CN1032490A - 新药物制剂及其制备方法 - Google Patents
新药物制剂及其制备方法 Download PDFInfo
- Publication number
- CN1032490A CN1032490A CN88109129A CN88109129A CN1032490A CN 1032490 A CN1032490 A CN 1032490A CN 88109129 A CN88109129 A CN 88109129A CN 88109129 A CN88109129 A CN 88109129A CN 1032490 A CN1032490 A CN 1032490A
- Authority
- CN
- China
- Prior art keywords
- metoprolol
- preparation
- dihydropyridine
- milligrams
- globule
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 48
- 239000008194 pharmaceutical composition Substances 0.000 title description 2
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 claims abstract description 56
- 229960002237 metoprolol Drugs 0.000 claims abstract description 53
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 claims abstract description 32
- 239000000203 mixture Substances 0.000 claims abstract description 27
- -1 hydroxypropyl Chemical group 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 claims description 13
- 229960001597 nifedipine Drugs 0.000 claims description 13
- 239000004359 castor oil Substances 0.000 claims description 10
- 235000019438 castor oil Nutrition 0.000 claims description 10
- 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 claims description 10
- 239000000758 substrate Substances 0.000 claims description 9
- 239000000463 material Substances 0.000 claims description 8
- 239000003405 delayed action preparation Substances 0.000 claims description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 6
- 239000000194 fatty acid Substances 0.000 claims description 6
- 229930195729 fatty acid Natural products 0.000 claims description 6
- 150000004665 fatty acids Chemical class 0.000 claims description 6
- RGHAZVBIOOEVQX-UHFFFAOYSA-N Metoprolol succinate Chemical class OC(=O)CCC(O)=O.COCCC1=CC=C(OCC(O)CNC(C)C)C=C1.COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 RGHAZVBIOOEVQX-UHFFFAOYSA-N 0.000 claims description 5
- 239000000480 calcium channel blocker Substances 0.000 claims description 5
- WSWCOQWTEOXDQX-MQQKCMAXSA-M (E,E)-sorbate Chemical compound C\C=C\C=C\C([O-])=O WSWCOQWTEOXDQX-MQQKCMAXSA-M 0.000 claims description 4
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 claims description 4
- 229940127291 Calcium channel antagonist Drugs 0.000 claims description 4
- 229920002678 cellulose Polymers 0.000 claims description 4
- 239000001913 cellulose Substances 0.000 claims description 4
- 229940075554 sorbate Drugs 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 239000000470 constituent Substances 0.000 claims description 3
- 150000002194 fatty esters Chemical class 0.000 claims description 2
- 229920006254 polymer film Polymers 0.000 claims 1
- 239000002897 polymer film coating Substances 0.000 claims 1
- 238000005507 spraying Methods 0.000 claims 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical group OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims 1
- 239000000674 adrenergic antagonist Substances 0.000 abstract description 11
- 238000009472 formulation Methods 0.000 abstract description 2
- 239000003814 drug Substances 0.000 description 47
- 239000003826 tablet Substances 0.000 description 31
- 229940079593 drug Drugs 0.000 description 25
- 238000000034 method Methods 0.000 description 17
- 239000000499 gel Substances 0.000 description 13
- 230000000694 effects Effects 0.000 description 10
- 239000008187 granular material Substances 0.000 description 9
- 210000002381 plasma Anatomy 0.000 description 9
- 239000001856 Ethyl cellulose Substances 0.000 description 7
- 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 7
- 239000011248 coating agent Substances 0.000 description 7
- 238000000576 coating method Methods 0.000 description 7
- 229920001249 ethyl cellulose Polymers 0.000 description 7
- 235000019325 ethyl cellulose Nutrition 0.000 description 7
- 239000005995 Aluminium silicate Substances 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- PZZYQPZGQPZBDN-UHFFFAOYSA-N aluminium silicate Chemical compound O=[Al]O[Si](=O)O[Al]=O PZZYQPZGQPZBDN-UHFFFAOYSA-N 0.000 description 6
- 235000012211 aluminium silicate Nutrition 0.000 description 6
- 229910000323 aluminium silicate Inorganic materials 0.000 description 6
- 238000013270 controlled release Methods 0.000 description 6
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 6
- 230000036470 plasma concentration Effects 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 239000011159 matrix material Substances 0.000 description 5
