WO2007049868A1 - Stabilized pharmaceutical oral preparation containing clopidogrel bisulfate - Google Patents
Stabilized pharmaceutical oral preparation containing clopidogrel bisulfate Download PDFInfo
- Publication number
- WO2007049868A1 WO2007049868A1 PCT/KR2006/004046 KR2006004046W WO2007049868A1 WO 2007049868 A1 WO2007049868 A1 WO 2007049868A1 KR 2006004046 W KR2006004046 W KR 2006004046W WO 2007049868 A1 WO2007049868 A1 WO 2007049868A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cellulose
- starch
- clopidogrel bisulfate
- stabilized pharmaceutical
- pharmaceutical composition
- Prior art date
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- 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 48
- 229960003958 clopidogrel bisulfate Drugs 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- 239000001913 cellulose Substances 0.000 claims abstract description 29
- 229920002678 cellulose Polymers 0.000 claims abstract description 28
- 229920002472 Starch Polymers 0.000 claims abstract description 22
- 239000008107 starch Substances 0.000 claims abstract description 20
- 235000019698 starch Nutrition 0.000 claims abstract description 20
- 239000003826 tablet Substances 0.000 claims description 39
- 235000010980 cellulose Nutrition 0.000 claims description 27
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 21
- 239000008187 granular material Substances 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- -1 hydroxypropoxy group Chemical group 0.000 claims description 7
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 6
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 5
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 5
- 229920002261 Corn starch Polymers 0.000 claims description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 4
- 229920000881 Modified starch Polymers 0.000 claims description 4
- 239000008120 corn starch Substances 0.000 claims description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 4
- 239000001856 Ethyl cellulose Substances 0.000 claims description 3
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 3
- 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 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 3
- 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 3
- 229920000609 methyl cellulose Polymers 0.000 claims description 3
- 239000001923 methylcellulose Substances 0.000 claims description 3
- 235000010981 methylcellulose Nutrition 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 2
- 239000007900 aqueous suspension Substances 0.000 claims description 2
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 claims description 2
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 claims description 2
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 claims description 2
- 229940099112 cornstarch Drugs 0.000 claims description 2
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 2
- 229920001249 ethyl cellulose Polymers 0.000 claims description 2
- 229960004667 ethyl cellulose Drugs 0.000 claims description 2
- 239000007902 hard capsule Substances 0.000 claims description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 2
- 229940071826 hydroxyethyl cellulose Drugs 0.000 claims description 2
- 229960002900 methylcellulose Drugs 0.000 claims description 2
- 229920001592 potato starch Polymers 0.000 claims description 2
- 229940116317 potato starch Drugs 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 229940100486 rice starch Drugs 0.000 claims description 2
- 239000006228 supernatant Substances 0.000 claims description 2
- 229940100445 wheat starch Drugs 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 15
- 239000002552 dosage form Substances 0.000 abstract description 3
- 230000000052 comparative effect Effects 0.000 description 17
- 229940032147 starch Drugs 0.000 description 15
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- 239000011248 coating agent Substances 0.000 description 9
- 239000000314 lubricant Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 229960003009 clopidogrel Drugs 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- 238000000576 coating method Methods 0.000 description 6
- 238000013112 stability test Methods 0.000 description 6
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 229940020573 plavix Drugs 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 3
- 229960000913 crospovidone Drugs 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000007922 dissolution test Methods 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 239000007941 film coated tablet Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- GNWCZBXSKIIURR-UHFFFAOYSA-N (2-docosanoyloxy-3-hydroxypropyl) docosanoate Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(CO)OC(=O)CCCCCCCCCCCCCCCCCCCCC GNWCZBXSKIIURR-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 229960004977 anhydrous lactose Drugs 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 229940069328 povidone Drugs 0.000 description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- WJFYLCXWEXZNHU-UHFFFAOYSA-N 2,3,3a,4-tetrahydrothieno[3,2-b]pyridine Chemical class N1C=CC=C2SCCC21 WJFYLCXWEXZNHU-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 229920001531 copovidone Polymers 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 235000010944 ethyl methyl cellulose Nutrition 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229920003087 methylethyl cellulose Polymers 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- WBWWGRHZICKQGZ-HZAMXZRMSA-N taurocholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@@H](O)C1 WBWWGRHZICKQGZ-HZAMXZRMSA-N 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
- 229940057977 zinc stearate Drugs 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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4365—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
Definitions
- the present invention relates to a stabilized oral preparation comprising clopidogrel bisulfate, and in particular the oral preparation herein further comprises starch and cellulose along with the crystalline form 1 or form 2 clopidogrel bisulfate, which is highly susceptible to moisture and produces hydrated product-related impurities when formulated into oral preparations, thus showing storage stability even in the same dosage form with the conventional preparations.
