation.
Another divisional application EP3643301 discloses to a pharmaceutical composition exhibits dissolution properties such that an amount of the drug equivalent to at least 77% dissolves within 30 minutes, wherein the dissolution test is performed in 900 mL of dissolution medium containing 0.05 M sodium phosphate at pH 6.8 with 0.05% SDS at 37°C using USP Apparatus 2 (paddle) at a rotation speed of 50-75 rpm.
Another divisional application EP3662899 is rather close with the EP3643301 patent document wherein EP3662899 patent document discloses to the dose/solubility ratio of the Apixaban in the tablet which is less than 250 mL. The given dissolution properties are same with the EP3643301 patent document.
WO2018150286 relates to a pharmaceutical composition comprising Apixaban having a D90 more than 100 microns, a diluent, a surfactant, a disintegrant and a lubricant wherein the prepared composition is manufactured by using a wet granulation process.
EP3405195 relates to a pharmaceutical composition comprising Apixaban or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable polymer wherein the polymer is graft copolymer of polyvinyl caprolactam, polyvinyl acetate and polyethylene glycol obtained by using of hot-melt method.
WO2019177318 relates to a pharmaceutical composition comprising Apixaban was prepared according to a preparation method comprising the steps of; mixing Apixaban and a water- soluble polymer to prepare a mixture; and wet kneading and vacuum drying of the mixture.
WO2017221209 relates to a pharmaceutical composition comprising the crystalline Apixaban particles having a D90 more than 100 microns and a pharmaceutically acceptable carrier wherein the crystalline Apixaban is Form M.
EP3243505 relates to a pharmaceutical composition comprising amorphous Apixaban or a salt thereof together with one or more pharmaceutically acceptable excipients or carriers, wherein the composition exhibits an in vitro dissolution profile measured in phosphate buffer at pH 6.8 containing 0.05 % weight/volume of sodium lauryl sulfate according to which: at least 30% of Apixaban is dissolved after 5 minutes and at least 60% of Apixaban is dissolved after 10 minutes.
EP2907507 relates to a pharmaceutical composition comprising Apixaban and a particularly selected polymer having low viscosity as binder.
W02017163170 relates to a pharmaceutical composition comprising Apixaban prepared by a non-aqueous wet granulation process wherein the composition releases at least 80% of Apixaban in 30 minutes.
EP3107530 relates to a pharmaceutical composition comprising Apixaban and a polymer having low viscosity as binder wherein the polymer is selected from the group consisting of povidone, hypromellose, hydroxypropyl cellulose, polyvinyl alcohol, copovidone, polyvinyl alcohol-polyethylene glycol graft copolymer, respectively having low viscosity, and a mixture thereof and wherein the composition prepared by wet granulation process.
W02017121340 relates to a pharmaceutical composition comprising non-micronized Apixaban and pharmaceutically acceptable excipients wherein the povidone is selected as binder as is dissolved in DMSO.
EP2554159 relates to a pharmaceutical composition comprising micronized Apixaban and a content uniformity enhancer manufactured by using direct compression.
WO2017182908 relates to a pharmaceutical composition comprising micronized Apixaban and pharmaceutically acceptable excipients manufactured by using direct compression wherein the amount of the micronized Apixaban is present up to 20% of the total weight.
TR2017/17703 relates to a pharmaceutical composition comprising Apixaban or a pharmaceutically acceptable salt thereof manufactured by using wet granulation method wherein Apixaban is dispersed into the solvent or solvent mixture to prepare the granulating fluid.
Based on the prior art given in the above, the particle size of Apixaban effects on the dissolution and absorption rate. Thus, it is often formulated in a composition having a reasonable particle size using proper manufacturing process, to achieve and maintain relatively fine particles to obtain proper in vitro dissolution profiles.
However, the inventors of the present invention have surprisingly succeeded in formulating a pharmaceutical composition comprising crystalline Apixaban particles having a D90 value more than 89 microns and at least one pharmaceutically acceptable excipient manufactured by using direct compression method and at least 85% of Apixaban is dissolved in 30 minutes when measured by using USP Apparatus 2 (paddle) method at a rotation speed of 75 rpm in 900 mL pH 6.8 phosphate buffer at 37°C temperature containing 0.05% weight/volume of sodium lauryl sulfate.
SUMMARY OF INVENTION
The object of this invention is to develop a solid oral pharmaceutical composition comprising a therapeutically effective amount of Apixaban or one of its pharmaceutically acceptable salts, and at least one pharmaceutically acceptable excipients.