- 230000007246 mechanism Effects 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 229960000939 metoprolol succinate Drugs 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- PVHUJELLJLJGLN-INIZCTEOSA-N (S)-nitrendipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC([N+]([O-])=O)=C1 PVHUJELLJLJGLN-INIZCTEOSA-N 0.000 description 3
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 208000024172 Cardiovascular disease Diseases 0.000 description 3
- 229920002907 Guar gum Polymers 0.000 description 3
- 238000009825 accumulation Methods 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 235000010980 cellulose Nutrition 0.000 description 3
- 239000000665 guar gum Substances 0.000 description 3
- 235000010417 guar gum Nutrition 0.000 description 3
- 229960002154 guar gum Drugs 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 229920001206 natural gum Polymers 0.000 description 3
- 229960005425 nitrendipine Drugs 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000005063 solubilization Methods 0.000 description 3
- 230000007928 solubilization Effects 0.000 description 3
- 238000013268 sustained release Methods 0.000 description 3
- 239000012730 sustained-release form Substances 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- 239000000230 xanthan gum Substances 0.000 description 3
- 229920001285 xanthan gum Polymers 0.000 description 3
- 235000010493 xanthan gum Nutrition 0.000 description 3
- 229940082509 xanthan gum Drugs 0.000 description 3
- RZTAMFZIAATZDJ-HNNXBMFYSA-N 5-o-ethyl 3-o-methyl (4s)-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-HNNXBMFYSA-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
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 235000009421 Myristica fragrans Nutrition 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 241001597008 Nomeidae Species 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 229910004298 SiO 2 Inorganic materials 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000002250 absorbent Substances 0.000 description 2
- 230000002745 absorbent Effects 0.000 description 2
- 208000037849 arterial hypertension Diseases 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000037058 blood plasma level Effects 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229940126534 drug product Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 229960003580 felodipine Drugs 0.000 description 2
- 239000007888 film coating Substances 0.000 description 2
- 238000009501 film coating Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000001115 mace Substances 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000003087 receptor blocking agent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical group OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 239000004925 Acrylic resin Substances 0.000 description 1
- 229920000178 Acrylic resin Polymers 0.000 description 1
- 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 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 229920003151 Eudragit® RL polymer Polymers 0.000 description 1
- 229920003152 Eudragit® RS polymer Polymers 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- ZBBHBTPTTSWHBA-UHFFFAOYSA-N Nicardipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZBBHBTPTTSWHBA-UHFFFAOYSA-N 0.000 description 1
- 229920002701 Polyoxyl 40 Stearate Polymers 0.000 description 1
- 229920002696 Polyoxyl 40 castor oil Polymers 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 241001390629 Stylocline Species 0.000 description 1
- 241000282454 Ursus arctos Species 0.000 description 1
- 238000005299 abrasion Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001800 adrenalinergic effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 235000013405 beer Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 229940096529 carboxypolymethylene Drugs 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000005961 cardioprotection Effects 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 229920003086 cellulose ether Polymers 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000007931 coated granule Substances 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- FSXVSUSRJXIJHB-UHFFFAOYSA-M ethyl prop-2-enoate;methyl 2-methylprop-2-enoate;trimethyl-[2-(2-methylprop-2-enoyloxy)ethyl]azanium;chloride Chemical compound [Cl-].CCOC(=O)C=C.COC(=O)C(C)=C.CC(=C)C(=O)OCC[N+](C)(C)C FSXVSUSRJXIJHB-UHFFFAOYSA-M 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000005003 heart tissue Anatomy 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- DNKKLDKIFMDAPT-UHFFFAOYSA-N n,n-dimethylmethanamine;2-methylprop-2-enoic acid Chemical compound CN(C)C.CC(=C)C(O)=O.CC(=C)C(O)=O DNKKLDKIFMDAPT-UHFFFAOYSA-N 0.000 description 1