- Clopidogrel bisulfate i.e. methyl(+)-(S)- ⁇ -(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl-5-acetate bisulfate is anti-thrombotic, which was first disclosed in European patent no. 281459.
- Clopidogrel bisulfate crystalline form 1 may be prepared following the synethsis method described in this patent.
- This European patent also describes about the enantiomers of tetrahydrothienopyridine derivatives and pharmaceutically acceptable salts thereof. Specifically, it discloses that the dextrorotatory isomer of clopidogrel bisulfate shows a superior antiplatelet activity while the levorotatory isomer has comparatively less superior activity and nature.
- U. S. patent no. 4,847,265 is directed to an isomeric clopidogrel, its pharmaceutical salts and a pharmaceutical formulation containing pharmaceutically acceptable excipients.
- U. S. patent no. 6,429,210 is directed to a clopidogrel bisulfate among various salts, and discloses that the crystalline form 2 has superior stability to the crystalline form 1.
- U. S. patent publication no. 2003/0096837 relates to a pharmaceutical formulation containing clopidogrel bisulfate and zinc stearate, stearic acid and sodium stearyl fumarate as lubricants, which further comprises crospovidone, sodium croscarmellose, sodium starch glycolate as disintegrants for improving stability.
- Plavix Sanofi-Synthelabo Korea
- Plavix contains 98 mg of clopidogrel bisulfate (i.e. 75 mg of clopidogrel) per a tablet.
- This tablet is film-coated, and the non-coated tablet comprises mannitol, hydrogenated caster oil, microciystalline cellulose, poly(ethylene glycol) 6000 and pregelatinized starch.
- Each tablet weighs about 240 mg.
- the present inventors performed extensive studies to solve the aforementioned problems, and finally completed the present invention by developing an oral preparation containing clopidogrel bisulfate irrespectively of its polymorphic form alo ng with starch and cellulose-based excipients, thus showing superior storage stability with equivalent drug release.
- the present invention aims to provide an oral preparation containing clopidogrel bisulfate, starch and cellulose with improved storage stability.
- the present invention relates to an oral preparation with improved storage stability, which comprises clopidogrel bisulfate as active ingredient and further comprises starch and cellulose.
- the present invention relates to a stabilized oral preparation containing starch and cellulose along with the clopirogrel bisulfate crystalline form 1 or form 2, which is susceptible to moisture and produces hydrated product-related impurities when formulated into oral preparations, thus showing storage stability even in the same dosage form with the conventional preparations and enabling improvement in stability and quality during the shelf life.
- Active ingredient herein is clopidogrel or salts thereof susceptible light and moisture.
- salts include without limitation bisulfate, hydrochloride , hydrobromide, taurocholate, and more preferably bisulfate.
- starch is selected for better storage stability of the clopidogrel preparation herein because starch has good compatibility with drugs and absorbs moisture within tablets, thus increasing the storage stability.
- Starch herein is preferred to take on reddish purple or dark blue when 0.1 N iodide solution is dropped on the hydrated slurry of the starch and pH value of the supernatant in 20 w/v% aqueous suspension is pH 4.0-8.0.
- More preferable examples of the starch herein include without limitation potato starch, corn starch, wheat starch, rice starch and pregelatinized starch, and 0.15-5 weight parts of starch is preferred relative to one weight part of clopidogrel bisulfate.
- An amount of below 0.15 weight parts may be insufficient to suppress the generation of product-related impurities, while an amount of above 5 weight parts may cause difficulty in tablet formulation.
- More preferable amount of starch is 0.3-1.5 weight parts relative to one weight part of clopidogrel bisulfate.
- the formulation herein comprises cellulose compatible with clopidogrel and its salts, thus improving storage stability of the clopidogrel preparation.
- the cellulose include without limitation cellulose purified from natural pulp, partially non-polarized cellulose and cellulose having 4-32% of hydroxypropoxy group.
- More preferable examples of the cellulose-based excipients include without limitation microcrystalline cellulose, crystalline cellulose, hydroxypropyl cellulose, hy- droxypropylmethyl cellulose, methyl cellulose, hydroxyethyl cellulose, ethyl cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium and a mixture thereof.
- cellulose-based excipients include without Ii mitation microcrystalline cellulose, hydroxypropyl cellulose and hydroxypropylmethyl cellulose.
