WO2008065674A1 - Préparation d'une dispersion moléculaire à écoulement libre comprenant une base de clopidrogel - Google Patents
Préparation d'une dispersion moléculaire à écoulement libre comprenant une base de clopidrogel Download PDFInfo
- Publication number
- WO2008065674A1 WO2008065674A1 PCT/IN2007/000173 IN2007000173W WO2008065674A1 WO 2008065674 A1 WO2008065674 A1 WO 2008065674A1 IN 2007000173 W IN2007000173 W IN 2007000173W WO 2008065674 A1 WO2008065674 A1 WO 2008065674A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- clopidogrel
- solid dispersion
- pharmaceutically acceptable
- polymer
- solid
- Prior art date
Links
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 title claims abstract description 90
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 title claims abstract description 90
- 229960003009 clopidogrel Drugs 0.000 title claims abstract description 90
- 239000006185 dispersion Substances 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title description 6
- 239000000203 mixture Substances 0.000 claims abstract description 46
- 229920000642 polymer Polymers 0.000 claims abstract description 30
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 29
- 239000007962 solid dispersion Substances 0.000 claims abstract description 22
- 239000004094 surface-active agent Substances 0.000 claims abstract description 21
- 239000002904 solvent Substances 0.000 claims abstract description 14
- 239000000758 substrate Substances 0.000 claims abstract description 14
- 239000007787 solid Substances 0.000 claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 claims abstract description 7
- 238000005507 spraying Methods 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims description 20
- 239000003826 tablet Substances 0.000 claims description 18
- 230000008569 process Effects 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- 239000000463 material Substances 0.000 claims description 10
- 229940079593 drug Drugs 0.000 claims description 9
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 8
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 8
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 8
- 239000002775 capsule Substances 0.000 claims description 7
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 7
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 5
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 5
- 229920000053 polysorbate 80 Polymers 0.000 claims description 5
- 229940068968 polysorbate 80 Drugs 0.000 claims description 5
- 238000005549 size reduction Methods 0.000 claims description 5
- 235000010980 cellulose Nutrition 0.000 claims description 4
- 229920002678 cellulose Polymers 0.000 claims description 4
- 239000001913 cellulose Substances 0.000 claims description 4
- 238000009826 distribution Methods 0.000 claims description 3
- 239000011877 solvent mixture Substances 0.000 claims description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 2
- 229920000858 Cyclodextrin Polymers 0.000 claims 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 claims description 2
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 2
- 229920001219 Polysorbate 40 Polymers 0.000 claims description 2
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 2
- 239000003456 ion exchange resin Substances 0.000 claims description 2
- 229920003303 ion-exchange polymer Polymers 0.000 claims description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 2
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 claims description 2
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 claims description 2
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 claims description 2
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 claims description 2
- 229940068977 polysorbate 20 Drugs 0.000 claims description 2
- 229940101027 polysorbate 40 Drugs 0.000 claims description 2
- 229940113124 polysorbate 60 Drugs 0.000 claims description 2
- 230000002829 reductive effect Effects 0.000 claims description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 229920003168 pharmaceutical polymer Polymers 0.000 claims 3
- 239000002270 dispersing agent Substances 0.000 claims 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 1
- 208000007536 Thrombosis Diseases 0.000 claims 1
- 229940124597 therapeutic agent Drugs 0.000 claims 1
- 239000002552 dosage form Substances 0.000 description 16
- 238000004090 dissolution Methods 0.000 description 13
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 12
- 239000008187 granular material Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 238000009472 formulation Methods 0.000 description 9
- FDEODCTUSIWGLK-RSAXXLAASA-N clopidogrel sulfate Chemical compound [H+].OS([O-])(=O)=O.C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl FDEODCTUSIWGLK-RSAXXLAASA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000011161 development Methods 0.000 description 6
- 239000012530 fluid Substances 0.000 description 6
- 235000019359 magnesium stearate Nutrition 0.000 description 6
- 238000012545 processing Methods 0.000 description 6
- 239000007921 spray Substances 0.000 description 5
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 239000008186 active pharmaceutical agent Substances 0.000 description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 4
- 239000008108 microcrystalline cellulose Substances 0.000 description 4
- -1 such as Polymers 0.000 description 4
- 235000021355 Stearic acid Nutrition 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000008117 stearic acid Substances 0.000 description 3
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M bisulphate group Chemical group S([O-])(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 229950010477 clopidogrel hydrogen sulphate Drugs 0.000 description 2
- 238000000975 co-precipitation Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- 238000012495 forced degradation study Methods 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000007873 sieving Methods 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 239000006104 solid solution Substances 0.000 description 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 238000010977 unit operation Methods 0.000 description 2
- 229920003169 water-soluble polymer Polymers 0.000 description 2
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 1
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 description 1
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010022562 Intermittent claudication Diseases 0.000 description 1
- 208000032382 Ischaemic stroke Diseases 0.000 description 1
- 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 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000006652 catabolic pathway Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000024980 claudication Diseases 0.000 description 1
- 239000007931 coated granule Substances 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 238000001739 density measurement Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000013020 final formulation Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000005243 fluidization Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 description 1
- 238000010951 particle size reduction Methods 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
- A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
Definitions
- the present invention relates to a free flowing molecular dispersion of clopidogrel base comprising clopidogrel base, a polymer, such as, hydroxypropylmethylcellulose or a mixture of polymers, such as, hydroxypropylmethylcellulose and ethyl cellulose, pharmaceutically acceptable excipients and optionally surfactant and a process for preparing the same.