It is an object of the present invention is to develop a solid oral pharmaceutical composition comprising Apixaban or one of its pharmaceutically acceptable salts, which is used for the treatment for preventing venous thromboembolism in adults following elective knee or hip replacement surgery and for reducing the risk of stroke or systemic embolism in adults with non-valvular atrial fibrillation.
The object of the present invention is to provide the pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and Apixaban that has a D90 value more than 89 microns either in particulate or crystalline form.
Another object of the present invention is to provide a pharmaceutical composition comprising Apixaban which can be manufactured as solid oral dosage forms, such as tablets having desired dissolution profiles.
Another object of the present invention is to provide a solid oral pharmaceutical composition comprising crystalline Apixaban and one or more pharmaceutically acceptable excipients manufactured by using direct compression method.
Another object of the present invention is to provide a solid oral pharmaceutical composition comprising Apixaban manufactured by using direct compression method wherein provided for the manufacture of tablets containing the active ingredient, filler, disintegrant, lubricant, glidant and surfactant selected as to be the most suitable ones with respect to the targeted form of administration.
Another object of the present invention relates to provide direct compression method for preparing a solid oral pharmaceutical composition, direct compression method comprising the steps: i. Apixaban and Sodium lauryl sulfate are screened through a proper sieve and stirred, ii. Silicon dioxide and specified amount of Lactose anhydrous are screened through a proper sieve and then added to the powder blend prepared in Step i and stirred, iii. Croscarmellose sodium and specified amount of Microcrystalline cellulose are screened through a proper sieve and then added to the powder blend prepared in Step ii and stirred, iv. The rest of the Microcrystalline cellulose and Lactose anhydrous are screened through a proper sieve and then added to the powder blend prepared in Step iii and stirred, v. Magnesium stearate is screened through a proper sieve and added to the powder blend prepared in Step iv and stirred to obtain a uniform final blend, vi. Tablet compression is performed with the final blend in Step v.
Another object of the present invention is to provide a solid oral pharmaceutical composition comprising Apixaban particles having a D90 value more than 89 microns and at least one pharmaceutically acceptable excipients manufactured by using direct compression method and at least 85% of Apixaban is dissolved in 30 minutes when measured by using USP Apparatus 2 (paddle) method at a rotation speed of 75 rpm in 900 mL pH 6.8 phosphate buffer at 37°C temperature containing 0.05% weight/volume of sodium lauryl sulfate.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a solid oral pharmaceutical composition comprising an Apixaban and at least one pharmaceutically acceptable excipient is developed in the immediate release dosage form wherein the prepared composition is manufactured by using direct compression method to get desired dissolution profile.
The term an "immediate release tablet" refers to dosage forms undergo rapid disintegration to smaller granules and subsequent degradation to fine particles to release the medicaments. In the present invention, immediate release may be provided of an appropriate pharmaceutically acceptable diluent or carrier, which diluent or carrier does not delay the rate of drug release and/or absorption.
In a preferred embodiment of the present invention is to provide a pharmaceutical composition for oral administration. Suitable solid oral dosage forms are selected from the group comprising tablets, capsules, granules, powders, and pellet or unit dose packets, preferably the solid oral dosage form is tablet. The term “apixaban” as used herein refers to apixaban in the form of free base or in the form of pharmaceutically acceptable salts, crystalline polymorph, solvates, hydrates, esters or in an amorphous form or mixtures thereof.
According to the literature knowledge, Apixaban is known to be highly water-soluble and relatively low oral bioavailability (about 50% for a single 10 mg dose) compound. However, one of its main document which is EP2538925 discloses a pharmaceutical composition comprising Apixaban lead to consistent in-vivo dissolution profiles which means that the particle size has an impact on Apixaban absorption rate when it has a D90 value equal or less than 89 microns. Moreover, it was also revealed that a prepared composition having a reasonable particle size of Apixaban using dry granulation process, to facilitate consistent in vitro dissolution.
Even if, there is a knowledge about the using large particles of Apixaban could result in less optimal exposures than micronized particles, in the present invention that the prepared pharmaceutical composition comprising Apixaban particles more than 89 microns exhibits a proper dissolution profile.
Thus, in a preferred embodiment of the present invention is to provide the pharmaceutical composition comprising Apixaban particles having a D90 more than 89 microns and at least one pharmaceutical acceptable excipient. The ranges of particle size preferred for use in the present invention is more than 89 microns, preferably D90 value more than 100 microns, more preferably D90 value is 139.6 microns. The particle size distribution of apixaban particles as described in the specification is characterized by D90 values. The term “D90” is defined as 90% of the volume of particles having a diameter less than a specified diameter.