- the preferable content of the cellulose-based excipients is 0.5-5 weight parts relative to one weight part of clopidogrel bisulfate. The content of below 0.5 weight parts may not be sufficient for securing stabilizing effect, while the content of above 5 weight parts may cause problem in administration due to the large size of the preparation. More preferable content is 0.5-1.2 weight parts relative to one weight part of clopidogrel bisulfate.
- the preparation herein may further comprise 0.3-5 weight parts of conventionally used pharmaceutically acceptable excipients such as disintegrants, binder, lubricants and coating agents relative to one weight part of clopidogrel bisulfate, and preferably may be formulated into powders, granules, hard capsules and tablets.
- pharmaceutically acceptable disintegrants include without limitation crospovidone, glycolate and croscarmellose sodium.
- pharmaceutically acceptable binder include without limitation povidone, copovidone and cellulose-based binder.
- Examples of pharmaceutically acceptable lubricants include without limitation magnesium stearate, sodium stearyl fumarate, talc, glyceryl fatty acid esters, glycerol dibehenate and other conventionally used lubricants.
- Examples of pharmaceutically acceptable coating agent include poly(vinyl alcohol), hydroxypropylmethyl cellulose, methyl cellulose and ethyl cellulose.
- Figure 1 shows the dissolution profiles of a commercial preparation and a preparation according to Example 2 at pH 2.0.
- Figure 2 shows the dissolution profiles of a commercial preparation and a preparation according to Example 6 at pH 2.0.
- Excipient granules were prepared with a high-shear mixer (SM-5, Sejong Mechanics, Korea) by incorporating excipients as shown in TABLE 1. Thus obtained excipient granules were dried and passed through a 30 mesh sieve. Then granules were admixed with active ingredient and lubricants, and compressed with a single punch press (ERWEKA) to produce round tablets. The round tablets were coated with coating base dissolved in distilled water by using a coating machine (SFC-30N, Sejong Mechanics, Korea), thus providing film-coated tablets.
- SFC-30N Sejong Mechanics, Korea
- Microcrystalline cellulose 2 36 60 79 91
- Coating agents Opadry AMB 7 10 10 10 10 10 10
- Excipient granules were prepared with a high-shear mixer (SM-5, Sejong Mechanics, Korea) by incorporating excipients as shown in TABLE 2. Thus obtained excipient granules were dried and passed through a 30 mesh sieve. Then granules were admixed with active ingredient and lubricants, and compressed with a single punch press (ERWEKA) to produce round tablets. The round tablets were coated with coating base dissolved in distilled water by using a coating machine (SFC-30N, Sejong Mechanics, Korea), thus providing film-coated tablets.
- SFC-30N Sejong Mechanics, Korea
- Excipient granules were prepared by incorporating excipients as in Examples 3 and 8 using a fluidized-bed granulator (DPL-I, Mendel Korea ). The temperatures at the inlet and the outlet of the granulator were controlled to 65 °C and 40 °C, respectively. The spraying quantity and the spraying pressure were adjusted to 10 mL/min and 0.8 kg/cm 2 , respctively. Thus obtained excipient granules were dried and passed through a 30 mesh sieve. The granules were admixed with active ingredient and lubricants, and compressed with a single punch press (ERWEKA) to produce round tablets. The round tablets were coated with coating base dissolved in distilled water by using a coating machine (SFC-30N, Sejong Mechanics, Korea), thus providing film-coated tablets.
- a coating machine SFC-30N, Sejong Mechanics, Korea
- Comparative Examples 1-6 and the Plavix tablets were subject to the stability tests.
- the test conditions were the same as described in ICH (International Conference on Harmonization) guideline. That is, a long-term test was performed at 25 °C and 60% RH, and a accelerated test was performed at 40 °C and 75% RH as open tests.
- the tablets in Examples here remarkably decreased the generation of the impurities A and C, thus showing superior stability, to the commercially available tablets and those of Comparative Examples herein.
- the tablets were by far superior to Comparative Example in terms of impurity A, irrespectively of polymorphic form.
- the crystalline form 1 tablets of Examples herein were superior to those of Comparative Examples, and the crystalline form 2 tablets of Examples herein showed equivalent or better stability than those of Comparative Examples. That is, the tablets of the present invention were ascertained to have an improved storage stability as compared to the commercially available tablets and and those of Comparative Examples.
- the clopidogrel bisulfate containing tablets according to the present invention further comprise predetermined amounts of starch and cellulose, thus improving the storage stability and enabling a longer shelf life and a better quality of products.