- 229960001783 nicardipine Drugs 0.000 description 1
- 229960000715 nimodipine Drugs 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000036581 peripheral resistance Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940081066 picolinic acid Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 229940099429 polyoxyl 40 stearate Drugs 0.000 description 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000001550 testis Anatomy 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
- 230000002792 vascular Effects 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
Images
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
-
- 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
- A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
Abstract
控制和延迟释放的、二氢吡啶(如非洛的平)和
β-肾上腺素能受体拮抗剂(如美多心安)的制剂以
及该新制剂的制备方法。
Description
本发明涉及两种药物的延迟释放药物制剂以及该制剂的制备方法，所说的两种药物之一是难溶于水的化合物，即一种二氢吡啶型的钙通道阻滞剂;另一药物是一种β-肾上腺素能受体拮抗剂美多心安（metoprolol）盐。
本发明的目的在于获得一种固体制剂，该制剂具有上述两种药物的高度的生物利用度，并且与胃肠道的持续吸收性能相结合，从而达到每日服用一次后在24小时内的均匀效果。
二氢吡啶类型钙拮抗剂药物和β-肾上腺素能受体拮抗剂已广泛应用于治疗心血管疾病。
所说的二氢吡啶类，诸如非洛的平（felodipine）、硝苯吡啶（nifedipine）、硝吡乙甲酯（nitrendipine），已普遍应用于治疗心血管疾病，如高动脉压和缺血性心脏病。二氢吡啶类能通过对血管平滑肌的直接作用降低血管阻力和心脏负荷。二氢吡啶类的特征在于：它在水中的溶解度极低，并且对这样的药物来说，由于它们在体内的溶解速度可能较低，所以经常可以观察到一种低而可变程度的吸收。
在现有文献中曾描述了若干增进药物吸收的方法，在DE-A-3024858中描述了一种方法，在该方法中使用了非晶态的、微溶的取代的二氢吡啶、硝吡胺甲酯，以便增进活性化合物从肠中的吸收。在EP-A-47899中描述了另一种方法，在该方法中使用了实际上不溶的二氢吡啶及硝苯吡啶的极小的结晶，以便增进生物利用度。这些方法和其它方法也在由S.H.Yakowsky编辑的《药物和药物科学》12卷中（Drugs and the Pharmaceutical Sciences，Vol 12）的“药物加溶技术”（“Techniques of Solubilization of drugs”）一文中描述过了。其中与本发明特别有关的是：可以使用表面活性加溶剂，来增进溶解度极低的药物的生物利用度。它阐明了吸收性质的改进可归于三个工艺：1）增进润湿、2）增进膜的渗透性和3）加溶性。
当服用二氢吡啶常规药片后，在体内血浆浓度随时间变化曲线的特征在于呈现出高峰值浓度和峰谷处的较低水平。血压反应反映血浆浓度曲线，即在峰值时有一显著效果而在24小时后效果大为减少。相应地，常规药片对于每日一次用药并不最相宜，而由一种高质量的控制释放的制剂所产生的更均匀的血浆浓度将是可取的。
通常，控制和延迟释放是通过不同的剂型控制药物的溶解和/或扩散来达到的。若干物质已经用于此目的，诸如蜡、脂肪物质、聚合物、天然树胶、合成树胶和半合成树胶。因为羟丙基甲基纤维素（HPMC）的pH独立性能以及它的半合成来源，所以在树胶中，它构成重要的一类。Alderman.D.A.在Int.J.Pharm.Tech. & Prod.Mfr1984年5卷3期1-9页中对供口服控释剂型的亲水性基质中的纤维素醚作了叙述。在US3087790、US4226849，US4357469和US4369172中公开了为产生所需结构的HPMC的化学处理方法以及这些性质的用途。SE-A-8008646-5描述了HPMC与羟丙基纤维素的混合物，用它来控制一种药物活性化合物的释放速度。
当使用亲水性基质时，在药片与胃肠液或唾液接触后，可溶聚合物形成一种包围在药片四周的明胶层。药物的释放受限于水渗入的速度、药物扩散的速度和形成凝胶的速度〔Bamba等人，Int.J.Pharm 1979年，2，307页〕。凝胶结构的磨蚀也是药物从系统中释放的重要机制。所用聚合物必须迅速水化，以便保护药片不致迅速分解（Alderman 1984）。
在水中具有很低溶解度的药物由于溶解不完全或溶解慢可能难于从胃肠道中加以吸收。结果，难于在不降低生物利用度的情况下通过控制这些药物的缓慢分解来增进有效作用的持续时间。（Bogentoft C和Sjoegren J，《为了药物和药物产品更加安全》（Towards Better Safety of Drugs and Pharmaceutical Procucts）D.D Breimer编辑，1980年，Elsevier/North Holland Biomedical Press）。
β-肾上腺素能受体拮抗剂对于心脏的肾上腺素能的兴奋性有阻断作用，从而降低心脏组织对氧的需要。显然，这可解释它们对心绞痛的有益作用和在心肌梗塞中的心脏保护作用。此外，β-肾上腺素能受体拮抗剂能使患高动脉压的大多数病人血压正常化，这可能是由于对血流周围阻力控制的附加作用所致。对于用β-肾上腺素能受体拮抗剂处理的患心血管病的病人来说，在血液中具有所给药物的恒定浓度是有利的。为了每日一次剂量给药，β-肾上腺素能受体拮抗剂美多心安被掺入不溶基质型的控制释放药片中，诸如Durules 。然而，因给药后大约50%剂量在几小时内被释放，所以从基质药片中释放药物是不能令人满意的。对于像具有较短半衰期的美多心安那样的药物来说需要较慢的释放速度，以便获得在24小时内的均匀血浆浓度。在20-24小时期间内美多心安的恒定释放将是可取的。具有这样性质的美多心安的制备方法在EP-A-220143中已描述过了。
业已表明β-肾上腺素能受体拮抗剂和舒张血管的二氢吡啶的结合对许多高血压病人是有利的，因为这两种药物具有协同作用（Hasson BG等人，Drugs 1985年29卷（增刊2）;131-135页;Eggerston R和Hansson L Eur.J.Clin.Pharmacol 1982年21卷389-390页）。除协同作用外，共同给药的优点是可以降低二种药物中任一种单独给药时所引起的反作用（Dean S和Kendall MJ Eur.J.Clin.Pharmacol 1983年24卷1-5页）。
在EP-A-163984中叙述了具有改善生物利用度的二氢吡啶衍生物和β-肾上腺素能受体拮抗剂固定结合的即时释放固态剂型。
然而，迄今还没有得到含有上述两种药物固定结合的制剂，它在每日一次剂量给药的期间内产生两种药物可再现的均匀的血浆浓度。上述两种药物之间理化性质的巨大差异，使得很难在常用控释系统基础上获得适宜的制剂。通过少次给药和改进病人的应变性，上述两种药物的控释制剂可以改善治疗（参看Hayes R.B.等人，Clin.Pharm.Ther.1977年22卷125-130页），上述制剂可用控释剂型获得。虽然对于每日一次给药的上述两种药物的控释制剂早有需求（早在1977年时就已提出），但是直到本发明人所开发的下文所描述的制剂以前，这种制剂迄今未得到。
本发明目的在于提供一种制剂，该制剂在每日一次二氢吡啶型的难溶于水的钙通道阻滞剂（诸如非洛的平或硝苯吡啶）和一种β-肾上腺素能受体拮抗剂（即一种美多心安盐）的两种药物给药后，在24小时期间内显出可再现的高吸收度以及均匀的血浆浓度。由于常规控释制剂不能使两种药物同时显出所需释放性能，因而有必要开发一种新型的控释制剂，该制剂利用多种控制有效组分释放的机制。由于两种药物掺进一种产品中，因而存在两个不同的机制来控制两种有效组分的释放，即一种机制是控制二氢吡啶部分，而另一机制是控制β-肾上腺素能受体拮抗剂部分。
按照本发明适用于控释制剂的二氢吡啶化合物是难溶的。本发明特别适于采用在水中溶解度小于0.1（重量）%，并且可在选择的加溶剂中或加溶剂和水的混合物中加溶的化合物。按照本发明适宜药物的例子有某些取代的二氢吡啶类，诸如硝苯吡啶和非洛的平。非洛的平是4-（2，3-二氯苯基）-1，4-二氢-2，6-二甲基-3，5-吡啶二羧酸乙基甲基酯;硝苯吡啶是1，4-二氢-2，6-二甲基-4-（2-硝基苯）-3，5-吡啶羧酸二甲基酯。其它例子有硝苯吡酯、硝苯丁甲酯和硝吡乙甲酯。
将二氢吡啶混以亲水性的溶胀剂，如羟丙基甲基纤维素（HPMC）。从这个混合物可制备固态剂型，诸如片剂或胶囊。当这样的制剂与水接触时，形成一种溶胀凝胶基质，药物从该基质被缓慢释放出来。
在各种所试验的不同亲水性的物质中，HPMC是一种适宜的凝胶形成物质，其它适宜的亲水性物质是瓜耳胶、黄原胶、羧亚甲基的和各种不同的纤维素性的物质，诸如：燃谆宋啬坪汪潜宋啬啤?
