CN101804029A - Atorvastatin liposome and preparation method thereof, and medicine composition containing atorvastatin - Google Patents
Atorvastatin liposome and preparation method thereof, and medicine composition containing atorvastatin Download PDFInfo
- Publication number
- CN101804029A CN101804029A CN201010172783A CN201010172783A CN101804029A CN 101804029 A CN101804029 A CN 101804029A CN 201010172783 A CN201010172783 A CN 201010172783A CN 201010172783 A CN201010172783 A CN 201010172783A CN 101804029 A CN101804029 A CN 101804029A
- Authority
- CN
- China
- Prior art keywords
- atorvastatin
- liposome
- mix homogeneously
- tablet
- pharmaceutically acceptable
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000002502 liposome Substances 0.000 title claims abstract description 204
- 239000000203 mixture Substances 0.000 title claims abstract description 129
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 title claims abstract description 117
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 title claims abstract description 117
- 229960005370 atorvastatin Drugs 0.000 title claims abstract description 117
- 238000002360 preparation method Methods 0.000 title claims abstract description 48
- 239000003814 drug Substances 0.000 title claims abstract description 39
- 150000003839 salts Chemical class 0.000 claims abstract description 30
- 229960000528 amlodipine Drugs 0.000 claims abstract description 29
- 150000003904 phospholipids Chemical class 0.000 claims abstract description 15
- 229960001770 atorvastatin calcium Drugs 0.000 claims description 142
- OJRHUICOVVSGSY-RXMQYKEDSA-N (2s)-2-chloro-3-methylbutan-1-ol Chemical compound CC(C)[C@H](Cl)CO OJRHUICOVVSGSY-RXMQYKEDSA-N 0.000 claims description 141
- ZPBWCRDSRKPIDG-UHFFFAOYSA-N amlodipine benzenesulfonate Chemical compound OS(=O)(=O)C1=CC=CC=C1.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl ZPBWCRDSRKPIDG-UHFFFAOYSA-N 0.000 claims description 101
- 239000003826 tablet Substances 0.000 claims description 91
- 238000002156 mixing Methods 0.000 claims description 77
- 229920003081 Povidone K 30 Polymers 0.000 claims description 76
- 229960004005 amlodipine besylate Drugs 0.000 claims description 74
- 239000008187 granular material Substances 0.000 claims description 70
- 238000000034 method Methods 0.000 claims description 53
- 238000001035 drying Methods 0.000 claims description 36
- 239000000463 material Substances 0.000 claims description 35
- 239000002245 particle Substances 0.000 claims description 34
- 230000033001 locomotion Effects 0.000 claims description 32
- 239000008194 pharmaceutical composition Substances 0.000 claims description 28
- 229940079593 drug Drugs 0.000 claims description 26
- 239000002775 capsule Substances 0.000 claims description 20
- 239000003795 chemical substances by application Substances 0.000 claims description 20
- 239000000872 buffer Substances 0.000 claims description 16
- 239000007779 soft material Substances 0.000 claims description 15
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 14
- 239000000787 lecithin Substances 0.000 claims description 14
- 235000010445 lecithin Nutrition 0.000 claims description 14
- 229940067606 lecithin Drugs 0.000 claims description 14
- 239000011230 binding agent Substances 0.000 claims description 12
- 239000007919 dispersible tablet Substances 0.000 claims description 12
- -1 fluidizer Substances 0.000 claims description 12
- 239000003085 diluting agent Substances 0.000 claims description 11
- 239000000314 lubricant Substances 0.000 claims description 11
- 238000007873 sieving Methods 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 239000000853 adhesive Substances 0.000 claims description 9
- 230000001070 adhesive effect Effects 0.000 claims description 9
- 235000010469 Glycine max Nutrition 0.000 claims description 8
- 239000007910 chewable tablet Substances 0.000 claims description 8
- 229940068682 chewable tablet Drugs 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 8
- 238000005469 granulation Methods 0.000 claims description 8
- 230000003179 granulation Effects 0.000 claims description 8
- 210000000214 mouth Anatomy 0.000 claims description 8
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims description 8
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 7
- 239000000823 artificial membrane Substances 0.000 claims description 7
- 238000001704 evaporation Methods 0.000 claims description 7
- 230000008020 evaporation Effects 0.000 claims description 7
- 239000000706 filtrate Substances 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- 239000012982 microporous membrane Substances 0.000 claims description 7
- 229940083466 soybean lecithin Drugs 0.000 claims description 7
- 230000009471 action Effects 0.000 claims description 6
- 239000002671 adjuvant Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 229940023488 pill Drugs 0.000 claims description 6
- 239000006187 pill Substances 0.000 claims description 6
- 238000010298 pulverizing process Methods 0.000 claims description 6
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 claims description 5
- 210000002969 egg yolk Anatomy 0.000 claims description 5
- 238000001694 spray drying Methods 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 4
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 4
- 238000004108 freeze drying Methods 0.000 claims description 4
- JEGUKCSWCFPDGT-UHFFFAOYSA-N h2o hydrate Chemical compound O.O JEGUKCSWCFPDGT-UHFFFAOYSA-N 0.000 claims description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 4
- XUKUURHRXDUEBC-SVBPBHIXSA-N (3s,5s)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SVBPBHIXSA-N 0.000 claims description 3
- 102000002322 Egg Proteins Human genes 0.000 claims description 3
- 108010000912 Egg Proteins Proteins 0.000 claims description 3
- 241000287828 Gallus gallus Species 0.000 claims description 3
- 235000021355 Stearic acid Nutrition 0.000 claims description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 3
- 210000004681 ovum Anatomy 0.000 claims description 3
- 239000008117 stearic acid Substances 0.000 claims description 3
- TWJNQYPJQDRXPH-UHFFFAOYSA-N 2-cyanobenzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1C#N TWJNQYPJQDRXPH-UHFFFAOYSA-N 0.000 claims description 2
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 claims description 2
- 235000021360 Myristic acid Nutrition 0.000 claims description 2
- TUNFSRHWOTWDNC-UHFFFAOYSA-N Myristic acid Natural products CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 claims description 2
- 235000021314 Palmitic acid Nutrition 0.000 claims description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 2
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 claims description 2
- 229960000367 inositol Drugs 0.000 claims description 2
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 claims description 2
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 7
- 230000008901 benefit Effects 0.000 abstract description 3
- 238000011161 development Methods 0.000 abstract description 2
- 239000004480 active ingredient Substances 0.000 abstract 1
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 abstract 1
- 230000029087 digestion Effects 0.000 abstract 1
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 78
- 239000000243 solution Substances 0.000 description 53
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 51
- 239000011734 sodium Substances 0.000 description 51
- 229910052708 sodium Inorganic materials 0.000 description 51
- 235000019359 magnesium stearate Nutrition 0.000 description 39
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 37
- 239000000741 silica gel Substances 0.000 description 37
- 229910002027 silica gel Inorganic materials 0.000 description 37
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 29
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 29
- 239000008108 microcrystalline cellulose Substances 0.000 description 29
- 229940016286 microcrystalline cellulose Drugs 0.000 description 29
- 206010013786 Dry skin Diseases 0.000 description 28
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical group [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 26
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 25
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 description 25
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 25
- 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 24
- 229930195725 Mannitol Natural products 0.000 description 24
- 239000000594 mannitol Substances 0.000 description 24
- 235000010355 mannitol Nutrition 0.000 description 24
- 230000001476 alcoholic effect Effects 0.000 description 23
- 239000004376 Sucralose Substances 0.000 description 18
- 235000019408 sucralose Nutrition 0.000 description 18
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 18
- 206010020772 Hypertension Diseases 0.000 description 14
- 229910000019 calcium carbonate Inorganic materials 0.000 description 13
- 235000010216 calcium carbonate Nutrition 0.000 description 13
- MZUOYVUQORIPHP-MNSAWQCASA-L magnesium;(3r,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoate Chemical compound [Mg+2].C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1.C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 MZUOYVUQORIPHP-MNSAWQCASA-L 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 12
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 10
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 9
- HTIQEAQVCYTUBX-KRWDZBQOSA-N (S)-amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-KRWDZBQOSA-N 0.000 description 8
- 241000220223 Fragaria Species 0.000 description 8
- 235000016623 Fragaria vesca Nutrition 0.000 description 8
- 235000011363 Fragaria x ananassa Nutrition 0.000 description 8
- 239000008351 acetate buffer Substances 0.000 description 8
- 229960000935 dehydrated alcohol Drugs 0.000 description 8
- 229950008554 levamlodipine Drugs 0.000 description 8
- 238000003556 assay Methods 0.000 description 7
- 239000008363 phosphate buffer Substances 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 230000008859 change Effects 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 229920001214 Polysorbate 60 Polymers 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 235000012000 cholesterol Nutrition 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 238000003801 milling Methods 0.000 description 5
- 239000011812 mixed powder Substances 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 5
- 206010002383 Angina Pectoris Diseases 0.000 description 4
- 208000024172 Cardiovascular disease Diseases 0.000 description 4
- 206010008190 Cerebrovascular accident Diseases 0.000 description 4
- 235000005979 Citrus limon Nutrition 0.000 description 4
- 244000131522 Citrus pyriformis Species 0.000 description 4
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 4
- 239000008118 PEG 6000 Substances 0.000 description 4
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 208000006011 Stroke Diseases 0.000 description 4