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Abstract
The present invention relates to a stabilized oral preparation comprising clopidogrel bisulfate, and in particular the oral preparation herein further comprises starch and cellulose along with the crystalline form 1 or form 2 clopidogrel bisulfate, which is susceptible to moisture and produces hydrated product-related impurities when formulated into oral preparations, thus showing storage stability even in the same dosage form with the conventional preparations.
Description
Description STABILIZED PHARMACEUTICAL ORAL PREPARATION
CONTAINING CLOPIDOGREL BISULFATE
Technical Field
[1]
[2] The present invention relates to a stabilized oral preparation comprising clopidogrel bisulfate, and in particular the oral preparation herein further comprises starch and cellulose along with the crystalline form 1 or form 2 clopidogrel bisulfate, which is highly susceptible to moisture and produces hydrated product-related impurities when formulated into oral preparations, thus showing storage stability even in the same dosage form with the conventional preparations.
[3]
Background Art
[4]
[5] Clopidogrel bisulfate, i.e. methyl(+)-(S)-α-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl-5-acetate bisulfate is anti-thrombotic, which was first disclosed in European patent no. 281459. Clopidogrel bisulfate crystalline form 1 may be prepared following the synethsis method described in this patent. This European patent also describes about the enantiomers of tetrahydrothienopyridine derivatives and pharmaceutically acceptable salts thereof. Specifically, it discloses that the dextrorotatory isomer of clopidogrel bisulfate shows a superior antiplatelet activity while the levorotatory isomer has comparatively less superior activity and nature.
[6] U. S. patent no. 4,847,265 is directed to an isomeric clopidogrel, its pharmaceutical salts and a pharmaceutical formulation containing pharmaceutically acceptable excipients. In particular, U. S. patent no. 6,429,210 is directed to a clopidogrel bisulfate among various salts, and discloses that the crystalline form 2 has superior stability to the crystalline form 1.
[7] Among prior art describing on the stability of clopidogrel and its salts, U. S. patent publication no. 2003/0096837 relates to a pharmaceutical formulation containing clopidogrel bisulfate and zinc stearate, stearic acid and sodium stearyl fumarate as lubricants, which further comprises crospovidone, sodium croscarmellose, sodium starch glycolate as disintegrants for improving stability.
[8] Currently marketed commercial product, Plavix ( Sanofi-Synthelabo Korea ), which was used herein as a control drug, contains 98 mg of clopidogrel bisulfate (i.e. 75 mg of clopidogrel) per a tablet. This tablet is film-coated, and the non-coated tablet
comprises mannitol, hydrogenated caster oil, microciystalline cellulose, poly(ethylene glycol) 6000 and pregelatinized starch. Each tablet weighs about 240 mg.
[9] However, there has been no report about a preparation containing clopidogrel bisulfate irrespectively of its polymorphic form along with starch and cellulose-based excipients according to the present invention.
[10] The present inventors performed extensive studies to solve the aforementioned problems, and finally completed the present invention by developing an oral preparation containing clopidogrel bisulfate irrespectively of its polymorphic form alo ng with starch and cellulose-based excipients, thus showing superior storage stability with equivalent drug release.
[11] Therefore, the present invention aims to provide an oral preparation containing clopidogrel bisulfate, starch and cellulose with improved storage stability.
[12]
Disclosure
[13]
[14] The present invention relates to an oral preparation with improved storage stability, which comprises clopidogrel bisulfate as active ingredient and further comprises starch and cellulose.
[15] Hereunder is provided a detailed description of the present invention.
[16] The present invention relates to a stabilized oral preparation containing starch and cellulose along with the clopirogrel bisulfate crystalline form 1 or form 2, which is susceptible to moisture and produces hydrated product-related impurities when formulated into oral preparations, thus showing storage stability even in the same dosage form with the conventional preparations and enabling improvement in stability and quality during the shelf life.
[17] Active ingredient herein is clopidogrel or salts thereof susceptible light and moisture. Preferable example of salts include without limitation bisulfate, hydrochloride , hydrobromide, taurocholate, and more preferably bisulfate.