最好主要使用羟丙基含量为4-12%（重量），特别是约8.5%（重量）、粘度低于100cps的HPMC，可加入较高粘度的HPMC以便获得药物释放的最适宜速率。粘度用标准方法测定，例如在美国药典（United States Pharmacopoeia）ⅩⅩⅠ1985年672页上所描述的。
在掺入基质中以前，二氢吡啶最好分散于非离子加溶剂中。该加溶剂允许用水或肠液稀释，而不至将二氢吡啶转变为难以吸收的形式。加溶剂的选择是很关键的。用一些常用加溶剂或共溶剂稀释可导致药物的沉淀。把二氢吡啶与加溶剂的混合物掺入亲水性凝胶基质中，可使药物具有延长和可控的释放性。
按照本发明适于控制释放二氢吡啶的加溶剂是非离子表面活性剂，特别是像含有聚乙二醇类这样一类的酯类或醚类。它们最好从聚乙氧基化的脂肪酸类，羟基化的脂肪酸类和脂肪醇类中选择，特别是从聚乙氧基化的蓖麻油、聚乙氧基化的氢化蓖麻油、由蓖麻油所制聚乙氧基化的脂肪酸或由氢化蓖麻油所制聚乙氧基化的脂肪酸中选择。最好的加溶剂是氧乙烯化甘油的氢化蓖麻油脂肪酸酯类，诸如聚烃氧基（Polyoxyl）40氢化 蓖麻油。已知市售的可用加溶剂以商品名称标示的有：Cremophor.Myrj，Polyoxyl 40 Stearate，Emerest 2675和Lipal 395。
按照本发明，在制剂中加溶剂和二氢吡啶之间的比例将是10∶1或较低，最好是6∶1或较低。
β-肾上腺素能受体阻滞剂以活性组分包衣珠的形式被掺入上述凝胶系统中，至少在15小时期间内能控制释放β-肾上腺素能受体阻滞剂美多心安。这是由制备大量小的、最好是密实的颗粒而达到的，该颗粒包含美多心安盐作为主要可溶性组分并且用水不溶的聚合物膜包衣。最好的包衣含纤维素类的非质子迁移衍生物作主成分。含有美多心安的小颗粒、小珠的粒度为0.25～2毫米，最好0.35～1.0毫米。小珠可以仅含有美多心安盐或含该盐与不溶性赋形剂混合物或含美多心安盐作包衣的不溶性芯。
在制剂中的美多心安的形式是外消旋物或者是对映体之一，最好是S-异构体。美多心安适宜的可溶性盐于25℃水中溶解度小于600毫克/毫升，最好为30～600毫克/毫升。适宜的盐类例子是由有机羧酸类形成的盐，可取的是低分子量的。尤其好的是外消旋美多心安的琥珀酸盐、富马酸盐或苯甲酸盐以及美多心安的S-对映体的苯甲酸盐或山梨酸盐。
供小珠包衣的适宜聚合物材料的例子是单独的或混合在一起的、不含质子迁移基团或丙烯酸树脂（如Eudragit RL 、Eudragit RS ）的可溶或不溶性纤维衍生物。特别好的是乙基纤维素与羟丙基甲基纤维素或羟丙基纤维素的混合物。
如上所述含美多心安的包衣小珠（按照本发明该小珠被掺入含有二氢吡啶的凝胶系统中）已在EP-A-220143中描述过了。在EP-A-220143中也描述了所说的小珠是一种制备长效美多心安制剂的适宜方法。
最终的制剂最好是片剂形式，它在形成凝胶的基质内既含有二氢吡啶又有美多心安小珠。美多心安珠占制剂的10～60%（重量），而凝胶形成剂占制剂的20-80%（重量）。所描述的控释系统的工艺性能优越，从而使它很宜于大量生产，药片可任意包膜以改善外观和稳定性。
在体内，药物吸收程度既高又能再现。在某一时期内药物在血浆中的浓度和作用由系统中药物释放速度控制。二氢吡啶的释放是由凝胶形成剂的性质所决定，并能在直到24小时的期间内持续。通过使用不同性质（例如粘度和凝胶强度）不同类型和数量的凝胶形成剂，易于改变释放速度以适应某些二氢吡啶的需要。主要通过聚合物膜的成分和厚度来改变美多心安从美多心安珠的释放速度。美多心安的释放一般可持续16～24小时。
通过精心选择填充剂和粘合剂以及凝胶形成剂材料，制剂可被加工成可接受的商品形式，诸如片剂，它显示出乎意料优越的对上述两种活性化合物的吸收性及作用的长期持续性。
在以下实施例中，按照本发明的制剂含有10～20毫克的二氢吡啶和95毫克的美多心安琥珀酸盐。然而，依照所用二氢吡啶和待处理的具体情况，二氢吡啶的量一般在2.5毫克到80毫克之间，作为琥珀酸盐的美多心安外消旋物量一般在40到200毫克之间。当包含作为山梨酸盐的美多心安S-对映体时，其对应量为25到120毫克之间。用其它美多心安盐时，其量因该盐的分子量不同而有差异。
实施例1
克
非洛的平（Felodipine） 10
聚烃氧基40氢化蓖麻油 25
Polyvidon K 90 24
羟丙基甲基纤维素 230
硅酸铝 94
乳糖 56
纤维素（微晶） 6
美多心安琥珀酸盐 95
SiO224
乙基纤维素 32
羟丙基甲基纤维素 8
按照本发明实施例1的组合物作成每片含10毫克非洛的平及95毫克美多心安琥珀酸盐的片剂，该片剂制备方法如下：
Ⅰ.将非洛的平溶解在聚烃氧基40氢化蓖麻油中，将所得的溶液与载体材料、HPMC、Polyvidon K 90、硅酸铝、乳糖和微晶纤维素小心地混合，此混合物和乙醇一起制成颗粒并干燥。
Ⅱ.将美多心安喷射到二氧化硅芯上形成0.5毫米直径的珠，该珠通过在一流化床内向珠上喷射一种溶液来包上聚合物膜，该溶液由在二氯甲烷与异丙醇中的乙基纤维素和HPMC组成。
将Ⅰ和Ⅱ产物混合，加入润滑剂并在制片机中通过压缩制成片剂。
非洛的平和美多心安从片剂中溶解的情况见表1：
表 1
在含有1%的十二烷基硫酸钠pH为6.5的磷酸盐缓冲剂中非洛的平和美多心安在体外的累积溶解量。
方法：USP溶解设备NO、2，每分钟50转。
在一定时间（小时）内释放百分数：
0 2 4 8 12 16 20
非洛的平 0 14 32 64 88 96 98
美多心安 0 5 16 39 65 86 95
实施例2
克
硝苯吡啶 20
Myrj 51 50
羟丙基甲基纤维素 200
黄原胶 15
瓜耳胶 15
羧基聚亚甲基 4
（Carboxypolymethylene）
硅酸铝 100
美多心安琥珀酸盐 95
SiO224
乙基纤维素 23
按照实施例2的组合物作成片剂，该片剂含有20毫克硝苯吡啶和95毫克美多心安琥珀酸盐，片剂制备方法如下：
Ⅰ.将硝苯吡啶溶解在Myrj 51中，并将所得溶液与载体物质、HPMC、黄原胶、瓜耳胶、羧基聚亚甲基和硅酸铝小心混合，所得混合物和乙醇一起作成颗粒并干燥。
Ⅱ.将美多心安喷射在二氧化硅芯上，以形成0.5毫米直径的珠，并用实施例1所述的乙基纤维素的聚合物膜包衣。
将Ⅰ和Ⅱ的产品混合，加入润滑剂在制片机中压缩成片剂。
在体外，硝苯吡啶和美多心安二者从药片中的溶解时间被延长，见表2：
表 2
硝苯吡啶和美多心安在含有1%十二烷基硫酸盐的pH为6.5的磷酸盐缓冲剂中的体外积累溶解量。
方法：USP溶解设备NO.2，每分钟100转。
在时间（小时）内的释放百分数
0 2 4 8 12 16 20
硝苯吡啶 0 12 26 44 72 90 98
美多心安 0 6 16 34 50 62 75
现在认为实施例1和实施例2二者同样是实施本发明的最佳方式。
下列参考例描述在生物药物学研究中所用的不同制剂。参考例A阐明了常规药片。参考例B阐明一种制剂，其中将美多心安掺在特别适合于二氢吡啶类的配方中。参考例C阐明一种制剂，其中将非洛的平掺入一种控制丸的制剂中。
参考例A
非洛的平10毫克的常规片剂和
美多心安100毫克常规片剂（100毫克美多心安酒石酸盐相当于95毫克美多心安琥珀酸盐）
参考例B
克
美多心安琥珀酸盐 95
聚烃氧基40氢化蓖麻油 25
羟丙基甲基纤维素 230
硅酸铝 94
按照参考例B的组合物作成每片含95毫克美多心安琥珀酸盐的亲水基质片剂，片剂以下法制备：
将美多心安与聚烃氧基40氢化蓖麻油混合，然后小心地混以载体物质HPMC和硅酸铝，此混合物与乙醇一起制成颗粒并干燥。加入润滑剂，通过制片机压缩成片。
此片剂在体外的溶解速度示于表3：
表 3
在pH6.8的磷酸盐缓冲剂中，美多心安在体外的累积溶解量。
方法：USP溶解设备NO.2，每分钟50转。
一定时间（小时）内的释放百分数：
0 1 4 8 12 20
0 23 59 86 99 100
参考例C
克
非洛的平 66
甲基纤维素 13
甘露醇 870
聚乙烯吡咯烷酮 30
克
微晶纤维素 40
乙基纤维素 34
聚乙二醇 41.8
按照参考例C的组合物制成控释胶囊，每个胶囊含有10毫克非洛的平，该胶囊以下法制备：
将非洛的平微粉化，小心混以载体、甘露醇、甲基纤维素、聚乙烯吡咯烷酮和纤维素。用水湿润该混合物并球化，将所得颗粒干燥并过筛，用级分为0.71-1.12的颗粒，将该级分的颗粒用溶解于二氯甲烷和异丙醇的混合物中的乙基纤维素和聚乙二醇包衣。将此包衣颗粒填入硬明胶胶囊中，在体外从颗粒向外释放非洛的平的情况与实施例1中的片剂相似。
将按照实施例1的延迟释放制剂（ER）给12个健康者作为单剂量服用，在图1和图2示出由作为固定组合物片（ER）的非洛的平和美多心安所产生的血浆平均曲线。所得到的二种药物在血浆中的浓度将导致在24小时内连续治疗期间的均匀效果。
在图1或图2中，服用单剂量常规药片后非洛的平和美多心安在血浆中的平均浓度（参考例A）与服用实施例1制剂后的情况作了比较，美多心安常规片给10位志愿者服用;而非洛的平常规片给12位志愿者服用。
参考例C的药丸以单剂量给6位健康者服用，经0.5、1、2、3、4、6、8和10小时后采集血浆样品，没有一个血浆样品能测出非洛的平。
按照本发明的制剂在体外实验中显示非洛的平和美多心安的实际上恒定和延迟的释放性（见表1）。体内实验的相应数据表明该产品也显示两种药物在血浆中具有可控的和均匀的浓度，见图1和图2。把上述的体内实验数据和服用常规药片后的情况相比，按照本发明的处方优点是明显的（见图1和图2）。服用常规药片后24小时，药物在血浆中的浓度极低，结果可预期其效果极差或没有效果。按照本发明硝苯吡啶和美多心安的固定混合物也显示出两种药物的所需延迟释放性（参照表2）。
正如从参考例B（见表3）的美多心安剂型在体外迅速释放所表明那样，在用于本发明二氢吡啶部分的亲水性溶胀基质内仅仅掺入一种美多心安盐是不可能达到所需的释放曲线的。与此类似，从一种不含加溶剂而掺入包衣珠内的药物产品不可能得到合意的二氢吡啶血浆水平。在参考例C中的健康人所做的体内研究结果表明在血浆中没有可检测得到的非洛的平。
为了减少血浆水平的波动，并为了允许二氢吡啶衍生物和美多心安每日一渭亮扛枰映偈头帕街忠┪铩Ｊ褂靡恢职聪钟屑际醯牡ヒ恢掷嗟目厥拖低巢荒艽锏秸庖荒康摹１痉⒚骼昧街植煌嘈偷目厥拖低常⒔洳羧朐谝恢侄捞睾托碌募列椭校佣峁┝肆街忠┪锏淖罴盐蘸统ばС中浴?