- 239000004106 carminic acid Substances 0.000 description 4
- 235000012730 carminic acid Nutrition 0.000 description 4
- 229940080423 cochineal Drugs 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 4
- 239000007888 film coating Substances 0.000 description 4
- 238000009501 film coating Methods 0.000 description 4
- 230000002209 hydrophobic effect Effects 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000002356 single layer Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- GHOSNRCGJFBJIB-UHFFFAOYSA-N Candesartan cilexetil Chemical compound C=12N(CC=3C=CC(=CC=3)C=3C(=CC=CC=3)C3=NNN=N3)C(OCC)=NC2=CC=CC=1C(=O)OC(C)OC(=O)OC1CCCCC1 GHOSNRCGJFBJIB-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- 229960004349 candesartan cilexetil Drugs 0.000 description 3
- 208000026106 cerebrovascular disease Diseases 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000002526 effect on cardiovascular system Effects 0.000 description 3
- 201000005577 familial hyperlipidemia Diseases 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 208000019622 heart disease Diseases 0.000 description 3
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 208000010125 myocardial infarction Diseases 0.000 description 3
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 3
- 229960000502 poloxamer Drugs 0.000 description 3
- 229920001983 poloxamer Polymers 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- GPNFRRPXCRWXHN-MNSAWQCASA-L strontium;(3r,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoate Chemical compound [Sr+2].C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1.C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 GPNFRRPXCRWXHN-MNSAWQCASA-L 0.000 description 3
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 2
- 206010061623 Adverse drug reaction Diseases 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- 239000002053 C09CA06 - Candesartan Substances 0.000 description 2
- 229940127291 Calcium channel antagonist Drugs 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 108010036176 Melitten Proteins 0.000 description 2
- 206010070863 Toxicity to various agents Diseases 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 239000000480 calcium channel blocker Substances 0.000 description 2
- QXDHJHQRJCJRAU-UHFFFAOYSA-N calcium;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Ca].OC(=O)CC(O)(C(O)=O)CC(O)=O QXDHJHQRJCJRAU-UHFFFAOYSA-N 0.000 description 2
- 229960000932 candesartan Drugs 0.000 description 2
- 239000002327 cardiovascular agent Substances 0.000 description 2
- 229940125692 cardiovascular agent Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 208000029078 coronary artery disease Diseases 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 229940008099 dimethicone Drugs 0.000 description 2
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 2
- 239000004205 dimethyl polysiloxane Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000000890 drug combination Substances 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 238000002651 drug therapy Methods 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 210000004211 gastric acid Anatomy 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 238000009413 insulation Methods 0.000 description 2
- 229940057995 liquid paraffin Drugs 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 229940057948 magnesium stearate Drugs 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- VDXZNPDIRNWWCW-JFTDCZMZSA-N melittin Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(N)=O)CC1=CNC2=CC=CC=C12 VDXZNPDIRNWWCW-JFTDCZMZSA-N 0.000 description 2
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 2
- 229910052753 mercury Inorganic materials 0.000 description 2
- 238000012856 packing Methods 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 2
- 229940083542 sodium Drugs 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- AGBQKNBQESQNJD-SSDOTTSWSA-N (R)-lipoic acid Chemical compound OC(=O)CCCC[C@@H]1CCSS1 AGBQKNBQESQNJD-SSDOTTSWSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- TZNOWAJJWCGILX-BTJKTKAUSA-N (z)-but-2-enedioic acid;3-o-ethyl 5-o-methyl 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound OC(=O)\C=C/C(O)=O.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl TZNOWAJJWCGILX-BTJKTKAUSA-N 0.000 description 1
- 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
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 1
- 206010002329 Aneurysm Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 206010003225 Arteriospasm coronary Diseases 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 208000031288 Combined hyperlipidaemia Diseases 0.000 description 1
- 208000003890 Coronary Vasospasm Diseases 0.000 description 1
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 1
- 208000002249 Diabetes Complications Diseases 0.000 description 1
- 206010012655 Diabetic complications Diseases 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 108010028554 LDL Cholesterol Proteins 0.000 description 1
- 102000000853 LDL receptors Human genes 0.000 description 1
- 108010001831 LDL receptors Proteins 0.000 description 1
- 241000406668 Loxodonta cyclotis Species 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 1
- 229920003110 Primojel Polymers 0.000 description 1
- ODHCTXKNWHHXJC-GSVOUGTGSA-N Pyroglutamic acid Natural products OC(=O)[C@H]1CCC(=O)N1 ODHCTXKNWHHXJC-GSVOUGTGSA-N 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 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
- 206010047295 Ventricular hypertrophy Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- UXKMFEPPKJZDAR-STOWLHSFSA-N [(1r,4s)-7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl]methanesulfonic acid;3-o-ethyl 5-o-methyl 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl UXKMFEPPKJZDAR-STOWLHSFSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 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 description 1
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 230000003113 alkalizing effect Effects 0.000 description 1
- AGBQKNBQESQNJD-UHFFFAOYSA-N alpha-Lipoic acid Natural products OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 229960005261 aspartic acid Drugs 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229940049950 atorvastatin 10 mg Drugs 0.000 description 1
- 230000000680 avirulence Effects 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 1
- 239000001639 calcium acetate Substances 0.000 description 1
- 229960005147 calcium acetate Drugs 0.000 description 1
- 235000011092 calcium acetate Nutrition 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- MKJXYGKVIBWPFZ-UHFFFAOYSA-L calcium lactate Chemical compound [Ca+2].CC(O)C([O-])=O.CC(O)C([O-])=O MKJXYGKVIBWPFZ-UHFFFAOYSA-L 0.000 description 1
- 239000001527 calcium lactate Substances 0.000 description 1
- 235000011086 calcium lactate Nutrition 0.000 description 1
- 229960002401 calcium lactate Drugs 0.000 description 1
- OLOZVPHKXALCRI-UHFFFAOYSA-L calcium malate Chemical compound [Ca+2].[O-]C(=O)C(O)CC([O-])=O OLOZVPHKXALCRI-UHFFFAOYSA-L 0.000 description 1
- 239000001362 calcium malate Substances 0.000 description 1
- 229940016114 calcium malate Drugs 0.000 description 1
- 235000011038 calcium malates Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 210000004413 cardiac myocyte Anatomy 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 201000011634 coronary artery vasospasm Diseases 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 229960003964 deoxycholic acid Drugs 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 235000018823 dietary intake Nutrition 0.000 description 1
- GXGAKHNRMVGRPK-UHFFFAOYSA-N dimagnesium;dioxido-bis[[oxido(oxo)silyl]oxy]silane Chemical compound [Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O GXGAKHNRMVGRPK-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229940114119 gentisate Drugs 0.000 description 1
- SYKWLIJQEHRDNH-KRPIADGTSA-N glutaryl-coa Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCSC(=O)CCCC(O)=O)O[C@H]1N1C2=NC=NC(N)=C2N=C1 SYKWLIJQEHRDNH-KRPIADGTSA-N 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical compound CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 235000019136 lipoic acid Nutrition 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000003550 mucous cell Anatomy 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960000715 nimodipine Drugs 0.000 description 1
- 230000008816 organ damage Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000036513 peripheral conductance Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 210000002706 plastid Anatomy 0.000 description 1
- 238000009702 powder compression Methods 0.000 description 1
- 229960002965 pravastatin Drugs 0.000 description 1
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000011125 single therapy Methods 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- FHHPUSMSKHSNKW-SMOYURAASA-M sodium deoxycholate Chemical compound [Na+].C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 FHHPUSMSKHSNKW-SMOYURAASA-M 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 229960002663 thioctic acid Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to an atorvastatin liposome and a preparation method thereof, and a medicine composition containing the atorvastatin liposome. The medicine composition has active ingredients of atorvastatin and/or amlodipine. The atorvastatin liposome comprises atorvastatin or pharmaceutically acceptable salts thereof and phospholipid, wherein the weight of the phospholipid is 1-10 times of the weight of the atorvastatin or pharmaceutically acceptable salts thereof. The medicine composition prepared by the atorvastatin liposome not only accords with requirements on Chinese Pharmacopoeia, but also has the advantages of more rapid digestion, more quick development of medicine effect and remarkable improvement of bioavailability compared with common atorvastatin medicine compositions.
Description
Technical field
The present invention relates to a kind of atorvastatin liposome, its preparation method and contain its pharmaceutical composition, the advantage that described atorvastatin liposome has is rapider than common atorvastatin stripping, the drug effect performance is faster, the bioavailability significance improves belongs to medical technical field.
Background technology
Because the change of The development in society and economy and people life style, population of China hypertension prevalence is sustainable growth trend.Hypertension is a kind of commonly encountered diseases frequently-occurring disease, also is the most important risk factor of cardiovascular and cerebrovascular disease.Blood pressure level and cardiovascular diseases's sickness rate are continuous positive correlation.Hypertensive important complication apoplexy, heart disease and nephropathy serious harm China people ' s health, the disability rate height that causes death brings white elephant (with reference to non-patent literature 1) for individual, family and society.