[18] Meanwhile, starch is selected for better storage stability of the clopidogrel preparation herein because starch has good compatibility with drugs and absorbs moisture within tablets, thus increasing the storage stability. Starch herein is preferred to take on reddish purple or dark blue when 0.1 N iodide solution is dropped on the hydrated slurry of the starch and pH value of the supernatant in 20 w/v% aqueous suspension is pH 4.0-8.0. More preferable examples of the starch herein include without limitation potato starch, corn starch, wheat starch, rice starch and pregelatinized starch, and 0.15-5 weight parts of starch is preferred relative to one weight part of clopidogrel bisulfate. An amount of below 0.15 weight parts may be insufficient to suppress the generation of product-related impurities, while an amount of
above 5 weight parts may cause difficulty in tablet formulation. More preferable amount of starch is 0.3-1.5 weight parts relative to one weight part of clopidogrel bisulfate.
[19] Further, the formulation herein comprises cellulose compatible with clopidogrel and its salts, thus improving storage stability of the clopidogrel preparation. Preferable examples of the cellulose include without limitation cellulose purified from natural pulp, partially non-polarized cellulose and cellulose having 4-32% of hydroxypropoxy group. More preferable examples of the cellulose-based excipients include without limitation microcrystalline cellulose, crystalline cellulose, hydroxypropyl cellulose, hy- droxypropylmethyl cellulose, methyl cellulose, hydroxyethyl cellulose, ethyl cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium and a mixture thereof. Most preferable examples of the cellulose-based excipients include without Ii mitation microcrystalline cellulose, hydroxypropyl cellulose and hydroxypropylmethyl cellulose. The preferable content of the cellulose-based excipients is 0.5-5 weight parts relative to one weight part of clopidogrel bisulfate. The content of below 0.5 weight parts may not be sufficient for securing stabilizing effect, while the content of above 5 weight parts may cause problem in administration due to the large size of the preparation. More preferable content is 0.5-1.2 weight parts relative to one weight part of clopidogrel bisulfate.
[20] The preparation herein may further comprise 0.3-5 weight parts of conventionally used pharmaceutically acceptable excipients such as disintegrants, binder, lubricants and coating agents relative to one weight part of clopidogrel bisulfate, and preferably may be formulated into powders, granules, hard capsules and tablets. Examples of the pharmaceutically acceptable disintegrants include without limitation crospovidone, glycolate and croscarmellose sodium. Further, examples of pharmaceutically acceptable binder include without limitation povidone, copovidone and cellulose-based binder. Examples of pharmaceutically acceptable lubricants include without limitation magnesium stearate, sodium stearyl fumarate, talc, glyceryl fatty acid esters, glycerol dibehenate and other conventionally used lubricants. Examples of pharmaceutically acceptable coating agent include poly(vinyl alcohol), hydroxypropylmethyl cellulose, methyl cellulose and ethyl cellulose.
[21] Thus obtained tablets further comprise predetermined amounts of starch and cellulose, thus improving the storage stability and enabling a longer shelf life and a better quality of products.
[22]
Description of Drawings
[23]
[24] Figure 1 shows the dissolution profiles of a commercial preparation and a
preparation according to Example 2 at pH 2.0.
[25] Figure 2 shows the dissolution profiles of a commercial preparation and a preparation according to Example 6 at pH 2.0. [26]
Best Mode
[27] [28] The present invention is described more specifically by the following Examples. Examples herein are meant only to illustrate the present invention, but in no way to limit the claimed invention.
[29] [30] Examples 1-4 [31] Excipient granules were prepared with a high-shear mixer (SM-5, Sejong Mechanics, Korea) by incorporating excipients as shown in TABLE 1. Thus obtained excipient granules were dried and passed through a 30 mesh sieve. Then granules were admixed with active ingredient and lubricants, and compressed with a single punch press (ERWEKA) to produce round tablets. The round tablets were coated with coating base dissolved in distilled water by using a coating machine (SFC-30N, Sejong Mechanics, Korea), thus providing film-coated tablets.
TABLE 1 ξredients (mg in a tablet) Ex. 1 Ex. 2 Ex. 3 Ex. 4
Active
Clopidogrel bisulf ate pharmaceutical 98 98 98 98 (Crystalline form I)1) ingredient
Microcrystalline cellulose2) 36 60 79 91
Corn starch3' 84 60 41 30
Excipient Low substituted hydroxypropyl granules 32 32 25 25 cellulose4)
Hydroxypropylmethyl cellulose5) 0.3 0.3 2.5 2.5
Lubricants Glycerol dibehenate6'
Coating agents Opadry AMB7) 10 10 10 10
1) Clopidogrel bisulfate, Dr. Reddy
2) Comprcccl, Mingtai
3) Corn starch, Susung Phamaceuticals
4) L-HPC, Shin-Etsu
5) Pharmacoat, Shin-Etsu
6) Compritol, Gattefosse
T) OPADRY AMB 80W44094, Colorcon
[32] [33] Examples 5-8 [34] Excipient granules were prepared with a high-shear mixer (SM-5, Sejong Mechanics, Korea) by incorporating excipients as shown in TABLE 2. Thus obtained excipient granules were dried and passed through a 30 mesh sieve. Then granules were
admixed with active ingredient and lubricants, and compressed with a single punch press (ERWEKA) to produce round tablets. The round tablets were coated with coating base dissolved in distilled water by using a coating machine (SFC-30N, Sejong Mechanics, Korea), thus providing film-coated tablets.