- a polymer such as, hydroxypropylmethylcellulose or a mixture of polymers, such as, hydroxypropylmethylcellulose and ethyl cellulose
- pharmaceutically acceptable excipients and optionally surfactant and a process for preparing the same.
- Clopidogrel is an inhibitor of induced platelet aggregation and acts by inhibiting the binding of adenosine diphosphate to its receptor. Clopidogrel is metabolized by the liver into active form. Its antiplatelet activity is extended in that it stops any platelet activity even up to ten days after administration. Chemically clopidogrel is methyl (+)- ([pound])-[deg.]c-(o-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate.
- U.S. Pat. No. 4,529,596 disclose clopidogrel. Clopidogrel's ability to inhibit platelet aggregation makes it an effective drug for reducing the incidence of ischemic strokes, heart attacks or claudication due to vascular diseases such as atherosclerosis. Clopidogrel reduces the chance of arterial blockage, thus preventing strokes and heart attacks.
- Clopidogrel is presently used as its bisulphate or hydrogensulphate salt.
- the hydrogensulphate salt has the disadvantage that concentrated sulfuric acid is required to prepare it, and that corresponding products have a very strong acidic reaction because of the acidic proton. These acidic properties have an adverse effect on compatibility with many pharmaceutical excipients and thus the stability of dosage forms made from it.
- EP1310245 describes that there is an interaction between platelet aggregation inhibitor clopidogrel and magnesium stearate where magnesium stearate causes degradation of clopidogrel.
- This invention purports to overcome this problem by using zinc stearate, stearic acid, sodium stearyl fumarate as lubricant instead of magnesium stearate.
- US5520928 relates to use of stearic acid
- WO0001364 relates to use of PEG and talc instead of magnesium stearate.
- US4591592 relates to use of a chelating agent such as stearic acid, benzoic acid, tartaric acid or fumaric acid and an antioxidant together with magnesium stearate.
- WO/2005/070464 decribes a stable pharmaceutical formulation of clopidogrel bisulphate wherein hydrogenated vegetable oil is used as lubricant.
- Clopidogrel base has not been used for formulation because it exists as an oil that is contaminated with solvents and clopidogrel acid. There is, therefore, an urgent need to make clopidogrel base that can be of use in pharmaceutical formulations.
- WO 2006031847 provides processes for preparing clopidogrel base substantially free of solvents and suitable for use in pharmaceutical formulations.
- clopidogrel due to its physical nature, there is still a problem of formulating the base in a stable and bioavailable formulation.
- the reports in the literature about clopidogrel are focussed on the development of either novel polymorphs of clopidogrel bisulphate or the development of amorphous clopidogrel bisulphate.
- the use of clopidogrel base as an active pharmaceutical ingredient for developing a pharmaceutical dosage form has not been explored. This is due to the fact that clopidogrel base occurs as an amorphous semisolid paste-like mass and, therefore, is not conducive to being converted into an acceptable solid oral formulation.
- clopidogrel base as an active pharmaceutical ingredient in pharmaceutical dosage forms thus requires that the clopidogrel base be processed so as to render it suitable for further processing to develop a dosage form.
- WO 2006/044548 relates to premixes comprising clopidogrel and a pharmaceutically acceptable excipient, and processes for the preparation of these compositions.
- a composition containing clopidogrel is prepared by adsorbing a solution containing clopidogrel base onto a pharmaceutical excipient or a mixture of pharmaceutical excipients and then removing solvent.
- this invention can have the problems of poor flowability and stability.
- This approach also has limitation of the maximum content of clopidogrel possible in these compositions. The flowability of the material is a limiting factor and it is generally difficult to make a composition with a clopidogrel content of more than 30 percent.