In recent years, hypertension prevention and control guide both domestic and external shows (with reference to non-patent literature 1,2), strengthen the blood pressure lowering dynamics, make hyperpietic's blood pressure reduce to 140/90 millimetres of mercury following (it is following that the best should be reduced to 130/80 millimetres of mercury) actively, enduringly, effectively the target organ damages such as heart and brain kidney that cause of alleviating hypertension.In addition, the administering drug combinations of hypertension drug, can treat all kinds hypertension, angina pectoris, atherosclerosis effectively, and prevention or cardiovascular and cerebrovascular diseases such as treatment diabetes, diabetic complication, apoplexy, myocardial infarction, cardiac insufficiency, renal function injury, ventricular hypertrophy, aneurysm, myocardial ischemia and glaucoma, reduce incident rate, mortality rate and the disability rate of cardiovascular and cerebrovascular disease, improve patients ' life quality, prolong patient's life-span.
Atorvastatin of the present invention or its pharmaceutically acceptable salt (with reference to patent documentation 1,2) are Statins blood lipid regulation medicine, belong to the HMG-CoA reductase inhibitor.Non-activity own, hydrolyzate after the oral absorption suppresses the rate-limiting enzyme hydroxyl first glutaryl CoA reductase in the cholesterol building-up process in vivo competitively, make the synthetic minimizing of cholesterol, also make the synthetic increase of low density lipoprotein receptor, main site of action is at liver, the result reduces cholesterolemia and low-density lipoprotein cholesterol level, moderate reduces serum triglyceride level and increases the blood hdl level, is mainly used in treatment or prevention hypercholesterolemia, combined hyperlipidemia familial, coronary heart disease or apoplexy.
The chemical name of Atorvastatin calcium is: [R-(R*, R*)]-2-(4-fluorophenyl)-β, δ-dihydroxy-5-(1-Methylethyl)-3-phenyl-4-[(anilino-) carbonyl]-1H-pyrroles-1-Calcium salt enanthate (2: 1) trihydrate, English name is: Atorvastatin Calcium.
The Atorvastatin calcium oral absorption is good, and because of extensive first pass metabolism in liver, absolute bioavailability is lower, is approximately 12%; In addition, the stable of Atorvastatin calcium also has the pH value of depending on, and it is more stable in neutrality or alkalescence.Therefore, the present invention mainly solves stability problem and the raising bioavailability problem of Atorvastatin calcium in gastric acid.
Atorvastatin mainly is with oral form administration in the prior art, the listing dosage form has tablet and capsule, described dosage form all is to adopt the simple atorvastatin calcium raw material drug that does not add any modification to add pH to make greater than 5 alkalizing agent, gained stability of formulation and bioavailability are poor, can not effectively bring into play the pharmacological activity of atorvastatin.
From people such as late 1960s Rahman at first use liposome as pharmaceutical carrier since, continuous progress along with science and technology, liposome preparation technology is progressively perfect, and the liposome mechanism of action is further illustrated, and liposome becomes the hot technology field of current research.Verified, liposome is fit to vivo degradation, avirulence and non-immunogenicity, the what is more important liposome can improve Drug therapy exponential sum bioavailability, reduces drug toxicity and reduce drug side effect as pharmaceutical carrier, has reduced drug dose thus.The applicant imagines with the liposome atorvastatin thus to obtain the pharmacological activity of expectation.
Phospholipid is the main component that constitutes the liposome bimolecular film, and it is inside that the hydrophilic and hydrophobic two kinds of groups in the phospholipid align into hydrophobic layer, the bilayer that hydrophilic layer is outside.The hydrophobic small molecules chemical compound can embed or be wrapped in the hydrophobic layer of phospholipid bilayer center.Atorvastatin or its pharmaceutically acceptable salt be wrapped in form liposome in the phospholipid, can improve atorvastatin Drug therapy exponential sum bioavailability, reduce drug toxicity and reduce drug side effect.
The inventor by creationary research, the atorvastatin liposome that discovery selects for use the excipient of certain content and composition to make, its drug content and envelop rate are far superior to the product of prior art, and make after the pharmaceutically acceptable dosage form, promote that medicine absorbs under one's belt, prolong drug is at the circulation time of blood, thereby also significance raising of bioavailability.
Amlodipine of the present invention or its pharmaceutically acceptable salt (with reference to patent documentation 3) are calcium channel blocker, and the retardance calcium ion is striden film and entered cardiac muscle and vascular smooth muscle cell.The mechanism of amlodipine antihypertensive function is direct loose vascular smooth muscle.Allevating angina pectoris cutter system really is also not sure fully, but it can reduce total peripheral vascular resistance by expansion periphery small artery and coronary artery, remove coronary vasospasm, reduce the afterload of heart, reduce the heart energy expenditure and the demand of oxygen, thus allevating angina pectoris.The amlodipine oral absorption is good, and is not subjected to the influence of dietary intake.6～12 hours blood drug level reaches to the peak after the administration, and absolute bioavailability is about 64～80%, and apparent volume of distribution is about 21L/kg, and eventually the end is eliminated the half-life and is about 35～50 hours, once a day, successive administration after 7～8 days blood drug level reach to stable state.
The chemical name of Amlodipine Besylate Tablet is: 3-ethyl-5-methyl-2-(the amino ethoxymethyl of 2-)-4-(2-chlorphenyl)-1, and 4-dihydro-6-methyl-3,5-pyridine dicarboxylate benzene sulfonate, English name is: amlodipine Besylate.
Hypertension usually coexists with hyperlipemia, they the two all be considered to develop into heart disease, finally cause the main hazard factor of disadvantageous heart attack.These risk factors are mainly owing to common mechanism.In addition, carry out hypertension therapeutic the patient one be better than the patient who carries out hyperlipemia treatment.Therefore, these two kinds of diseases being carried out single therapy is favourable to the patient.People such as Jukema are in " circulation ", and 1995 (Suppl.1) disclose calcium channel blocker and lipid lowerers (for example, the HMG-CoA reductase inhibitor) on the 1-197, particularly the evidence of Pravastatin combination and cooperation treatment.People such as Orkhov are at " cardiovascular drugs and treatment " (Cardiovascular Drug and therany), disclose amlodipine on 1997,11,350 and have cut down the atherosclerotic purposes of his spit of fland therapeutic alliance with drawing.
International publication application WO99/11259, Chinese patent CN1617717A, CN1351492A, CN1268053A, CN1117566C and CN101062035A disclose the combination that comprises amlodipine and atorvastatin, be mainly used in treatment or prevention of arterial and related heart disease, be selected from hypertension, myocardial infarction, hyperlipemia, atherosclerosis, arteriosclerosis, coronary artery disease, mental and physical efforts congestive heart failure, apoplexy or angina pectoris.Therefore, need the patient of double treatment can use this two kinds of medicines during expectation.Wish and to use this two kinds of medicines with the single dose form in addition, even more.
We find astoundingly and unexpectedly, though known between amlodipine and the atorvastatin is incompatibility, but amlodipine and atorvastatin can be mixed with the single dose form, it is stable and has and use the bioavailability of medicine equivalence separately with separate dosage forms, and contains very low-level impurity and/or catabolite.The amlodipine besylate and atorvastatin calcium sheet, China is in approval listing in 2008.
Chinese patent CN101391098A discloses a kind of melittin Liposomal formulation, it is characterized in that being made up of for 10～140 parts 1 part of melittin, phosphatidase 15～40 part, 1.3～10 parts in cholesterol, poloxamer.Prepared liposome adjuvant content is higher, and drug content is less; The overall dimensions of the pharmaceutical composition made of liposome is too big thus, is not suitable for the higher kind of drug content.
Chinese patent CN101229157A discloses a kind of pharmaceutical composition that comprises the Candesartan ester liposome, it is characterized in that being made up of the phospholipid of candesartan Cilexetil and 0.5～10 times, and prepared candesartan Cilexetil liposome encapsulation is higher.The decomposition that said composition can suppress candesartan Cilexetil keeps its long-term stability, thereby prolongs the effect duration of Candesartan ester formulation.
Chinese patent CN100336507A discloses a kind of preparation method of Nimodipime nanometer liposome, it is characterized in that being made up of nimodipine 10mg, hydrogenation egg yolk lecithin 150mg, cholesterol 20mg, poloxamer 200mg, sodium deoxycholate 10mg.Prepared liposome also is that adjuvant content is higher, and drug content is less; The overall dimensions of the pharmaceutical composition made of liposome is too big thus, also is not suitable for the higher kind of drug content.
Pharmaceutical composition of the present invention, 1 administration every day, the patient takes medicine very convenient like this; Improve the compliance that the patient takes medicine simultaneously, improved patient's quality of life.