TABLE 2
[35] [36] Examples 9-10 [37] Excipient granules were prepared by incorporating excipients as in Examples 3 and 8 using a fluidized-bed granulator (DPL-I, Mendel Korea ). The temperatures at the inlet and the outlet of the granulator were controlled to 65 °C and 40 °C, respectively. The spraying quantity and the spraying pressure were adjusted to 10 mL/min and 0.8 kg/cm2, respctively. Thus obtained excipient granules were dried and passed through a 30 mesh sieve. The granules were admixed with active ingredient and lubricants, and compressed with a single punch press (ERWEKA) to produce round tablets. The round tablets were coated with coating base dissolved in distilled water by using a coating machine (SFC-30N, Sejong Mechanics, Korea), thus providing film-coated tablets.
[38] [39] Comparative Example 1
(5) [40] Tablets of the same content with the commercial marketed product, Plavix ( Sanofi-Synthelabo Korea ) were prepared as control drugs. 98 mg of clopidogrel bisulfate crystalline form 1, 68 mg of mannitol, 34 mg of polyethyleneglycol, 31.0 mg of microcrystalline cellulose, 12.9 mg of low substituted hydroxypropyl cellulose and 3.3 mg of hydrogenated castor oil were admixed per a tablet and compressed to produce tablets.
[41]
[42] Comparative Example 2
[43] 98 mg of clopidogrel bisulfate crystalline form 1, 68.8 mg of anhydrous lactose for direct compression, 68.8 mg of anhydrous dibasic calcium phosphate, 2.48 mg of povidone, 7.44 mg of crospovidone and 2.48 mg of magnesium stearate were admixed per a tablet and compressed to produce tablets.
[44]
[45] Comparative Example 3
[46] 98 mg of clopidogrel bisulfate crystalline form 1, 10.5 mg of pregelatinized starch,
7.5 mg of polyethyleneglycol, 107.925 mg of anhydrous lactose, 12.9 mg of micro- crystalline cellulose and 3.3 mg of hydrogenated castor oil were admixed per a tablet and compressed to produce tablets.
[47]
[48] Comparative Example 4
[49] Tablets were prepared by using clopidogrel bisulfate crystalline form 2 and the same excipients as in Comparative Example 1.
[50]
[51] Comparative Example 5
[52] Tablets were prepared by using clopidogrel bisulfate crystalline form 2 and the same excipients as in Comparative Example 2.
[53]
[54] Comparative Example 6
[55] Tablets were prepared by using clopidogrel bisulfate crystalline form 2 and the same excipients as in Comparative Example 3.
[56]
[57] Test Example 1: Stability test
[58] The clopidogrel bisulfate tablets prepared in Examples 1, 2, 5, 7, 9 and 10 and
Comparative Examples 1-6 and the Plavix tablets (Sanofi-Synthelabo Korea) were subject to the stability tests. The test conditions were the same as described in ICH (International Conference on Harmonization) guideline. That is, a long-term test was performed at 25 °C and 60% RH, and a accelerated test was performed at 40 °C and 75% RH as open tests.
[59] The analysis was performed according to USP 3215-3216. Most product-related impurities were ascertained to be hydrolysis byproducts (RRT 0.5, Impurity A) and R- enantiomer (RRT 2.0, Impurity C) in terms of RRT (the relative retention time). USP recommended that impurity A, impurity C, unknown impurity and total impurity should be below 0.2%, 1.0%, 0.1% and 1.2%, respectively. The increased amounts of the product-related impurities were calculated relative to initial values, and provided in
TABLEs 3-6 below.