- clopidogrel base when processed to form a molecular dispersion or a solid solution in certain pharmaceutically acceptable polymers allows the formation of a free flowing granular powder containing clopidogrel base, with enhanced flowability,dissolution and stability.
- an object of the invention is to provide clopidogrel base in powder form which is free flowing and has enhanced stability and adequate dissolution.
- Another object is to provide clopidogrel base which is easily and conveniently processed into pharmaceutical compositions.
- a further object is to provide a process of preparation of clopidogrel base in powder form which is free flowing and has enhanced stability.
- a molecular dispersion comprising clopidogrel base and a pharmaceutically acceptable polymer, pharmaceutically acceptable excipients and optionally a surfactant.
- a molecular dispersion comprising clopidogrel base, a pharmaceutically acceptable polymer, pharmaceutically, acceptable excipients, substrate of inert component and optionally a surfactant.
- a formulation of clopidogrel needs to have sufficient flowability and compressibility to be converted into a tablet or to be filled into capsules.
- clopidogrel being an oily liquid, can not be processed either in a tablet or a capsule. Its conversion into a molecular dispersion affords a granular solid material that can be conveniently subjected to unit operations like size reduction and granulation that may be required to impart flowability and compressibility. If a dispersion does not form ciopidogrel will remain a liquid mixed with excipients and will not acquire properties needed for formulation into a tablet or a capsule.
- the blend of present invention is easily isolated in the form of stable, free-flowing granules, which exhibit good processing characteristics and can be easily and conveniently processed into pharmaceutical compositions (such as, for example, tablets, capsules, and the like).
- Blend refers to a solid composition, comprising generally of powders or granules, of clopidogrel base coated as a molecular dispersion in a water-soluble or insoluble polymer and a surfactant, onto at least one pharmaceutically acceptable excipient that is compatible with clopidogrel base to form a tertiary "molecular dispersion” or a “solid solution or dispersion”.
- solid dispersion refers to the dispersion of one or more active ingredient in an inert carrier or matrix at solid state prepared by melting (fusion), solvent, or the melting solvent method.
- Such drug-carrier combinations can also be prepared through coprecipitation of the two or more compounds from a common solvent.
- the present invention is about a similar process using a fluid bed processor to accomplish coprecipitation of the drug- polymer- surfactant coprecipitate from a common solvent on to a pharmaceutically acceptable excipient or excipient mixture.
- the approach involves a fluidized bed coating system, wherein a drug-carrier solution is sprayed onto the granular surface of excipients to produce either granules ready for tableting or drug-coated granules for encapsulation in one step.
- the method has been applied for both controlled- and immediate-release solid dispersions.
- the invention describes a molecular dispersion containing clopidogrel prepared by spraying a solution comprising clopidogrel base and a pharmaceutically acceptable polymer, either alone or in combination with another polymer, onto a pharmaceutical excipient or a mixture of pharmaceutical excipients and then removing solvent in a fluid-bed processor.
- the molecular dispersion of clopidogrel thus prepared can be used directly, or used in combination with additional excipients to prepare desired pharmaceutical dosage forms.
- the process can be carried out in a fluid bed processor using a bottom spray, a top spray or a tangential spray attachment.
- the flowability, processability and other characteristics of the clopidogrel base dispersion of the invention can be readily controlled through the choice of appropriate pharmaceutically acceptable excipients onto which the clopidogrel-polymer solution is coated; and by varying the process variables like the spray rate and the degree of fluidization. Further control on the particle size distribution can be exercised by subjecting the molecular dispersion obtained from the process to a size-reduction step.
- the flowability of the clopidogrel base is significantly enhanced by its conversion into the molecular dispersion blend according to this application. Such a significant improvement in the flow properties of a material indicates superior handling capabilities during processing into pharmaceutical dosage forms.
- Another important solid-state property of a pharmaceutical compound is its rate of dissolution in an aqueous fluid.
- the rate of dissolution of an active ingredient in a patient's stomach or in intestinal fluids can have therapeutic consequences because it affects the rate at which an orally-administered active ingredient reaches the bloodstream.
- the development of solid dispersions as a practically viable method to enhance bioavailability of poorly water-soluble drugs overcame the limitations of previous approaches such as salt formation, solubilization by cosolvents, and particle size reduction. Once the solid dispersion is exposed to aqueous media & the carrier dissolved, the dispersed drug is released as very fine, colloidal particles. Because of greatly enhanced surface area obtained in this way, the dissolution rate and the bioavailability of poorly water-soluble drugs are generally expected to be high.