Non-patent literature 1: Chinese hypertension prevention and control guide revised edition in 2005,4-5,9,31-32
Non-patent literature 2:2007 Europe hypertension association and ESC's hypertension guide new highlight. Chinese hypertension magazine, the 15th the 9th phase of volume of JIUYUE in 2007,708-710
Patent documentation 1: U.S. Pat 5273995
Patent documentation 2: U.S. Pat 4681893
Patent documentation 3: U.S. Pat 4572909
Patent documentation 4: Chinese patent CN101391098A
Patent documentation 5: Chinese patent CN101229157A
Patent documentation 6: Chinese patent CN100336507A
Summary of the invention
Problem to be solved by this invention is that the defective that overcomes prior art provides a kind of atorvastatin liposome and preparation method thereof, purpose is to solve stability problem and the raising bioavailability problem of atorvastatin in gastric acid, stable composition with levels of impurities and/or catabolite is provided, and described impurity and/or degraded may betide preparation of compositions and/or lay up period subsequently.
Another object of the present invention also is to provide a kind of pharmaceutical composition that comprises the atorvastatin liposome and preparation method thereof, described pharmaceutical composition can be pharmaceutically acceptable various dosage forms, includes but not limited to tablet, capsule, chewable tablet, oral cavity disintegration tablet, drop pill, granule or dispersible tablet.
Another object of the present invention also is to provide a kind of pharmaceutical composition that comprises atorvastatin liposome and amlodipine or its pharmaceutically acceptable salt simultaneously and preparation method thereof, described pharmaceutical composition can be pharmaceutically acceptable various dosage forms, includes but not limited to tablet, capsule, chewable tablet, oral cavity disintegration tablet, drop pill, granule or dispersible tablet.
The technical scheme that the present invention solves is as follows:
A kind of atorvastatin liposome is characterized in that, described atorvastatin liposome is made up of atorvastatin or its pharmaceutically acceptable salt and phospholipid, and wherein the weight of phospholipid is atorvastatin or its pharmaceutically acceptable salt 1～10 times.
Described atorvastatin or its pharmaceutically acceptable salt comprise its hydroxy metabolite product, are selected from Atorvastatin calcium, sodium atorvastatin, atorvastatin magnesium or atorvastatin strontium.Atorvastatin or its pharmaceutically acceptable salt can crystallizations, especially hydrate and polycrystalline form exist for partially crystallizable or amorphous forms, solvate.Chinese patent CN1423634A, CN1157374C, CN101215253A, CN1489463A, CN1260213C, CN1942439A, CN101027282A, CN101048141A, CN101263114A, CN101268047A, CN101370774A, CN101395132A, CN101437791A, CN101492406A, CN101516842A, CN101600688A, CN101643443A, CN101684090, US5969156, US6121461 are incorporated herein by reference in its entirety.
As a preferred embodiment of the present invention, described atorvastatin or its pharmaceutically acceptable salt are preferably Atorvastatin calcium.
Wherein, described phospholipid is selected from one or more in hydrogenated soy phosphatidyl choline, soybean lecithin, Ovum Gallus domesticus Flavus lecithin, hydrogenated yolk lecithin, two stearic acid lecithin, two palmitic acid lecithin, two myristic acid lecithin, EPG, egg yolk lecithin acyl serine, the egg yolk lecithin acyl inositol; Be preferably hydrogenated soy phosphatidyl choline, soybean lecithin, Ovum Gallus domesticus Flavus lecithin or hydrogenated yolk lecithin; Most preferably be hydrogenated soy phosphatidyl choline.
The present invention also provides a kind of method for preparing the atorvastatin liposome, comprises the steps:
(1) phospholipid of atorvastatin or its pharmaceutically acceptable salt and 1～10 times is dissolved in 1～20 times the organic solvent, mix homogeneously, recording volume filters, and evaporation is removed organic solvent and is made immobilized artificial membrane, drying;
(2) the adding pH value is 6.5～10.0 buffer, soaks 1～2 hour, and high-speed stirred after 5～20 minutes, to 30 POVIDONE K 30 BP/USP 30 solution that wherein slowly dropping is dissolved with same buffer, concentration is 0.5～1.0mg/ml, and is supplied buffer to original volume;
(3) filtering with microporous membrane that is 0.8 μ m with above-mentioned liposome turbid liquor diameter, filtrate lyophilization or spray drying with obtaining promptly get the atorvastatin liposome.
Above-mentioned atorvastatin liposome is at the buffer that preparation process added, and is selected from phosphate buffer, structure rafter phthalate buffer, carbonate buffer solution, borate buffer solution, the acetate buffer one or more; Be preferably acetate buffer or phosphate buffer.Described buffer pH value is 6.5～10.0, is preferably pH value 7.0～8.5.
In the above-mentioned preparation method, organic solvent is selected from one or more in dehydrated alcohol, methanol, the tert-butyl alcohol, n-butyl alcohol, isopropyl alcohol, acetone, ether, benzyl alcohol, the normal hexane; Be preferably dehydrated alcohol, isopropyl alcohol or the tert-butyl alcohol; Most preferably be dehydrated alcohol.The amount of used organic solvent is 1～20 times of atorvastatin; Be preferably 3～10 times.
The present invention also provides a kind of pharmaceutical composition, it is characterized in that, is made up of atorvastatin liposome of the present invention and pharmaceutically acceptable carrier.The dosage of wherein said atorvastatin or its pharmaceutically acceptable salt is counted 5.00mg～320.00mg with atorvastatin.
Described pharmaceutically acceptable carrier can be selected from diluent, disintegrating agent, binding agent, fluidizer, lubricant, dissolubility promoter and their combination.The amount of pharmaceutically acceptable every kind of carrier in pharmaceutical composition can change in the normal ranges of this area.
Suitable diluent can be selected from microcrystalline Cellulose, optimize microcrystalline Cellulose, Powderd cellulose, saccharide, sugar derivatives, calsium supplement and their combination; Calsium supplement is selected from calcium carbonate, calcium phosphate, calcium hydrogen phosphate, Malic acid citric acid calcium, Citric acid calcium, calcium malate, calcium lactate or calcium acetate;
Suitable disintegrants can be selected from carboxymethylstach sodium, polyvinylpolypyrrolidone, primojel, L-hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, dried starch and their combination;
Suitable bonding can be selected from polyvidone, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, pre-paying starch, starch and their combination; Polyvidone is preferably 30 POVIDONE K 30 BP/USP 30;
Suitable fluidizer can be selected from micropowder silica gel, magnesium trisilicate, cellulose powder, starch, Talcum and their combination;
Examples of suitable lubricants can be selected from magnesium stearate, calcium stearate, stearic acid, calcium silicates, Talcum and their combination;
Suitable dissolubility promoter can be selected from polyvinylpolypyrrolidone, polyvidone, sodium lauryl sulphate, polyoxyethylene sorbitan monoleate and their combination; Polyvidone is preferably 30 POVIDONE K 30 BP/USP 30.
The present invention also provides a kind of pharmaceutical composition, it is characterized in that, is made up of atorvastatin liposome of the present invention and amlodipine or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.The dosage of wherein said atorvastatin or its pharmaceutically acceptable salt is counted 5.00mg～320.00mg with atorvastatin; The dosage of described amlodipine or its pharmaceutically acceptable salt is counted 0.625mg～40.00mg with amlodipine.Described atorvastatin or its pharmaceutically acceptable salt can crystallizations, partially crystallizable or amorphous forms, solvate especially hydrate and polycrystalline form exist, be selected from Atorvastatin calcium, sodium atorvastatin, atorvastatin magnesium or atorvastatin strontium; Described amlodipine or its pharmaceutically acceptable salt can also crystallizations, partially crystallizable or amorphous forms, solvate especially hydrate and polycrystalline form exist, can be selected from Amlodipine Besylate Tablet, Levamlodipine besylate, L-Aspartic Acid amlodipine, Amlodipine mesylate, amlodipine maleate, amlodipine camsylate, amlodipine niacin, pyroglutamic acid amlodipine, amlodipine gentisate or thioctic acid amlodipine.Described pharmaceutically acceptable carrier can also be selected from above-mentioned diluent, disintegrating agent, binding agent, fluidizer, lubricant, dissolubility promoter and their combination.
As a preferred embodiment of the present invention, it is characterized in that described atorvastatin liposome is preferably the Atorvastatin calcium liposome, described amlodipine or its pharmaceutically acceptable salt are preferably Amlodipine Besylate Tablet.
The pharmaceutical composition that comprises atorvastatin liposome of the present invention can be selected from tablet, capsule, chewable tablet, oral cavity disintegration tablet, drop pill, granule or dispersible tablet.The method of the prepared pharmaceutical composition of the present invention is the routine techniques of pharmaceutical preparation production field, can adopt wet granulation, dry granulation or direct powder compression; The tablet that comprises amlodipine besylate and atorvastatin can the monolayer tabletting, also can double-deck tabletting, if double-deck tabletting, can adopt the atorvastatin liposome is ground floor and amlodipine is the second layer; Tablet can randomly carry out film coating, can be the gastric solubleness coating, also can be enteric coating.