TABLE 3. Stability tests of commercial preparations and those in Examples 1, 2 & 9 (open test, 3 weeks)
TABLE 4. Stability tests of preparations in Comparative Examples 1, 2 & 3 (open test, 3 weeks
TABLE 5. Stability tests of commercial preparations and those in Examples 5, 7 & 10 (open test, 3 weeks)
TABLE 6. Stability tests of preparations in Comparative Examples 4, 5 & 6 (open test, 3 weeks
[60] As shown in TABLEs 3-6 above, the tablets in Examples here remarkably decreased the generation of the impurities A and C, thus showing superior stability, to the commercially available tablets and those of Comparative Examples herein. In particular, the tablets were by far superior to Comparative Example in terms of impurity A, irrespectively of polymorphic form. With respect to the impurity C, the
crystalline form 1 tablets of Examples herein were superior to those of Comparative Examples, and the crystalline form 2 tablets of Examples herein showed equivalent or better stability than those of Comparative Examples. That is, the tablets of the present invention were ascertained to have an improved storage stability as compared to the commercially available tablets and and those of Comparative Examples.
[61]
[62] Test Example 2: Dissolution test
[63] The clopidogrel bisulfate tablets of Example 2 and 6, and the Plavix® 75 mg tablets
( Sanofi-Synthelabo Korea ) were subject to the dissolution test according to method II Paddle test as described in the Korean Pharmacopoeia VIII, respectively. The dissolution test was performed at pH 2.0 as recommended in USP 25, and media was 1000 mL and paddle rotation speed was 50 rpm.
[64] 4 mL of the sample was taken at 5, 10, 15 and 30 minutes, and filtered with 45 μm membrane filter. The solution was analyzed using the absorption spectrophotometer at a wavelength of 240 nm.
[65] The tablets of Examples herein were asctained to show equivalent dissolution behavior as compared to the commercially availale tablets (figure 1).
[66]
Industrial Applicability
[67]
[68] As set forth above, the clopidogrel bisulfate containing tablets according to the present invention further comprise predetermined amounts of starch and cellulose, thus improving the storage stability and enabling a longer shelf life and a better quality of products.
Claims
[1] A stabilized pharmaceutical composition comprising clopidogrel bisulfate along with 0.15-5 weight parts of starch and 0.5-5 weight parts of cellulose relative to one weight part of the clopidogrel bisulfate.
[2] The stabilized pharmaceutical composition of claim 1, wherein the starch in the supernatant of 20w/v% aqueous suspension is pH 4.0-8.0.
[3] The stabilized pharmaceutical composition of claim 2, wherein the starch is selected from the group consisting of potato starch, corn starch, wheat starch, rice starch and pregelatinized starch.
[4] The stabilized pharmaceutical composition of claim 1, which comprises 0.3-1.5 weight parts of the starch relative to one weight part of clopidogrel bisulfate.
[5] The stabilized pharmaceutical composition of claim 1, wherein the cellulose is selected from the group consisting of cellulose purified from natural pulp, partially non-polarized cellulose and cellulose having 4-32% of hydroxypropoxy group.
[6] The stabilized pharmaceutical composition of claim 5, wherein the cellulose- based excipients are selected from the group consisting of microcrystalline cellulose, crystalline cellulose, hydroxypropylcellulose, hydroxypropylmethyl- cellulose, methylcellulose, hydroxyethylcellulose, ethylcellulose, car- boxymethylcellulose calcium, carboxymethyl cellulose sodium and a mixture thereof.
[7] The stabilized pharmaceutical composition of claim 1, which comprises 0.5-1.2 weight parts of cellulose relative to one weight part of clopidogrel bisulfate.