- the commercial use of such systems has been limited primarily because of manufacturing problems with solid dispersion systems.
- the components are required to be in a finely divided form.
- the clopidogrel molecular dispersion blend of the present invention can be subject to operations such as size reduction, particle size classification, such as, by sieving, blending with other components, and the like, without substantial alteration of the flow properties and other important features of the blend.
- Clopidogrel base occurs as a semisolid mass which is difficult to handle and to process into a pharmaceutical formulation.
- the flowability of the clopidogrel base is significantly enhanced by its conversion into the dispersion according to this invention.
- the clopidogrel formulation of the invention is preferably based on compositions having a substrate forming inert component which may comprise of microcrystalline cellulose, a cyclodextrine or an ion-exchange resin.
- the substrate forming inert component is coated with a formulation which comprises clopidogrel, a water soluble polymer (either alone or in combination with another polymer) and a surface active agent, dissolved in a suitable solvent or a solvent mixture.
- the substrate forming inert component is typically in a concentration of 20- 50% of the final product weight.
- the substrate forming component is granulated with a pharmaceutically acceptable binder to provide uniformly sized granules to facilitate coating in a fluid bed processor.
- Clopidogrel may comprise from 10 to 40 weight % and preferably 30 to 40 wt % of the final formulation.
- Polymers to form the molecular dispersion, are selected from water soluble polymers like hydroxypropylmethylcellulose, hydroxypropylcellulose and methylcellulose; either alone or in combination with ethylcellulose. These polymers are used at a level of 10 to 100% of the clopidogrel weight.
- the surface active agent is any pharmaceutically acceptable, non-toxic surfactant. Suitable surface active agents include sodium lauryl sulfate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 and the like. The surface active agent are present at a level of from 0.1 to 5 wt % and preferably 0.25 to 2.5 wt % based on the total weight of the drug-polymer composition.
- the drug-polymer solution is prepared in a solvent mixture which consists of one or more solvents from isopropanol, ethanol, dichloromethane, acetone and water.
- the molecular dispersion is formed by spraying the substrate granules with an aqueous or non-aqueous solution which contains the clopidogrel, the polymer(s) and the surface active agent.
- the material is dried in the same coater till the moisture content is reduced to a level below 2%.
- the dried material is powdered using a suitable size-reduction equipment to get a material of the desired size distribution. This is further combined with commonly used excipients to make the desired pharmaceutical dosage form.
- the clopidogrel molecular dispersion blend of the invention can be further processed, either alone or with other active agents into various pharmaceutical dosage forms as is, or by combining with pharmaceutically acceptable excipients.
- the different pharmaceutical dosage forms where the clopidogrel molecular dispersion blend of the invention finds utility include, for example, tablets, capsules (hard and soft gelatin), granules, lozenges, sachets, pills, oral solutions, suspensions, and the like.
- Other pharmaceutically acceptable additives may be used as required for conversion of the blend into the final pharmaceutical dosage form and may include diluents, lubricants, glidants, disintegrating agents, wetting agents, and the like.
- the clopidogrel molecular dispersion blend renders clopidogrel base amenable for processing into a pharmaceutical dosage forms.
- This blend offers numerous advantages to the formulator. It occurs as free flowing granules and thereby allows itself to be directly compressed. Consequently, various unit operations as granulation, drying, milling, sieving and the like can be avoided.
- the enhanced flow property and density enables compression of clopidogrel molecular dispersion blend into tablets, with or without granulation, and filling into capsules or sachets.
- a clopidogrel base molecular dispersion blend was prepared, using the following:
- Microcrystalline cellulose is granulated by mixing with a 12 percent solution of polyvinylpyrrolidone in isopropanol. This mixture is dried in a draught of air.
- the dried material is powdered and the 18 to 40 mesh size fraction is collected for coating with the clopidogrel molecular dispersion.
- 360 g of clopidogrel base is dissolved in a solution of 272.5g of hydroxypropylmethylcellulose and 7g of Polysorbate 80 in 5054g of isopropanol and 720 g of water, with stirring.
- Granulated microcrystalline cellulose is loaded in to a bottom spray attachment of a fluid bed processor.
- Microcrystalline cellulose granules are coated with the clopidogrel:HPMC:Polysorbate 80 solution.
- the coated material is dried at 40-45° until a loss on drying at 105° of 1-2 percent by weight is achieved. 6.
- the dried granules are sifted through a 40 ASTM mesh sieve.