In the present invention, Apixaban is a low dose drug which is constituted less than 5% weight by the total weight of the composition. The mixing and formulation of low dose drugs can be difficult due to problem related to content uniformity. Thus, selection of proper manufacturing step is critical to develop a homogenous low dose drug. It is known that the manufacturing may be performed by the methods like direct compression, dry granulation or wet-granulation before tableting. In the present invention, the manufacturing method is selected as direct compression method.
The term “direct compression” refers to being a relatively quick process where the powdered materials are compressed directly without changing the physical and chemical properties of the drug. The active ingredient(s), direct compression excipients and other auxiliary substances, such as a glidant and lubricant are blended in a twin shell blender or similar low shear apparatus before being compressed into tablets. This type of mixing is believed to be essential in order to prepare “pharmaceutically acceptable” dosage forms.
The advantages of direct compression include uniformity of blend; few manufacturing steps, i.e., the overall process involves weighing of powders, blending and compression, hence less cost; elimination of heat and moisture, prime particle dissociation and physical stability.
In a preferred embodiment of the present invention is to provide a solid oral pharmaceutical composition comprising Apixaban having a D90 value more than 89 microns by using direct compression method which involves blending and compression. Moreover, the prepared pharmaceutically composition is also provided for the manufacture of tablets containing at least one pharmaceutically acceptable excipient is selected from fillers, disintegrants, binders, lubricants, surfactants and mixtures thereof.
In a preferred embodiment, the pharmaceutical composition comprising at least one pharmaceutically acceptable filler, preferably selected from which can be selected from dibasic
calcium phosphate dehydrate, polysaccharides, primarily microcrystalline cellulose, lactose anhydrous, mannitol, sugar's, sorbitol, sucrose, inorganic salts, primarily calcium salts and the like and mixtures thereof. Preferably, filler is a combination of lactose anhydrous and microcrystalline cellulose.
In a preferred embodiment, the pharmaceutical composition comprising at least one pharmaceutically acceptable disintegrant preferably selected from croscarmellose sodium, sodium starch glycolate, crospovidone, corn starch, pregelatinized starch, low-substituted hydroxypropyl cellulose and microcrystalline cellulose. Preferably, the disintegrant is croscarmellose sodium.
In a preferred embodiment, the pharmaceutical composition comprising at least one pharmaceutically acceptable glidant preferably selected from colloidal silicon dioxide, powdered cellulose, talc, tribasic calcium phosphate. Preferably, the glidant is colloidal silicon dioxide.
In a preferred embodiment, the pharmaceutical composition comprising at least one pharmaceutically acceptable lubricant preferably selected from sodium stearyl fumarate, magnesium stearate, calcium stearate tale, stearic acid and mixtures thereof. Preferably, the lubricant is magnesium stearate.
In a preferred embodiment, the pharmaceutical composition comprising at least one pharmaceutically acceptable surfactant preferably selected from polyoxyethylene fatty alcohol ethers, sorbitan fatty acid esters, stearyl alcohol, poloxamers, potassium laureate, sodium lauryl sulfate, benzalkonium chloride and mixtures thereof. Preferably, the surfactant is sodium lauryl sulfate.
The embodiment in accordance with the present invention was designed with adjusted quantitative composition composed of pharmaceutically acceptable ingredients mentioned above by using direct compression method.
The embodiment. Example 1 is given in the below.
The proposed embodiment based on the invention provides an immediate release oral solid pharmaceutical composition wherein the amounts in w/w% of the total composition are as stated below:
Example 1: Unit Formula
in this embodiment of the present invention, detailed manufacturing steps of a solid dosage form are presented below: i. Apixaban and Sodium lauryl sulfate are screened through a proper sieve and stirred, ii. Silicon dioxide and specified amount of Lactose anhydrous are screened through a proper sieve and then added to the powder blend prepared in Step i and stirred, iii. Croscarmellose sodium and specified amount of Microcrystalline cellulose were screened through a proper sieve and then added to the powder blend prepared in Step ii and stirred, iv. The rest of the Microcrystalline cellulose and Lactose anhydrous were screened through a proper sieve and then added to the powder blend prepared in Step iii and stirred, v. Magnesium stearate was screened through a proper sieve and is added to the powder granulation prepared in Step iv and are stirred to obtain a uniform final blend, vi. Tablet compression was performed with the final blend in Step v.
The obtained tablets were subjected to in vitro dissolution study and the dissolution conditions were designated considering the gastrointestinal pathway of orally applied solid dosage forms.