Claims (11)
1、一种日服一次的控制释放制剂，含有美多心安和二氢吡啶型难溶于水的钙通道阻滞剂的混合物，其特征在于，美多心安是包含在小珠内，小珠含有作为主要溶解组分的美多心安盐并且用水不溶性聚合物膜包衣，二氢吡啶被分散于非离子加溶剂中，由此，分散的二氢吡啶和含有美多心安的小珠被掺入与水接触时能形成溶胀凝胶的基质中。
2、按照权利要求1所述的制剂，其特征在于，所述的非离子加溶剂选自下列一组物质：聚乙氧基化的蓖麻油、聚乙氧基化的氢化蓖麻油、从蓖麻油所制的聚乙氧基化的脂肪酸或从氢化蓖麻油所制的聚乙氧基化的脂肪酸。
3、按照权利要求1所述的制剂，其特征在于，所述的非离子加溶剂是氧乙烯化甘油的氢化蓖麻油脂肪酸酯类。
4、按照权利要求1所述的制剂，其特征在于，所述的二氢吡啶是非洛的平。
5、按照权利要求1所述的制剂，其特征在于，所述的二氢吡啶是硝苯吡啶。
6、按照权利要求1所述的制剂，其特征在于，所说的凝胶形成基质含有羟丙基甲基纤维素。
7、按照权利要求1所述的制剂，其特征在于，所述的美多心安是以它的琥珀酸盐形式加入。
8、按照权利要求1所述的制剂，其特征在于，所述的二氢吡啶的量在2.5毫克到80毫克之间，美多心安琥珀酸盐外消旋物的量在40毫克到200毫克之间。
9、按照权利要求1所述的制剂，其特征在于，所述的美多心安是以S-对映体山梨酸盐的形式加入，其量在25毫克到120毫克之间。
10、按照权利要求1所述的制剂，其特征在于，所述的美多心安是以其S-对映体的苯甲酸盐或山梨酸盐的形式加入。
11、含有美多心安和二氢吡啶型难溶于水的钙通道阻滞剂混合物的控制释放制剂的制备方法，其特征在于，所述的美多心安包含在小珠内，小珠含有作为主要溶解组分的美多心安盐，所述的小珠用含不带质子迁移基团的纤维素衍生物的水不溶性聚合物膜喷雾包衣，所述二氢吡啶分散于非离子加溶剂中，随后，将小珠和二氢吡啶二者都掺入在与水接触时能形成溶胀凝胶的基质中。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE8703881A SE8703881D0 (sv) | 1987-10-08 | 1987-10-08 | New pharmaceutical preparation |
| SE8703881-6 | 1987-10-08 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1032490A true CN1032490A (zh) | 1989-04-26 |
| CN1029935C CN1029935C (zh) | 1995-10-11 |
Family
ID=20369795
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN88109129A Expired - Lifetime CN1029935C (zh) | 1987-10-08 | 1988-10-08 | 制备新药物制剂的方法 |
Country Status (26)
| Country | Link |
|---|---|
| US (1) | US4942040A (zh) |
| EP (1) | EP0311582B1 (zh) |
| JP (1) | JP2619936B2 (zh) |
| KR (1) | KR960009411B1 (zh) |
| CN (1) | CN1029935C (zh) |
| AT (1) | ATE84412T1 (zh) |
| AU (1) | AU615211B2 (zh) |
| CA (1) | CA1312286C (zh) |
| CY (1) | CY1896A (zh) |
| DE (1) | DE3877492T2 (zh) |
| DK (1) | DK175085B1 (zh) |
| ES (1) | ES2053815T3 (zh) |
| FI (1) | FI92903C (zh) |
| GR (1) | GR3006788T3 (zh) |
| HK (1) | HK6296A (zh) |
| HU (1) | HU210461A9 (zh) |
| IE (1) | IE63084B1 (zh) |
| IL (1) | IL87922A (zh) |
| IS (1) | IS1584B (zh) |
| MX (1) | MX169243B (zh) |
| MY (1) | MY104065A (zh) |
| NO (1) | NO177375C (zh) |
| NZ (1) | NZ226245A (zh) |
| PH (1) | PH25568A (zh) |
| PT (1) | PT88711B (zh) |
| SE (1) | SE8703881D0 (zh) |
Families Citing this family (53)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5268182A (en) * | 1988-06-24 | 1993-12-07 | Abbott Laboratories | Sustained-release drug dosage units of terazosin |
| GB9025251D0 (en) * | 1990-11-20 | 1991-01-02 | Solomon Montague C | Nifedipine dosage forms |
| ATE141049T1 (de) * | 1991-03-18 | 1996-08-15 | Sepracor Inc | Zubereitung und verfahren enthaltend optisch reines s-metoprolol |
| US5834496A (en) * | 1991-12-02 | 1998-11-10 | Sepracor, Inc. | Methods for treating hypertension using optically pure S(-) felodipine |
| IL104192A (en) * | 1992-02-17 | 1998-01-04 | Siegfried Ag Pharma | Pharmaceutical dosage forms having prolonged release rate of zero order of the active ingredient |
| US6726930B1 (en) * | 1993-09-09 | 2004-04-27 | Penwest Pharmaceuticals Co. | Sustained release heterodisperse hydrogel systems for insoluble drugs |
| US5662933A (en) * | 1993-09-09 | 1997-09-02 | Edward Mendell Co., Inc. | Controlled release formulation (albuterol) |
| US5455046A (en) * | 1993-09-09 | 1995-10-03 | Edward Mendell Co., Inc. | Sustained release heterodisperse hydrogel systems for insoluble drugs |
| US5773025A (en) | 1993-09-09 | 1998-06-30 | Edward Mendell Co., Inc. | Sustained release heterodisperse hydrogel systems--amorphous drugs |
| US6818229B1 (en) | 1993-09-20 | 2004-11-16 | Kos Pharmaceuticals, Inc. | Intermediate release nicotinic acid compositions for treating hyperlipidemia |
| US6676967B1 (en) | 1993-09-20 | 2004-01-13 | Kos Pharmaceuticals, Inc. | Methods for reducing flushing in individuals being treated with nicotinic acid for hyperlipidemia |
| US6080428A (en) | 1993-09-20 | 2000-06-27 | Bova; David J. | Nicotinic acid compositions for treating hyperlipidemia and related methods therefor |
| US6746691B2 (en) | 1993-09-20 | 2004-06-08 | Kos Pharmaceuticals, Inc. | Intermediate release nicotinic acid compositions for treating hyperlipidemia having unique biopharmaceutical characteristics |
| US6129930A (en) | 1993-09-20 | 2000-10-10 | Bova; David J. | Methods and sustained release nicotinic acid compositions for treating hyperlipidemia at night |
| US5399358A (en) * | 1993-11-12 | 1995-03-21 | Edward Mendell Co., Inc. | Sustained release formulations for 24 hour release of metroprolol |
| US5399359A (en) * | 1994-03-04 | 1995-03-21 | Edward Mendell Co., Inc. | Controlled release oxybutynin formulations |
| US5399362A (en) * | 1994-04-25 | 1995-03-21 | Edward Mendell Co., Inc. | Once-a-day metoprolol oral dosage form |
| JP3279318B2 (ja) * | 1994-04-25 | 2002-04-30 | ペンウェスト ファーマシューティカルズ カンパニー | 持続放出性賦形剤 |
| US5478572A (en) * | 1994-09-06 | 1995-12-26 | Bristol-Myers Squibb Co. | Gepirone dosage form |
| US5945125A (en) * | 1995-02-28 | 1999-08-31 | Temple University | Controlled release tablet |