The present invention also provides a kind of preparation to comprise the method for the pharmaceutical composition of above-mentioned atorvastatin liposome, comprises the steps:
(A) the atorvastatin liposome is pulverized, sieved;
(B) with diluent, in disintegrating agent, add disintegrating agent, binding agent, fluidizer, lubricant, dissolubility promoter and carry out drying respectively, the pulverizing of sieving;
(C) diluent that will sieve, in disintegrating agent, fluidizer, dissolubility promoter mix homogeneously in blender;
The atorvastatin liposome that (D) will sieve and the above-mentioned adjuvant of mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;
(E) adhesive water or ethanol water are made 2～15% bonding solution, do to bind and use;
(F) incite somebody to action the various supplementary materials of mix homogeneously, add to bind in the solution and make soft material, the granulation of sieving, oven dry, the granulate that sieves makes atorvastatin liposome particles I;
(G) will add disintegrating agent, lubricant and atorvastatin liposome particles I in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases, make atorvastatin particulate lipid body II, standby;
(H) drug content among the mensuration atorvastatin liposome particles II, the calculating sheet is heavy or grain is heavy;
(I) use rotary tablet machine that atorvastatin liposome particles II is pressed into tablet or dispersible tablet, perhaps use the capsule subpackage machine that atorvastatin liposome particles II is distributed into capsule.
The present invention also provides a kind of preparation to comprise the method for the pharmaceutical composition of above-mentioned atorvastatin liposome and amlodipine or its pharmaceutically acceptable salt, comprises the steps:
(A) the atorvastatin liposome is pulverized, sieved;
(B) amlodipine or its pharmaceutically acceptable salt are carried out drying, the pulverizing of sieving, then with the atorvastatin liposome that has sieved in blender by the equivalent method mix homogeneously that progressively increases;
(C) with diluent, in disintegrating agent, add disintegrating agent, binding agent, fluidizer, lubricant, dissolubility promoter and carry out drying respectively, the pulverizing of sieving;
(D) diluent that will sieve, in disintegrating agent, fluidizer, dissolubility promoter mix homogeneously in blender;
(E) will be mix homogeneously atorvastatin liposome, amlodipine or its pharmaceutically acceptable salt and the above-mentioned adjuvant of mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;
(F) adhesive water or ethanol water are made 2～15% bonding solution, do to bind and use;
(G) incite somebody to action the various supplementary materials of mix homogeneously, add to bind in the solution and make soft material, the granulation of sieving, oven dry, the granulate that sieves makes amlodipine besylate and atorvastatin granule I;
(H) will add disintegrating agent, lubricant and amlodipine besylate and atorvastatin granule I in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases, make amlodipine besylate and atorvastatin granule II, standby;
(I) two drug contents among the mensuration amlodipine besylate and atorvastatin granule II, the calculating sheet is heavy or grain is heavy;
(J) use rotary tablet machine that amlodipine besylate and atorvastatin granule II is pressed into tablet or dispersible tablet, perhaps use the capsule subpackage machine that amlodipine besylate and atorvastatin granule II is distributed into capsule.
Tablet and the capsule that comprises above-mentioned atorvastatin liposome of the present invention carried out the dissolution test, dissolution all reaches more than 90%, illustrate that the pharmaceutical composition that comprises above-mentioned atorvastatin liposome of the present invention not only satisfies the Chinese Pharmacopoeia requirement, and having rapidlyer than common atorvastatin liposome drug combination stripping, drug effect is brought into play advantage faster.Simultaneously owing to atorvastatin of the present invention is adopted the form of liposome, and to preparation technology's research control, realized the targeted delivery of medicine, can make medicine arrive gastrointestinal tract mucous cell quickly and accurately, thereby performance curative effect, improved bioavailability, brought convenience to clinical application.
Compare with prior art, the pharmaceutical composition that comprises above-mentioned atorvastatin liposome provided by the invention has following unforeseeable technique effect:
(1) atorvastatin liposome of the present invention do not comprise emulsifying agents such as cholesterol and poloxamer, thereby drug content is higher, and its envelop rate still surpasses 90%;
(2) pharmaceutical composition that contains above-mentioned atorvastatin liposome of the present invention, not only dissolution and bioavailability are higher than prior art products far away, and bring great convenience to clinical application;
(3) pharmaceutical composition that contains the atorvastatin liposome of the present invention has been avoided the peak valley phenomenon in the drug release process, has the permanent effect of slow release, can bring into play drug action more fully, and toxic and side effects is little;
(4) because Atorvastatin calcium, atorvastatin magnesium or atorvastatin strontium are water-soluble hardly, atorvastatin liposome interior of the present invention is added with dissolubility promoter such as 30 POVIDONE K 30 BP/USP
30, the outside also is added with dissolubility promoter such as 30 POVIDONE K 30 BP/USP
30Or polyvinylpolypyrrolidone, thereby bioavailability is further enhanced;
(5) adopt conventional process equipment, but commercial scale, high efficiency production, and constant product quality is a kind of uniqueness and blanket, low-cost industrial preparation method.
The pharmaceutical composition that comprises above-mentioned atorvastatin liposome provided by the invention is carried out stability test to be investigated: placed respectively 10 days under high temperature is 60 ℃, high humility (relative humidity 90% scholar 5%), illumination 4500LX condition, every detection index has no significant change; Carried out accelerated test 6 months under temperature is 40 ℃, relative humidity 75% scholar 5% condition, every detection index does not all have significant change; In temperature is that 25 ℃, relative humidity are to carry out long term test 24 months under 60% scholar, 10% condition, and every detection index does not also all have significant change.
With the pharmaceutical composition that comprises above-mentioned atorvastatin liposome provided by the invention, carry out acute toxicity test and abnormal toxicity test inspection, the result is all up to specification, and safety obtains proof.
The specific embodiment
Describe the present invention in detail below in conjunction with embodiment.
Embodiment 1: the preparation of atorvastatin magnesium liposome
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) | Dosage 4 (mg) |
| Atorvastatin magnesium | ??5.00 | ??10.00 | ??20.00 | ??40.00 |
| Hydrogenated yolk lecithin | ??5.00 | ??10.00 | ??20.00 | ??40.00 |
| Amount to | ??10.00 | ??20.00 | ??40.00 | ??80.00 |
Preparation method:
(1) hydrogenated yolk lecithin of atorvastatin magnesium and 1 times is dissolved in 1 times the tert-butyl alcohol, mix homogeneously, recording volume filters, and evaporation is removed the tert-butyl alcohol and is made immobilized artificial membrane, vacuum drying;
(2) the adding pH value is 10.0 structure rafter phthalate buffer, soaked 1 hour, and high-speed stirred, after 5 minutes,, concentration dissolved with same structure rafter phthalate buffer to wherein slowly dripping is the 30 POVIDONE K 30 BP/USP of 0.5mg/ml
30Solution, and supply buffer to original volume;
(3) filtering with microporous membrane that is 0.8 μ m with above-mentioned liposome turbid liquor diameter, the filtrate lyophilization with obtaining promptly gets the atorvastatin magnesium liposome.
Embodiment 2: the preparation of Atorvastatin calcium liposome
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) | Dosage 4 (mg) |
| Atorvastatin calcium | ??20.00 | ??40.00 | ??80.00 | ??160.00 |
| Soybean lecithin | ??60.00 | ??120.00 | ??240.00 | ??480.00 |
| Amount to | ??80.00 | ??160.00 | ??320.00 | ??640.00 |
Preparation method:
(1) soybean lecithin of Atorvastatin calcium and 3 times is dissolved in 10 times the n-butyl alcohol, mix homogeneously, recording volume filters, and evaporation is removed n-butyl alcohol and is made immobilized artificial membrane, vacuum drying;
(2) the adding pH value is 6.5 phosphate buffer, soaked 1.5 hours, and high-speed stirred, after 10 minutes,, concentration dissolved with same phosphate buffer to wherein slowly dripping is the 30 POVIDONE K 30 BP/USP of 0.75mg/ml
30Solution, and supply buffer to original volume;
(3) filtering with microporous membrane that is 0.8 μ m with above-mentioned liposome turbid liquor diameter, the filtrate lyophilization with obtaining promptly gets the Atorvastatin calcium liposome.
Embodiment 3: the preparation of Atorvastatin calcium liposome
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) | Dosage 4 (mg) |
| Atorvastatin calcium | ??20.00 | ??40.00 | ??80.00 | ??160.00 |
| Soybean lecithin | ??100.00 | ??200.00 | ??400.00 | ??800.00 |
| Amount to | ??120.00 | ??240.00 | ??480.00 | ??960.00 |
Preparation method:
(1) soybean lecithin of Atorvastatin calcium and 5 times is dissolved in 10 times the dehydrated alcohol, mix homogeneously, recording volume filters, and evaporation is removed dehydrated alcohol and is made immobilized artificial membrane, vacuum drying;
(2) the adding pH value is 9.0 acetate buffer, soaked 1 hour, and high-speed stirred, after 15 minutes,, concentration dissolved with same acetate buffer to wherein slowly dripping is the 30 POVIDONE K 30 BP/USP of 0.75mg/ml
30Solution, and supply buffer to original volume;
(3) filtering with microporous membrane that is 0.8 μ m with above-mentioned liposome turbid liquor diameter, the filtrate spray drying with obtaining promptly gets the Atorvastatin calcium liposome.