The dissolution test is carried out in pH 6.8 phosphate buffer medium containing sodium lauryl sulfate. Other conditions are defined as; volume of dissolution medium is 900 ml, temperature of study is 37°C±0.5, rotation speed is 75 rpm, apparatus is paddle and the duration of dissolution study is 60 minutes.
Table 1: The results of dissolution study belongs to Example 1
Based on the results presented in Table 1 above, the in-vitro dissolution results of Example 1 were similar with the Reference drug product. In accordance with FDA regulations, similarity of two drug products can be compared based on the results of in vitro dissolution profile studies of these drug products by using a similarity factor f2. The similarity factor Ϊ2 is the most common comparison index and if the estimated value is between 50 -100, the dissolution profiles of two drug products in comparison are concluded as similar. In the present invention, the similarity factor Ϊ2 of Example 1 was calculated as 55.0 which means the developed formulation was suitable and the prepared pharmaceutical composition is proper as it was intended.
While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.
Claims
1. A solid oral pharmaceutical composition comprising Apixaban and at least one pharmaceutically acceptable excipient manufactured by using direct compression method, wherein Apixaban is in crystalline form having a D90 value more than 89 microns and at least 85% of Apixaban is dissolved in 30 minutes when measured by using USP Apparatus 2 (paddle) method at a rotation speed of 75 rpm in 900 mL pH 6.8 phosphate buffer at 37°C temperature containing 0.05% weight/volume of sodium lauryl sulfate.
2. A solid oral pharmaceutical composition according to Claim 1, wherein the Apixaban particles have a D90 value more than 100 microns, preferably D90 value is 139.6 micron.
3. A solid oral pharmaceutical composition according to Claim 1 or 2, wherein at least one pharmaceutically acceptable excipient is selected from fillers, disintegrants, glidant, surfactants, lubricants and mixtures thereof.
4. A solid oral pharmaceutical composition according to Claim 3, wherein at least one pharmaceutically acceptable excipient is a filler, preferably selected from calcium phosphate dehydrate, polysaccharides, primarily microcrystalline cellulose, lactose anhydrous, mannitol, sugars, sorbitol, sucrose, inorganic salts, primarily calcium salts and the like and mixtures thereof.
5. A solid oral pharmaceutical composition according to Claim 4, wherein the filler is a combination of lactose anhydrous and microcrystalline cellulose.
6. A solid oral pharmaceutical composition according to Claim 3, wherein at least one pharmaceutically acceptable excipient is a disintegrant, preferably selected from croscarmellose sodium, sodium starch g!yeo!ate, crospovidone, corn starch, pregelatinized starch, low -substituted hydroxypropyl cellulose and microcrystalline cellulose.
7. A solid oral pharmaceutical composition according to Claim 6, wherein the disintegrant is croscarmellose sodium.
8. A solid oral pharmaceutical composition according to Claim 3, wherein at least one pharmaceutically acceptable excipient is a glidant preferably selected from colloidal silicon dioxide, powdered cellulose, talc, tribasic calcium phosphate.
9. A solid oral pharmaceutical composition according to Claim 8, wherein the glidant is colloidal silicon dioxide.
10. A solid oral pharmaceutical composition according to Claim 3, wherein at least one pharmaceutically acceptable excipient is a lubricant preferably selected from sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid and mixtures thereof.
11. A solid oral pharmaceutical composition according to Claim 10, wherein the lubricant is magnesium stearate.
12. A solid oral pharmaceutical composition according to Claim 3, wherein at least one pharmaceutically acceptable excipient is a surfactant, preferably selected from polyoxyethylene fatty alcohol ethers, sorbitan fatty acid esters, stearyl alcohol, poloxamers, potassium laureate, sodium lauryl sulfate, benzalkonium chloride and mixtures thereof.
13. A solid oral pharmaceutical composition according to Claim 12, wherein the surfactant is sodium lauryl sulfate.
14. A solid oral pharmaceutical composition according to any one of the preceding claims, comprising:
15. A direct compression method for preparing a solid oral pharmaceutical composition according to any one of the preceding claims, wherein the process comprising the steps of; i. Apixaban and Sodium lauryl sulfate are screened through a proper sieve and stirred, ii. Silicon dioxide and specified amount of Lactose anhydrous are screened through a proper sieve and then added to the powder blend prepared in Step i and stirred, iii. Croscarmellose sodium and specified amount of Microcrystalline cellulose are screened through a proper sieve and then added to the powder blend prepared in Step ii and stirred, iv. The rest of the Microcrystalline cellulose and Lactose anhydrous are screened through a proper sieve and then added to the powder blend prepared in Step iii and stirred,
v. Magnesium stearate was screened through a proper sieve and is added to the powder granulation prepared in Step iv and are stirred to obtain a uniform final blend, vi. Tablet compression was performed with the final blend in Step v.