| AU2068797A (en) * | 1996-01-29 | 1997-08-20 | Edward Mendell Co. Inc. | Sustained release excipient |
| US5783212A (en) * | 1996-02-02 | 1998-07-21 | Temple University--of the Commonwealth System of Higher Education | Controlled release drug delivery system |
| WO1998001117A1 (en) * | 1996-07-08 | 1998-01-15 | Edward Mendell Co., Inc. | Sustained release matrix for high-dose insoluble drugs |
| US6056977A (en) | 1997-10-15 | 2000-05-02 | Edward Mendell Co., Inc. | Once-a-day controlled release sulfonylurea formulation |
| US6416786B1 (en) * | 1998-12-11 | 2002-07-09 | Nostrum Pharmaceuticals, Inc. | Sustained release tablet containing hydrocolloid and cellulose ether |
| US6555139B2 (en) | 1999-06-28 | 2003-04-29 | Wockhardt Europe Limited | Preparation of micron-size pharmaceutical particles by microfluidization |
| AU762291B2 (en) | 1999-09-30 | 2003-06-19 | Penwest Pharmaceutical Co. | Sustained release matrix systems for highly soluble drugs |
| US10179130B2 (en) | 1999-10-29 | 2019-01-15 | Purdue Pharma L.P. | Controlled release hydrocodone formulations |
| EP2295043A1 (en) | 1999-10-29 | 2011-03-16 | Euro-Celtique S.A. | Controlled release hydrocodone formulations |
| IL152021A0 (en) * | 2000-04-11 | 2003-04-10 | Sankyo Co | Pharmaceutical compositions containing pyridine derivatives |
| US6375972B1 (en) | 2000-04-26 | 2002-04-23 | Control Delivery Systems, Inc. | Sustained release drug delivery devices, methods of use, and methods of manufacturing thereof |
| CN101317825A (zh) | 2000-10-30 | 2008-12-10 | 欧罗赛铁克股份有限公司 | 控释氢可酮制剂 |
| EP2311460A1 (en) * | 2001-07-06 | 2011-04-20 | Endo Pharmaceuticals Inc. | Oxymorphone controlled release formulations |
| CA2459014C (en) * | 2001-09-14 | 2010-08-10 | Scolr, Inc. | Amino acid modulated extended release dosage form |
| US20040009220A1 (en) * | 2001-12-31 | 2004-01-15 | Vinay Sharma | Rate-controlled beta blockers and process for forming same |
| MXPA04009701A (es) * | 2002-04-05 | 2005-05-27 | Penwest Pharmaceuticals Co | Formulaciones de metoprolol de liberacion sostenida. |
| US8871241B2 (en) | 2002-05-07 | 2014-10-28 | Psivida Us, Inc. | Injectable sustained release delivery devices |
| US20080051428A1 (en) * | 2002-05-15 | 2008-02-28 | Davis Paul J | Pyrroloquinoline quinone drugs and methods of use thereof |
| US20050267143A1 (en) * | 2002-05-15 | 2005-12-01 | Davis Paul J | Pyrroloquinoline quinone drugs for treatment of cardiac injury and methods of use thereof |
| US7276514B2 (en) * | 2002-05-15 | 2007-10-02 | Charitable Leadership Foundation - Medical Technology Acceleration Program | Pyrroloquinoline quinone drugs for treatment of cardiac injury and methods of use thereof |
| KR20030095600A (ko) * | 2002-06-12 | 2003-12-24 | 환인제약 주식회사 | 펠로디핀을 포함하는 제어방출형 조성물 및 그 제조방법 |
| US7314640B2 (en) * | 2003-07-11 | 2008-01-01 | Mongkol Sriwongjanya | Formulation and process for drug loaded cores |
| US20070092573A1 (en) | 2005-10-24 | 2007-04-26 | Laxminarayan Joshi | Stabilized extended release pharmaceutical compositions comprising a beta-adrenoreceptor antagonist |
| TW200736245A (en) * | 2005-11-29 | 2007-10-01 | Sankyo Co | Acid addition salts of optically active dihydropyridine derivatives |
| TW200806648A (en) * | 2005-11-29 | 2008-02-01 | Sankyo Co | Acid addition salts of dihydropyridine derivatives |
| US8445018B2 (en) | 2006-09-15 | 2013-05-21 | Cima Labs Inc. | Abuse resistant drug formulation |
| PL2255791T3 (pl) * | 2009-04-03 | 2012-05-31 | Zakl Farmaceutyczne Polpharma Sa | Kompozycja farmaceutyczna o przedłużonym uwalnianiu zawierająca bursztynian metoprololu |
| WO2011143118A2 (en) * | 2010-05-11 | 2011-11-17 | Cima Labs Inc. | Alcohol-resistant formulations |
| MX2012012991A (es) * | 2010-05-11 | 2012-11-30 | Cima Labs Inc | Formas de dosificacion oral de liberacion prolongada resistentes al alcohol y que contienen metoprolol. |
| RU2570752C2 (ru) * | 2011-08-26 | 2015-12-10 | Вокхардт Лимитед | Способы лечения сердечно-сосудистых нарушений |
| GB2512059B (en) * | 2013-03-18 | 2016-08-31 | Rolls Royce Plc | An independently moveable machine tool |
| CN113143877A (zh) * | 2021-05-07 | 2021-07-23 | 苏州康恒研新药物技术有限公司 | 一种琥珀酸美托洛尔微丸缓释片的制备方法 |
| CN114712319B (zh) * | 2022-03-25 | 2024-01-09 | 北京诺康达医药科技股份有限公司 | 一种非洛地平盐酸普萘洛尔复方制剂及其制备方法 |
Family Cites Families (50)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3870790A (en) * | 1970-01-22 | 1975-03-11 | Forest Laboratories | Solid pharmaceutical formulations containing hydroxypropyl methyl cellulose |
| CH532038A (de) * | 1970-05-25 | 1972-12-31 | Ciba Geigy Ag | Verfahren zur Herstellung von neuen Cycloheptenderivaten |
| US3951821A (en) * | 1972-07-14 | 1976-04-20 | The Dow Chemical Company | Disintegrating agent for tablets |
| US4123382A (en) * | 1973-05-25 | 1978-10-31 | Merck & Co., Inc. | Method of microencapsulation |