[8] The stabilized pharmaceutical composition of claim 1, wherein the clopidogrel bisulfate is crystalline form 1 or form 2
[9] The stabilized pharmaceutical composition of claim 1, wherein the preparation is selected from the group consisting of powders, granules, hard capsules and tablets.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020050100460A KR20070044323A (en) | 2005-10-24 | 2005-10-24 | Stabilized pharmaceutical oral preparation containing clopidogrel bisulfate |
| KR10-2005-0100460 | 2005-10-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2007049868A1 true WO2007049868A1 (en) | 2007-05-03 |
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ID=37967949
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/KR2006/004046 WO2007049868A1 (en) | 2005-10-24 | 2006-10-09 | Stabilized pharmaceutical oral preparation containing clopidogrel bisulfate |
Country Status (4)
| Country | Link |
|---|---|
| KR (1) | KR20070044323A (en) |
| AR (1) | AR056721A1 (en) |
| TW (1) | TW200727898A (en) |
| WO (1) | WO2007049868A1 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009048557A1 (en) * | 2007-10-10 | 2009-04-16 | Mallinckrodt Baker, Inc. | Directly compressible high functionality granular microcrystalline cellulose based excipient, manufacturing process and use thereof |
| EP2095815A1 (en) | 2008-02-26 | 2009-09-02 | Laboratorios Lesvi, S.L. | Pharmaceutical formulations containing clopidogrel |
| CN103717207A (en) * | 2011-07-12 | 2014-04-09 | 三进制药株式会社 | Spherical particles of clopidogrel bisulfate, pharmaceutical composition including same, and method for manufacturing same |
| WO2015189650A1 (en) | 2014-06-13 | 2015-12-17 | Skillpharm Kft. | Clopidogrel for use in the treatment of benign prostatic hyperplasia |
| CN109528669A (en) * | 2018-12-25 | 2019-03-29 | 哈尔滨珍宝制药有限公司 | Bisulfate clopidogrel composition, clopidogrel hydrogen sulfate tablet and preparation method thereof |
| CN112999180A (en) * | 2019-12-20 | 2021-06-22 | 青岛黄海制药有限责任公司 | Clopidogrel hydrogen sulfate crystal form II tablet and preparation method thereof |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111166745A (en) * | 2020-01-19 | 2020-05-19 | 成都施贝康生物医药科技有限公司 | Composition containing racemic oxypyramine or salt thereof and application |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2792836A1 (en) * | 1999-04-30 | 2000-11-03 | Sanofi Sa | PHARMACEUTICAL COMPOSITION IN UNIT FORM CONTAINING ASPIRIN AND CLOPIDOGREL HYDROGENOSULFATE |
| EP1310245A1 (en) * | 2001-11-09 | 2003-05-14 | SHERMAN, Bernard Charles | Clopidogrel bisulfate tablet formulation |
| WO2005070464A2 (en) * | 2004-01-21 | 2005-08-04 | Biofarma Ilac Sanayi Ve Ticaret A.S. | A tablet formulation of clopidogrel bisulphate |
-
2005
- 2005-10-24 KR KR1020050100460A patent/KR20070044323A/en not_active Application Discontinuation
-
2006
- 2006-10-09 WO PCT/KR2006/004046 patent/WO2007049868A1/en active Application Filing
- 2006-10-23 TW TW095138977A patent/TW200727898A/en unknown
- 2006-10-24 AR ARP060104644A patent/AR056721A1/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2792836A1 (en) * | 1999-04-30 | 2000-11-03 | Sanofi Sa | PHARMACEUTICAL COMPOSITION IN UNIT FORM CONTAINING ASPIRIN AND CLOPIDOGREL HYDROGENOSULFATE |
| EP1310245A1 (en) * | 2001-11-09 | 2003-05-14 | SHERMAN, Bernard Charles | Clopidogrel bisulfate tablet formulation |
| WO2005070464A2 (en) * | 2004-01-21 | 2005-08-04 | Biofarma Ilac Sanayi Ve Ticaret A.S. | A tablet formulation of clopidogrel bisulphate |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009048557A1 (en) * | 2007-10-10 | 2009-04-16 | Mallinckrodt Baker, Inc. | Directly compressible high functionality granular microcrystalline cellulose based excipient, manufacturing process and use thereof |
| EP2095815A1 (en) | 2008-02-26 | 2009-09-02 | Laboratorios Lesvi, S.L. | Pharmaceutical formulations containing clopidogrel |
| CN103717207A (en) * | 2011-07-12 | 2014-04-09 | 三进制药株式会社 | Spherical particles of clopidogrel bisulfate, pharmaceutical composition including same, and method for manufacturing same |
| WO2015189650A1 (en) | 2014-06-13 | 2015-12-17 | Skillpharm Kft. | Clopidogrel for use in the treatment of benign prostatic hyperplasia |
| CN109528669A (en) * | 2018-12-25 | 2019-03-29 | 哈尔滨珍宝制药有限公司 | Bisulfate clopidogrel composition, clopidogrel hydrogen sulfate tablet and preparation method thereof |
| CN112999180A (en) * | 2019-12-20 | 2021-06-22 | 青岛黄海制药有限责任公司 | Clopidogrel hydrogen sulfate crystal form II tablet and preparation method thereof |
| CN112999180B (en) * | 2019-12-20 | 2022-08-30 | 青岛黄海制药有限责任公司 | Clopidogrel hydrogen sulfate crystal form II tablet and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20070044323A (en) | 2007-04-27 |
| AR056721A1 (en) | 2007-10-17 |
| TW200727898A (en) | 2007-08-01 |
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