Embodiment 4: the preparation of Atorvastatin calcium liposome
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) | Dosage 4 (mg) |
| Atorvastatin calcium | ??10.00 | ??20.00 | ??40.00 | ??80.00 |
| Hydrogenated soy phosphatidyl choline | ??70.00 | ??140.00 | ??280.00 | ??560.00 |
| Amount to | ??80.00 | ??160.00 | ??3200.00 | ??640.00 |
Preparation method:
(1) hydrogenated soy phosphatidyl choline of Atorvastatin calcium and 7 times is dissolved in 15 times the dehydrated alcohol, mix homogeneously, recording volume filters, and evaporation is removed dehydrated alcohol and is made immobilized artificial membrane, vacuum drying;
(2) the adding pH value is 7.5 acetate buffer, soaked 1.5 hours, and high-speed stirred, after 15 minutes,, concentration dissolved with same acetate buffer to wherein slowly dripping is the 30 POVIDONE K 30 BP/USP of 0.85mg/ml
30Solution, and supply buffer to original volume;
(3) filtering with microporous membrane that is 0.8 μ m with above-mentioned liposome turbid liquor diameter, the filtrate spray drying with obtaining promptly gets the Atorvastatin calcium liposome.
Embodiment 5: the preparation of Atorvastatin calcium liposome
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) | Dosage 4 (mg) |
| Atorvastatin calcium | ??10.00 | ??20.00 | ??40.00 | ??80.00 |
| Hydrogenated soy phosphatidyl choline | ??100.00 | ??200.00 | ??400.00 | ??800.00 |
| Amount to | ??110.00 | ??220.00 | ??440.00 | ??880.00 |
Preparation method:
(1) hydrogenated soy phosphatidyl choline of Atorvastatin calcium and 10 times is dissolved in 20 times the dehydrated alcohol, mix homogeneously, recording volume filters, and evaporation is removed dehydrated alcohol and is made immobilized artificial membrane, vacuum drying;
(2) the adding pH value is 7.5 acetate buffer, soaked 2 hours, and high-speed stirred, after 20 minutes,, concentration dissolved with same acetate buffer to wherein slowly dripping is the 30 POVIDONE K 30 BP/USP of 1.0mg/ml
30Solution, and supply buffer to original volume;
(3) filtering with microporous membrane that is 0.8 μ m with above-mentioned liposome turbid liquor diameter, the filtrate spray drying with obtaining promptly gets the Atorvastatin calcium liposome.
Embodiment 6: the tablet that comprises the Atorvastatin calcium liposome
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) | Dosage 4 (mg) |
| Atorvastatin calcium liposome * | ??10.00 | ??20.00 | ??40.00 | ??80.00 |
| Calcium carbonate | ??9.90 | ??19.79 | ??39.58 | ??79.15 |
| 30 POVIDONE K 30 BP/USP 30 | ??2.50 | ??5.00 | ??10.00 | ??20.00 |
| Polyvinylpolypyrrolidone | ??1.00 | ??2.00 | ??4.00 | ??8.00 |
| In add carboxymethylstach sodium | ??0.55 | ??1.10 | ??2.20 | ??4.40 |
| Add carboxymethylstach sodium | ??0.28 | ??0.55 | ??1.10 | ??2.20 |
| Micropowder silica gel | ??0.20 | ??0.41 | ??0.82 | ??1.65 |
| Magnesium stearate | ??0.58 | ??1.15 | ??2.30 | ??4.60 |
| Sheet is heavy | ??25.00 | ??50.00 | ??100.00 | ??200.00 |
*--the dosage of-Atorvastatin calcium liposome calculates with atorvastatin, and is as follows.
Preparation method:
(A) the Atorvastatin calcium liposome is pulverized, crossed 80 mesh sieves;
(B) with calcium carbonate, 30 POVIDONE K 30 BP/USP 30, polyvinylpolypyrrolidone, in add carboxymethylstach sodium, add carboxymethylstach sodium, micropowder silica gel and magnesium stearate be respectively at 80 ℃ of dryings 6 hours, cross 80 mesh sieves and pulverize;
(C) calcium carbonate that will sieve, polyvinylpolypyrrolidone, in add carboxymethylstach sodium and micropowder silica gel mix homogeneously in blender;
The calcium carbonate of the Atorvastatin calcium liposome that (D) will sieve and mix homogeneously, polyvinylpolypyrrolidone, in add carboxymethylstach sodium and micropowder silica gel in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;
(E) 30 POVIDONE K 30 BP/USP 30 usefulness purified water are made 10% 30 POVIDONE K 30 BP/USP 30 solution, made adhesive and use;
(F) will be the various supplementary materials of mix homogeneously, add in 30 POVIDONE K 30 BP/USP 30 solution and make soft material, cross 18 mesh sieves and granulate, 16 mesh sieve granulate are crossed in 60 ℃ of oven dry, make Atorvastatin calcium liposome particles I;
(G) will add carboxymethylstach sodium, magnesium stearate and Atorvastatin calcium liposome particles I in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases, make Atorvastatin calcium liposome particles II, standby;
(H) drug content among the mensuration Atorvastatin calcium liposome particles II, it is heavy to calculate sheet;
(I) use rotary tablet machine that Atorvastatin calcium liposome particles II is pressed into 10000.
Embodiment 7: the capsule that comprises the Atorvastatin calcium liposome
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) | Dosage 4 (mg) |
| The Atorvastatin calcium liposome | ??10.00 | ??20.00 | ??40.00 | ??80.00 |
| Microcrystalline Cellulose | ??9.90 | ??19.79 | ??39.58 | ??79.15 |
| 30 POVIDONE K 30 BP/USP 30 | ??2.50 | ??5.00 | ??10.00 | ??20.00 |
| Polyvinylpolypyrrolidone | ??1.00 | ??2.00 | ??4.00 | ??8.00 |
| In add carboxymethylstach sodium | ??0.55 | ??1.10 | ??2.20 | ??4.40 |
| Add carboxymethylstach sodium | ??0.28 | ??0.55 | ??1.10 | ??2.20 |
| Micropowder silica gel | ??0.20 | ??0.41 | ??0.82 | ??1.65 |
| Magnesium stearate | ??0.58 | ??1.15 | ??2.30 | ??4.60 |
| Sheet is heavy | ??25.00 | ??50.00 | ??100.00 | ??200.00 |
Preparation method:
(A) the Atorvastatin calcium liposome is pulverized, crossed 80 mesh sieves;
(B) with microcrystalline Cellulose, 30 POVIDONE K 30 BP/USP 30, polyvinylpolypyrrolidone, in add carboxymethylstach sodium, add carboxymethylstach sodium, micropowder silica gel and magnesium stearate be respectively at 80 ℃ of dryings 6 hours, cross 80 mesh sieves and pulverize;
(C) microcrystalline Cellulose that will sieve, polyvinylpolypyrrolidone, in add carboxymethylstach sodium and micropowder silica gel mix homogeneously in blender;
The microcrystalline Cellulose of the Atorvastatin calcium liposome that (D) will sieve and mix homogeneously, polyvinylpolypyrrolidone, in add carboxymethylstach sodium and micropowder silica gel in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;
(E) 30 POVIDONE K 30 BP/USP 30 usefulness purified water are made 10% 30 POVIDONE K 30 BP/USP 30 solution, made adhesive and use;
(F) will be the various supplementary materials of mix homogeneously, add in 30 POVIDONE K 30 BP/USP 30 solution and make soft material, cross 24 mesh sieves and granulate, 18 mesh sieve granulate are crossed in 60 ℃ of oven dry, make Atorvastatin calcium liposome particles I;
(G) will add carboxymethylstach sodium, magnesium stearate and Atorvastatin calcium liposome particles I in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases, make Atorvastatin calcium liposome particles II, standby;
(H) drug content among the mensuration Atorvastatin calcium liposome particles II, it is heavy to calculate grain;
(I) use the capsule subpackage machine that Atorvastatin calcium liposome particles II is distributed into capsule, make 10000.
Embodiment 8: the dispersible tablet that comprises the atorvastatin magnesium liposome
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) | Dosage 4 (mg) |
| The atorvastatin magnesium liposome | ??20.00 | ??40.00 | ??80.00 | ??160.00 |
| Mannitol | ??12.54 | ??25.08 | ??50.15 | ??100.30 |
| Polyvinylpolypyrrolidone | ??5.00 | ??10.00 | ??20.00 | ??40.00 |
| Carboxymethylstach sodium | ??1.65 | ??3.30 | ??6.60 | ??13.20 |
| Micropowder silica gel | ??0.41 | ??0.82 | ??1.65 | ??3.30 |
| Magnesium stearate | ??0.40 | ??0.80 | ??1.60 | ??3.20 |
| Sheet is heavy | ??40.00 | ??80.00 | ??160.00 | ??320.00 |
Preparation method:
(A) the atorvastatin magnesium liposome is pulverized, crossed 80 mesh sieves;
(B) with mannitol, polyvinylpolypyrrolidone, carboxymethylstach sodium, micropowder silica gel and magnesium stearate respectively at 80 ℃ of dryings 6 hours, cross 100 mesh sieves and pulverize, then mix homogeneously;
The mannitol of the atorvastatin magnesium liposome that (C) will sieve and mix homogeneously, polyvinylpolypyrrolidone, carboxymethylstach sodium, micropowder silica gel, magnesium stearate in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;
(D) mixed powder that above-mentioned mixing is obtained uses the compacting of lift-over compacting machine to form compacting material;
(E) will be the compacting material cross 18 mesh sieves and mill and form the material of having milled;
(F) mixing of materials of will milling forms the atorvastatin magnesium liposome particles, and is standby;
(G) use rotary tablet machine the atorvastatin magnesium liposome particles to be pressed into 10000 dispersible tablet.