| DE2336218C3 (de) * | 1973-07-17 | 1985-11-14 | Byk Gulden Lomberg Chemische Fabrik Gmbh, 7750 Konstanz | Orale Arzneiform |
| SE418247B (sv) * | 1975-11-17 | 1981-05-18 | Haessle Ab | Sett att framstella kroppar med reglerad frigoring av en aktiv komponent |
| US4016880A (en) * | 1976-03-04 | 1977-04-12 | Alza Corporation | Osmotically driven active agent dispenser |
| US4291016A (en) * | 1976-07-27 | 1981-09-22 | Sandoz Ltd. | Enteric coated mixture of 4-(2-hydroxy-3-isopropylamino-propoxy) indole and sodium lauryl sulphate |
| GB1542414A (en) * | 1976-08-19 | 1979-03-21 | Standard Telephones Cables Ltd | Arrangements for the controlled release of biologically active materials |
| DE2642032A1 (de) * | 1976-09-18 | 1978-03-30 | Merck Patent Gmbh | Siliciumdioxidhaltige zubereitungen und verfahren zu ihrer herstellung |
| GB1576376A (en) * | 1977-03-30 | 1980-10-08 | Benzon As Alfred | Multiple-unit drug dose |
| US4256108A (en) * | 1977-04-07 | 1981-03-17 | Alza Corporation | Microporous-semipermeable laminated osmotic system |
| SE426548B (sv) * | 1978-12-05 | 1983-01-31 | Haessle Ab | Fast farmaceutisk beredning innehallande en terapeutiskt effektiv hjertglykosid och en polymer |
| US4226849A (en) * | 1979-06-14 | 1980-10-07 | Forest Laboratories Inc. | Sustained release therapeutic compositions |
| US4357469A (en) * | 1979-06-14 | 1982-11-02 | Forest Laboratories, Inc. | Carrier base material for prolonged release therapeutic compositions |
| CA1146866A (en) * | 1979-07-05 | 1983-05-24 | Yamanouchi Pharmaceutical Co. Ltd. | Process for the production of sustained release pharmaceutical composition of solid medical material |
| US4309406A (en) * | 1979-07-10 | 1982-01-05 | American Home Products Corporation | Sustained release pharmaceutical compositions |
| US4309404A (en) * | 1979-08-09 | 1982-01-05 | American Home Products Corporation | Sustained release pharmaceutical compositions |
| US4259314A (en) * | 1979-12-10 | 1981-03-31 | Hans Lowey | Method and composition for the preparation of controlled long-acting pharmaceuticals |
| DE3033919A1 (de) * | 1980-09-09 | 1982-04-22 | Bayer Ag, 5090 Leverkusen | Feste arzneizubereitungen enthaltend nifedipin und verfahren zu ihrer herstellung |
| CH655658B (zh) * | 1980-09-18 | 1986-05-15 | ||
| US4439195A (en) * | 1980-10-14 | 1984-03-27 | Alza Corporation | Theophylline therapy |
| US4326525A (en) * | 1980-10-14 | 1982-04-27 | Alza Corporation | Osmotic device that improves delivery properties of agent in situ |
| US4428883A (en) * | 1981-03-06 | 1984-01-31 | The University Of Kentucky Research Foundation | Novel method of administering β-blockers and novel dosage forms containing same |
| IT1144911B (it) * | 1981-03-19 | 1986-10-29 | Pharmatec Spa | Composizione farmaceutica a rilascio controllato contenente ibuprofen |
| GB2098867B (en) * | 1981-05-21 | 1984-10-24 | Wyeth John & Brother Ltd | Sustained release pharmaceutical composition |
| JPS57209223A (en) * | 1981-06-19 | 1982-12-22 | Tanabe Seiyaku Co Ltd | Microcapsule for intracranial anti hypotension and its production |
| US4369272A (en) * | 1981-07-07 | 1983-01-18 | E. I. Du Pont De Nemours And Company | Process for preparing polyolefin resin extended pigments comprising salt milling crude pigment with the resin |
| US4484921A (en) * | 1982-02-01 | 1984-11-27 | Alza Corporation | Theophylline therapy utilizing osmotic delivery |
| US4642233A (en) * | 1982-03-22 | 1987-02-10 | Alza Corporation | Gastrointestinal drug delivery system comprising a hydrogel reservoir containing a plurality of tiny pills |
| US4449983A (en) * | 1982-03-22 | 1984-05-22 | Alza Corporation | Simultaneous delivery of two drugs from unit delivery device |
| US4649043A (en) * | 1982-03-22 | 1987-03-10 | Alza Corporation | Drug delivery system for delivering a plurality of tiny pills in the gastrointestinal tract |
| US4434153A (en) * | 1982-03-22 | 1984-02-28 | Alza Corporation | Drug delivery system comprising a reservoir containing a plurality of tiny pills |
| JPS58170712A (ja) * | 1982-03-31 | 1983-10-07 | Chiyoda Yakuhin Kk | インドメタシン徐放錠 |
| US4415547A (en) * | 1982-06-14 | 1983-11-15 | Sterling Drug Inc. | Sustained-release pharmaceutical tablet and process for preparation thereof |
| US4681583A (en) * | 1982-12-20 | 1987-07-21 | Alza Corporation | System for dispersing drug in biological environment |
| DE3247118A1 (de) * | 1982-12-20 | 1984-06-20 | Cassella Ag, 6000 Frankfurt | Neue substituierte 1,4-dihydropyridine, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel |
| US4578075A (en) * | 1982-12-20 | 1986-03-25 | Alza Corporation | Delivery system housing a plurality of delivery devices |
| DE3307422A1 (de) * | 1983-03-03 | 1984-09-06 | Bayer Ag, 5090 Leverkusen | Fluessigzubereitungen von dihydropyridinen, ein verfahren zu ihrer herstellung, sowie ihre verwendung bei der bekaempfung von erkrankungen |