- the tablets made above are coated with a 5 percent solution of hydroxypropylmethylcellulose (6 cps) in a mixture of isopropanol and water, further comprising of titanium dioxide and red ferric oxide as pigments, triethylcitrate as the plasticizer and talc and lactose as the antitack.
- 6 cps hydroxypropylmethylcellulose
- the dissolution of clopidogrel from the tablets made from the molecular dispersion blend as described above and the pure clopidogrel was determined in various dissolution medium in a paddle type dissolution tester.
- the amount of clopidogrel dissolved at regular intervals till one hour was estimated by using a UV specrophotometric method.
- Dissolution of the pure clopidogrel base and its dissolution from tablets made from 5 its molecular dispersion in hydroxypropylmethylcellulose is given below.
- the enhancement in dissolution is obvious.
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Abstract
La présente invention concerne une dispersion moléculaire solide à écoulement libre comprenant une base de clopidogrel, au moins un polymère pharmaceutiquement acceptable, au moins un excipient pharmaceutiquement acceptable et éventuellement un surfactant. La présente invention concerne également un procédé de préparation d'une dispersion solide comprenant les étapes suivantes : dissolution d'une base de clopidogrel dans un polymère solide pharmaceutiquement acceptable, ou d'un mélange de polymères ou d'un mélange d'un polymère et d'un surfactant; et retrait du solvant par vaporisation de ladite solution sur un substrat comprenant un excipient pharmaceutiquement acceptable, dans un processeur à lit fluidisé.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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EP07827489A EP2086510A1 (fr) | 2006-11-27 | 2007-04-30 | Préparation d'une dispersion moléculaire à écoulement libre comprenant une base de clopidrogel |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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IN2191/CHE/2006 | 2006-11-27 | ||
IN2191CH2006 | 2006-11-27 |
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WO2008065674A1 true WO2008065674A1 (fr) | 2008-06-05 |
WO2008065674A8 WO2008065674A8 (fr) | 2008-10-09 |
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PCT/IN2007/000173 WO2008065674A1 (fr) | 2006-11-27 | 2007-04-30 | Préparation d'une dispersion moléculaire à écoulement libre comprenant une base de clopidrogel |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN114732788A (zh) * | 2022-04-14 | 2022-07-12 | 浙江高跖医药科技股份有限公司 | 一种硫酸氢氯吡格雷固体制剂及其制备工艺 |
CN115212180A (zh) * | 2022-09-03 | 2022-10-21 | 深圳市信宜特科技有限公司 | 一种阿司匹林和硫酸氢氯吡格雷的复方制剂及其制备方法 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2006074066A1 (fr) * | 2004-12-30 | 2006-07-13 | Nektar Therapeutics | Formulation non cristalline comprenant du clopidogrel |
-
2007
- 2007-04-30 EP EP07827489A patent/EP2086510A1/fr not_active Withdrawn
- 2007-04-30 WO PCT/IN2007/000173 patent/WO2008065674A1/fr active Application Filing
Patent Citations (1)
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---|---|---|---|---|
WO2006074066A1 (fr) * | 2004-12-30 | 2006-07-13 | Nektar Therapeutics | Formulation non cristalline comprenant du clopidogrel |
Non-Patent Citations (2)
Title |
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ANAND V ET AL: "ION-EXCHANGE RESINS: CARRYING DRUG DELIVERY FORWARD", DDT - DRUG DISCOVERY TODAY, ELSEVIER SCIENCE LTD, GB, vol. 6, no. 17, 17 September 2001 (2001-09-17), pages 905 - 914, XP001127363, ISSN: 1359-6446 * |
HO H-O ET AL: "The preparation and characterization of solid dispersions on pellets using a fluidized-bed system", INTERNATIONAL JOURNAL OF PHARMACEUTICS 09 AUG 1996 NETHERLANDS, vol. 139, no. 1-2, 9 August 1996 (1996-08-09), pages 223 - 229, XP002455273, ISSN: 0378-5173 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114732788A (zh) * | 2022-04-14 | 2022-07-12 | 浙江高跖医药科技股份有限公司 | 一种硫酸氢氯吡格雷固体制剂及其制备工艺 |
CN115212180A (zh) * | 2022-09-03 | 2022-10-21 | 深圳市信宜特科技有限公司 | 一种阿司匹林和硫酸氢氯吡格雷的复方制剂及其制备方法 |
CN115212180B (zh) * | 2022-09-03 | 2024-05-10 | 深圳市信宜特科技有限公司 | 一种阿司匹林和硫酸氢氯吡格雷的复方制剂及其制备方法 |
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WO2008065674A8 (fr) | 2008-10-09 |
EP2086510A1 (fr) | 2009-08-12 |
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