Embodiment 9: the tablet that comprises the Atorvastatin calcium liposome
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) | Dosage 4 (mg) |
| The Atorvastatin calcium liposome | ??20.00 | ??40.00 | ??80.00 | ??160.00 |
| Microcrystalline Cellulose | ??10.21 | ??20.42 | ??40.85 | ??81.70 |
| 30 POVIDONE K 30 BP/USP 30 | ??5.00 | ??10.00 | ??20.00 | ??40.00 |
| Carboxymethylstach sodium | ??1.50 | ??3.00 | ??6.00 | ??12.00 |
| Micropowder silica gel | ??0.41 | ??0.82 | ??1.65 | ??3.30 |
| Magnesium stearate | ??0.38 | ??0.75 | ??1.50 | ??3.00 |
| Sheet is heavy | ??37.50 | ??75.00 | ??150.00 | ??300.00 |
Preparation method:
(A) the Atorvastatin calcium liposome is pulverized, crossed 80 mesh sieves;
(B) with microcrystalline Cellulose, 30 POVIDONE K 30 BP/USP 30, carboxymethylstach sodium, micropowder silica gel and magnesium stearate respectively at 60 ℃ of dryings 6 hours, cross 100 mesh sieves and pulverize, then mix homogeneously;
The Atorvastatin calcium liposome that (C) will sieve and the microcrystalline Cellulose, 30 POVIDONE K 30 BP/USP 30, carboxymethylstach sodium, micropowder silica gel, magnesium stearate of mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;
(D) measure drug content, it is heavy to calculate sheet, connects with diameter 8mm punch die straightening and makes tablet, makes 10000, and the control tablet hardness is 4.0～6.0kg;
(E) stir with Opadry II and an amount of purified water and make coating solution, the above-mentioned tablet of suppressing is carried out film coating.
Embodiment 10: the granule that comprises the Atorvastatin calcium liposome
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) | Dosage 4 (mg) |
| The Atorvastatin calcium liposome | ??20.00 | ??40.00 | ??80.00 | ??160.00 |
| Mannitol | ??18.72 | ??37.45 | ??74.90 | ??149.80 |
| 30 POVIDONE K 30 BP/USP 30 | ??5.00 | ??10.00 | ??20.00 | ??40.00 |
| Sucralose | ??1.25 | ??2.50 | ??5.00 | ??10.00 |
| Strawberry essence | ??0.02 | ??0.05 | ??0.10 | ??0.20 |
| Grain is heavy | ??45.00 | ??90.00 | ??180.00 | ??360.00 |
Preparation method:
(A) the Atorvastatin calcium liposome is pulverized, crossed 80 mesh sieves;
(B) with mannitol, sucralose respectively at 60 ℃～80 ℃ dryings 6 hours, cross 80 mesh sieves and pulverize, then mix homogeneously;
The Atorvastatin calcium liposome that (C) will sieve and the mannitol, sucralose of mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;
(D) 30 POVIDONE K 30 BP/USP 30 of getting recipe quantity is dissolved in the 50% an amount of alcoholic solution, makes 10% 30 POVIDONE K 30 BP/USP 30 alcoholic solution, uses as binding agent;
(E) will be the various supplementary materials of mix homogeneously and the strawberry essence of recipe quantity, add in 10% 30 POVIDONE K 30 BP/USP 30 alcoholic solution and make soft material, cross 24 mesh sieves and granulate, 55 ℃ of oven dry, 18 order granulate make the Atorvastatin calcium liposome particles;
(F) use the granule racking machine to be distributed into granule exsiccant Atorvastatin calcium liposome particles, make 10000 bags, promptly.
Embodiment 11: the oral cavity disintegration tablet that comprises the Atorvastatin calcium liposome
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) | Dosage 4 (mg) |
| The Atorvastatin calcium liposome | ??20.00 | ??40.00 | ??80.00 | ??160.00 |
| Microcrystalline Cellulose | ??15.00 | ??30.00 | ??60.00 | ??120.00 |
| Mannitol | ??8.28 | ??16.55 | ??33.10 | ??66.20 |
| 30 POVIDONE K 30 BP/USP 30 | ??5.00 | ??10.00 | ??20.00 | ??40.00 |
| Sodium bicarbonate | ??0.48 | ??0.95 | ??1.90 | ??3.80 |
| Sucralose | ??1.25 | ??2.50 | ??5.00 | ??10.00 |
| Sheet is heavy | ??50.00 | ??100.00 | ??200.00 | ??400.00 |
Preparation method:
(A) the Atorvastatin calcium liposome is pulverized, crossed 80 mesh sieves;
(B) with microcrystalline Cellulose, mannitol, 30 POVIDONE K 30 BP/USP 30, sodium bicarbonate, sucralose respectively at 60 ℃～80 ℃ dryings 4 hours, cross 100 mesh sieves and pulverize, then mix homogeneously;
The Atorvastatin calcium liposome that (C) will sieve and the microcrystalline Cellulose, mannitol, 30 POVIDONE K 30 BP/USP 30, sodium bicarbonate, sucralose of mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;
(D) 30 POVIDONE K 30 BP/USP 30 of getting recipe quantity is dissolved in the 50% an amount of alcoholic solution, makes 50% alcoholic solution of 10% 30 POVIDONE K 30 BP/USP 30, as binding agent;
(E) will be the various supplementary materials of mix homogeneously, add in 50% alcoholic solution of 10% 30 POVIDONE K 30 BP/USP 30 and make soft material, cross 18 mesh sieves and granulate, 55 ℃ of oven dry, 16 order granulate make the Atorvastatin calcium liposome particles;
(F) measure intermediate content, it is heavy to calculate sheet according to assay, is pressed into oral cavity disintegration tablet with φ 8mm drift, makes 10000, promptly.
Embodiment 12: the drop pill that comprises the Atorvastatin calcium liposome
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) | Dosage 4 (mg) |
| The Atorvastatin calcium liposome | ??1.00 | ??2.00 | ??4.00 | ??8.00 |
| ??PEG6000 | ??3.10 | ??6.20 | ??12.40 | ??24.80 |
| Polyoxyethylene sorbitan monoleate | ??0.02 | ??0.05 | ??0.10 | ??0.20 |
| Ball is heavy | ??4.12 | ??8.25 | ??16.50 | ??33.00 |
Preparation method:
(A) the Atorvastatin calcium liposome is pulverized, crossed 80 mesh sieves;
(B) PEG6000 of recipe quantity and polyoxyethylene sorbitan monoleate mixing post-heating to 55 ℃～60 ℃ are made fusion;
(C) the Atorvastatin calcium liposome is added in the fused solution stir, move in the funnel 55 ℃～60 ℃ insulations, adjusting dropping funnel size, dimethicone with-20～-5 or liquid paraffin are the cooling phase, the system of dripping, make 10000 balls, filter, wash, select ball, get final product.Once oral 10 balls, once-a-day.
Embodiment 13: the chewable tablet that comprises the Atorvastatin calcium liposome
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) | Dosage 4 (mg) |
| The Atorvastatin calcium liposome | ??20.00 | ??40.00 | ??80.00 | ??160.00 |
| Magnesium stearate | ??0.50 | ??1.00 | ??2.00 | ??4.00 |
| 30 POVIDONE K 30 BP/USP 30 | ??4.50 | ??9.00 | ??18.00 | ??36.00 |
| Sorbitol | ??13.50 | ??27.00 | ??54.00 | ??108.00 |
| 0.5% cochineal solution | ??0.40 | ??0.80 | ??1.60 | ??3.20 |
| 0.25% lemon yellow solution | ??0.40 | ??0.80 | ??1.60 | ??3.20 |
| Sucralose | ??0.50 | ??1.00 | ??2.00 | ??4.00 |
| Mannitol | ??10.0 | ??20.00 | ??40.00 | ??80.00 |
| Strawberry essence | ??0.20 | ??0.40 | ??0.80 | ??1.60 |
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) | Dosage 4 (mg) |
| Sheet is heavy | ??50.00 | ??100.00 | ??200.00 | ??400.00 |
Preparation method:
(A) the Atorvastatin calcium liposome is pulverized, crossed 80 mesh sieves;
(B) with magnesium stearate, sucralose, mannitol and sorbitol respectively at 60 ℃～80 ℃ dryings 4 hours, cross 100 mesh sieves and pulverize, then mix homogeneously;
The Atorvastatin calcium liposome that (C) will sieve and the magnesium stearate, sucralose, mannitol, sorbitol of mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;
(D) 30 POVIDONE K 30 BP/USP 30 of getting recipe quantity is dissolved in the 50% an amount of alcoholic solution, makes 50% alcoholic solution of 10% 30 POVIDONE K 30 BP/USP 30, as binding agent;
(E) will be the various supplementary materials of mix homogeneously and 0.5% cochineal solution, 0.25% lemon yellow solution, the strawberry essence of recipe quantity, add in 50% alcoholic solution of 10% 30 POVIDONE K 30 BP/USP 30 and make soft material, crossing 18 mesh sieves granulates, 55 ℃ of oven dry, 16 order granulate make the Atorvastatin calcium liposome particles;
(F) measure intermediate content, it is heavy to calculate sheet according to assay, is pressed into chewable tablet with φ 8mm drift, makes 10000, promptly.