| PH18946A (en) * | 1983-04-21 | 1985-11-14 | Elan Corp Plc | Controlled absorption pharmaceutical composition |
| GB2146531B (en) * | 1983-09-15 | 1987-04-29 | Stc Plc | Controlled release system |
| SE457505B (sv) * | 1984-01-10 | 1989-01-09 | Lejus Medical Ab | Laminatbelagd oral farmaceutisk komposition och foerfarande foer dess framstaellning |
| AU571312B2 (en) * | 1984-02-10 | 1988-04-14 | Nycomed Danmark A/S | Diffusion coated multiple-units dosage form |
| GB2154874B (en) * | 1984-02-29 | 1987-11-04 | Sandoz Ltd | Bromoscriptine compositions |
| IT1206166B (it) * | 1984-07-26 | 1989-04-14 | Sigma Tau Ind Farmaceuti | Dispositivo per rilasciare una sostanza in un fluido di dissoluzione con cinetica di ordine zero e procedimento per la sua preparazione |
| US4794111A (en) * | 1984-05-23 | 1988-12-27 | Bayer Aktiengesellschaft | Dihydropyridine preparations containing β-blockers |
| DE3419131A1 (de) * | 1984-05-23 | 1985-11-28 | Bayer Ag, 5090 Leverkusen | Dihydropyridinkombinationspraeparate und verfahren zu ihrer herstellung |
| GB2159715B (en) * | 1984-06-04 | 1988-05-05 | Sterwin Ag | Pharmaceutical composition in sustained release unit dose form and process for its preparation |
| SE455836B (sv) * | 1985-10-11 | 1988-08-15 | Haessle Ab | Beredning med kontrollerad frisettning innehallande ett salt av metoprolol samt metod for framstellning av denna beredning |
| US4808413A (en) * | 1987-04-28 | 1989-02-28 | E. R. Squibb & Sons, Inc. | Pharmaceutical compositions in the form of beadlets and method |
-
1987
- 1987-10-08 SE SE8703881A patent/SE8703881D0/xx unknown
-
1988
- 1988-09-16 AU AU22374/88A patent/AU615211B2/en not_active Expired
- 1988-09-20 NZ NZ226245A patent/NZ226245A/xx unknown
- 1988-09-22 ES ES88850319T patent/ES2053815T3/es not_active Expired - Lifetime
- 1988-09-22 EP EP88850319A patent/EP0311582B1/en not_active Expired - Lifetime
- 1988-09-22 DE DE8888850319T patent/DE3877492T2/de not_active Expired - Lifetime
- 1988-09-22 AT AT88850319T patent/ATE84412T1/de not_active IP Right Cessation
- 1988-09-27 NO NO884269A patent/NO177375C/no not_active IP Right Cessation
- 1988-09-27 IE IE292188A patent/IE63084B1/en not_active IP Right Cessation
- 1988-09-29 US US07/250,945 patent/US4942040A/en not_active Expired - Lifetime
- 1988-09-29 PH PH37615A patent/PH25568A/en unknown
- 1988-10-05 IL IL87922A patent/IL87922A/xx active Protection Beyond IP Right Term
- 1988-10-06 MY MYPI88001120A patent/MY104065A/en unknown
- 1988-10-06 DK DK198805586A patent/DK175085B1/da active
- 1988-10-06 MX MX013316A patent/MX169243B/es unknown
- 1988-10-06 IS IS3398A patent/IS1584B/is unknown
- 1988-10-07 KR KR88013076A patent/KR960009411B1/ko not_active IP Right Cessation
- 1988-10-07 PT PT88711A patent/PT88711B/pt not_active IP Right Cessation
- 1988-10-07 CA CA000579566A patent/CA1312286C/en not_active Expired - Lifetime
- 1988-10-07 JP JP63252209A patent/JP2619936B2/ja not_active Expired - Lifetime
- 1988-10-07 FI FI884636A patent/FI92903C/fi not_active IP Right Cessation
- 1988-10-08 CN CN88109129A patent/CN1029935C/zh not_active Expired - Lifetime
-
1993
- 1993-01-14 GR GR930400002T patent/GR3006788T3/el unknown
-
1994
- 1994-12-15 HU HU94P/P00056P patent/HU210461A9/hu unknown
-
1996
- 1996-01-11 HK HK6296A patent/HK6296A/xx not_active IP Right Cessation
- 1996-09-27 CY CY189696A patent/CY1896A/xx unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1029935C (zh) | 制备新药物制剂的方法 | |
| CN1025150C (zh) | 能延续释放的新药物制剂的制备方法 | |
| CN1023293C (zh) | 一种含有美多心安盐的控制释放制剂的制备方法 | |
| CN1053339C (zh) | 受控释放吗啡制剂 | |
| CN1525855A (zh) | 治疗与预防心脏病与循环系统疾病的日服一次疗法用口服的控释医药组合物 | |
| CN1607947A (zh) | 包含3－(3－二甲基氨基－1－乙基－2－甲基－丙基)苯酚并能提供活性成分的延迟释放的药物 | |
| JP2012518008A (ja) | 非晶質ｃｄｄｏ−ｍｅを含有する遅延放出性経口投薬組成物 | |
| EP0851758A1 (en) | Pharmaceutical formulation | |
| CN1178659C (zh) | 控释活性化合物的药物制剂 | |
| CN1198599C (zh) | 长期释放药物的缓释性制剂 | |
| US20080300322A1 (en) | Delivery vehicles containing rosin resins | |
| CN1183960A (zh) | 用于口服的含有活性成分硝苯吡啶的缓释药物组合物 | |
| CN1682696A (zh) | 择时缓释微丸及其制剂 | |
| US20060073200A1 (en) | Lercanidipine capsules | |
| CN1903194A (zh) | 辛伐他汀的缓、控释制剂及其制备方法 | |
| CN1093254A (zh) | 含有麦角溴烟酯的控释药物组合物 | |
| RU2411035C2 (ru) | Лекарственная форма с модифицированным высвобождением 6-метил-2-этил-3-гидроксипиридина сукцината | |
| CN1895250A (zh) | 一种格列喹酮的缓释制剂 | |
| CN1165311C (zh) | 结合雌激素药物缓释组合物及其制备方法 | |
| CN1596896A (zh) | 氨氯地平、厄贝沙坦复方制剂 | |
| CN1079233C (zh) | 治疗心血管病和良性前列腺增生的药物组合物 | |
| CN1530104A (zh) | 一种治疗放化疗呕吐的缓释微丸及其制备方法 | |
| CN1102323A (zh) | 缓释组合物及制备药用组合物的方法 | |
| CN1589790A (zh) | 阿比朵尔缓释片及其制备方法 | |
| CN1823799A (zh) | 一种灯盏花素缓释制剂及其制备方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C15 | Extension of patent right duration from 15 to 20 years for appl. with date before 31.12.1992 and still valid on 11.12.2001 (patent law change 1993) | ||
| OR01 | Other related matters | ||
| C17 | Cessation of patent right | ||
| CX01 | Expiry of patent term |