16. A solid oral pharmaceutical composition according to any one of the preceding claims, wherein the composition is in the form of tablet.
17. A solid oral pharmaceutical composition according to any one of the preceding claims for use in the treatment of Venous thromboembolism in adults following elective knee or hip replacement surgery and for reducing the risk of stroke or systemic embolism in adults with non-valvular Atrial fibrillation.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/TR2020/051184 WO2022115051A1 (en) | 2020-11-27 | 2020-11-27 | Direct compression method for non-micronised apixaban formulations |
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| Publication Number | Publication Date |
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| EP4251271A1 true EP4251271A1 (en) | 2023-10-04 |
| EP4251271A4 EP4251271A4 (en) | 2024-07-31 |
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| Application Number | Title | Priority Date | Filing Date |
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| EP20963793.3A Pending EP4251271A4 (en) | 2020-11-27 | 2020-11-27 | DIRECT COMPRESSION PROCESS FOR NON-MICRONIZED APIXABAN FORMULATIONS |
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| WO (1) | WO2022115051A1 (en) |
Family Cites Families (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2002341693B2 (en) | 2001-09-21 | 2008-05-29 | Bristol-Myers Squibb Holdings Ireland Unlimited Company | Lactam-containing compounds and derivatives thereof as factor Xa inhibitors |
| SG182750A1 (en) | 2010-02-25 | 2012-08-30 | Bristol Myers Squibb Co | Apixaban formulations |
| EP2554159A1 (en) | 2011-08-04 | 2013-02-06 | ratiopharm GmbH | Dosage forms comprising apixaban and content uniformity enhancer |
| CA2873949A1 (en) * | 2012-05-24 | 2013-11-28 | Ratiopharm Gmbh | Dosage forms comprising apixaban and matrix former |
| EP2907507A1 (en) | 2014-02-17 | 2015-08-19 | Sandoz Ag | Pharmaceutical composition comprising apixaban |
| WO2017121340A1 (en) | 2016-01-12 | 2017-07-20 | 广东东阳光药业有限公司 | Araxaban solid composition and preparation method therefor |
| EP3195860A1 (en) | 2016-01-22 | 2017-07-26 | STADA Arzneimittel AG | Method for producing an apixaban granulate |
| WO2017163170A1 (en) | 2016-03-21 | 2017-09-28 | Sun Pharmaceutical Industries Limited | Pharmaceutical composition comprising apixaban |
| WO2017182908A1 (en) | 2016-04-18 | 2017-10-26 | Emcure Pharmaceuticals Limited | Pharmaceutical compositions of apixaban |
| EP3243505A1 (en) | 2016-05-13 | 2017-11-15 | Zaklady Farmaceutyczne Polpharma SA | A pharmaceutical composition comprising amorphous apixaban |
| WO2017221209A1 (en) | 2016-06-23 | 2017-12-28 | Lupin Limited | Pharmaceutical formulations of apixaban |
| EP3582777A4 (en) | 2017-02-17 | 2020-12-23 | Unichem Laboratories Ltd | Pharmaceutical composition of apixaban |
| TR201717703A2 (en) | 2017-11-10 | 2019-05-21 | Ali Raif Ilac Sanayi Ve Ticaret Anonim Sirketi | APIXABAN FORMULATIONS |
| TR201722523A2 (en) * | 2017-12-28 | 2019-07-22 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | SOLID ORAL PHARMACEUTICAL COMPOSITIONS CONTAINING APIXABAN |
| KR102128321B1 (en) | 2018-03-13 | 2020-06-30 | 주식회사 종근당 | Solubilization formulation comprising apixaban and preparation method for the same |
| KR20190130411A (en) * | 2018-05-14 | 2019-11-22 | 신일제약주식회사 | Pharmaceutical formulation comprising apixaban and method for preparing the same |
| EP3669866A1 (en) * | 2018-12-19 | 2020-06-24 | KRKA, d.d., Novo mesto | Pharmaceutical composition comprising apixaban |
-
2020
- 2020-11-27 WO PCT/TR2020/051184 patent/WO2022115051A1/en unknown
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| EP4251271A4 (en) | 2024-07-31 |
| WO2022115051A1 (en) | 2022-06-02 |
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