Embodiment 14: the tablet that comprises Atorvastatin calcium liposome and Amlodipine Besylate Tablet
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) | Dosage 4 (mg) |
| The Atorvastatin calcium liposome | ??10.00 | ??20.00 | ??40.00 | ??80.00 |
| Amlodipine Besylate Tablet | ??6.94 | ??6.94 | ??6.94 | ??6.94 |
| Calcium carbonate | ??2.95 | ??12.85 | ??32.64 | ??72.21 |
| 30 POVIDONE K 30 BP/USP 30 | ??2.50 | ??5.00 | ??10.00 | ??20.00 |
| Polyvinylpolypyrrolidone | ??1.00 | ??2.00 | ??4.00 | ??8.00 |
| In add carboxymethylstach sodium | ??0.55 | ??1.10 | ??2.20 | ??4.40 |
| Add carboxymethylstach sodium | ??0.28 | ??0.55 | ??1.10 | ??2.20 |
| Micropowder silica gel | ??0.20 | ??0.41 | ??0.82 | ??1.65 |
| Magnesium stearate | ??0.58 | ??1.15 | ??2.30 | ??4.60 |
| Sheet is heavy | ??25.00 | ??50.00 | ??100.00 | ??200.00 |
Preparation method:
(A) the Atorvastatin calcium liposome is pulverized, crossed 80 mesh sieves;
(B) with Amlodipine Besylate Tablet in 80 ℃ of dryings 6 hours, cross 100 mesh sieves and pulverize, then with the Atorvastatin calcium liposome that has sieved in blender by the equivalent method mix homogeneously that progressively increases;
(C) with calcium carbonate, 30 POVIDONE K 30 BP/USP 30, polyvinylpolypyrrolidone, in add carboxymethylstach sodium, add carboxymethylstach sodium, micropowder silica gel and magnesium stearate be respectively at 80 ℃ of dryings 6 hours, cross 100 mesh sieves and pulverize;
(D) calcium carbonate that will sieve, polyvinylpolypyrrolidone, in add carboxymethylstach sodium and micropowder silica gel mix homogeneously in blender;
(E) will be Atorvastatin calcium liposome, the Amlodipine Besylate Tablet of mix homogeneously, with the calcium carbonate of mix homogeneously, polyvinylpolypyrrolidone, in add carboxymethylstach sodium and micropowder silica gel in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;
(F) 30 POVIDONE K 30 BP/USP 30 usefulness purified water are made 10% 30 POVIDONE K 30 BP/USP 30 solution, made adhesive and use;
(G) will be the various supplementary materials of mix homogeneously, add in 30 POVIDONE K 30 BP/USP 30 solution and make soft material, cross 24 mesh sieves and granulate, 18 mesh sieve granulate are crossed in 60 ℃ of oven dry, make amlodipine besylate and atorvastatin calcium granule I;
(H) will add carboxymethylstach sodium, magnesium stearate and amlodipine besylate and atorvastatin calcium granule I in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases, make amlodipine besylate and atorvastatin calcium granule II, standby;
(I) two drug contents among the mensuration amlodipine besylate and atorvastatin calcium granule II, it is heavy to calculate sheet;
(J) use rotary tablet machine that amlodipine besylate and atorvastatin calcium granule II is pressed into 10000.
Embodiment 15: the capsule that comprises Atorvastatin calcium liposome and Amlodipine Besylate Tablet
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) | Dosage 4 (mg) |
| The Atorvastatin calcium liposome | ??10.00 | ??20.00 | ??40.00 | ??80.00 |
| Amlodipine Besylate Tablet | ??13.88 | ??13.88 | ??13.88 | ??13.88 |
| Microcrystalline Cellulose | ??8.01 | ??29.91 | ??73.70 | ??161.27 |
| 30 POVIDONE K 30 BP/USP 30 | ??2.50 | ??5.00 | ??10.00 | ??20.00 |
| Polyvinylpolypyrrolidone | ??1.50 | ??3.00 | ??6.00 | ??12.00 |
| In add carboxymethylstach sodium | ??0.55 | ??1.10 | ??2.20 | ??4.40 |
| Add carboxymethylstach sodium | ??0.28 | ??0.55 | ??1.10 | ??2.20 |
| Micropowder silica gel | ??0.20 | ??0.41 | ??0.82 | ??1.65 |
| Magnesium stearate | ??0.58 | ??1.15 | ??2.30 | ??4.60 |
| Sheet is heavy | ??37.50 | ??75.00 | ??150.00 | ??300.00 |
Preparation method:
(A) the Atorvastatin calcium liposome is pulverized, crossed 80 mesh sieves;
(B) with Amlodipine Besylate Tablet in 80 ℃ of dryings 6 hours, cross 100 mesh sieves and pulverize, then with the Atorvastatin calcium liposome that has sieved in blender by the equivalent method mix homogeneously that progressively increases;
(C) with microcrystalline Cellulose, 30 POVIDONE K 30 BP/USP 30, polyvinylpolypyrrolidone, in add carboxymethylstach sodium, add carboxymethylstach sodium, micropowder silica gel and magnesium stearate be respectively at 80 ℃ of dryings 6 hours, cross 100 mesh sieves and pulverize;
(D) microcrystalline Cellulose that will sieve, polyvinylpolypyrrolidone, in add carboxymethylstach sodium and micropowder silica gel mix homogeneously in blender;
(E) will be Atorvastatin calcium liposome, the Amlodipine Besylate Tablet of mix homogeneously, with the microcrystalline Cellulose of mix homogeneously, polyvinylpolypyrrolidone, in add carboxymethylstach sodium and micropowder silica gel in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;
(F) 30 POVIDONE K 30 BP/USP 30 usefulness 50% alcoholic solution is made 10% 30 POVIDONE K 30 BP/USP 30 alcoholic solution, make adhesive and use;
(G) will be the various supplementary materials of mix homogeneously, add in 30 POVIDONE K 30 BP/USP 30 alcoholic solution and make soft material, cross 18 mesh sieves and granulate, 16 mesh sieve granulate are crossed in 60 ℃ of oven dry, make amlodipine besylate and atorvastatin calcium granule I;
(H) will add carboxymethylstach sodium, magnesium stearate and amlodipine besylate and atorvastatin calcium granule I in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases, make amlodipine besylate and atorvastatin calcium granule II, standby;
(I) two drug contents among the mensuration amlodipine besylate and atorvastatin calcium granule II, it is heavy to calculate grain;
(J) use the capsule subpackage machine that amlodipine besylate and atorvastatin calcium granule II is distributed into capsule, make 10000.
Embodiment 16: the dispersible tablet that comprises Atorvastatin calcium liposome and Amlodipine Besylate Tablet
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) | Dosage 4 (mg) |
| The Atorvastatin calcium liposome | ??20.00 | ??40.00 | ??80.00 | ??160.00 |
| Amlodipine Besylate Tablet | ??1.74 | ??3.47 | ??6.94 | ??13.88 |
| Mannitol | ??10.82 | ??21.63 | ??43.26 | ??86.52 |
| Polyvinylpolypyrrolidone | ??5.00 | ??10.00 | ??20.00 | ??40.00 |
| Carboxymethylstach sodium | ??1.65 | ??3.30 | ??6.60 | ??13.20 |
| Micropowder silica gel | ??0.41 | ??0.82 | ??1.65 | ??3.30 |
| Magnesium stearate | ??0.40 | ??0.80 | ??1.60 | ??3.20 |
| Sheet is heavy | ??40.00 | ??80.00 | ??160.00 | ??320.00 |
Preparation method:
(A) the Atorvastatin calcium liposome is pulverized, crossed 80 mesh sieves;
(B) with Amlodipine Besylate Tablet in 80 ℃ of dryings 4 hours, cross 100 mesh sieves and pulverize, then with the atorvastatin liposome that has sieved in blender by the equivalent method mix homogeneously that progressively increases;
(C) with mannitol, polyvinylpolypyrrolidone, carboxymethylstach sodium, micropowder silica gel and magnesium stearate respectively at 80 ℃ of dryings 6 hours, cross 100 mesh sieves and pulverize, then mix homogeneously;
(D) will be Atorvastatin calcium liposome, the Amlodipine Besylate Tablet of mix homogeneously, with the mannitol of mix homogeneously, polyvinylpolypyrrolidone, carboxymethylstach sodium, micropowder silica gel, magnesium stearate in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;
(E) mixed powder that above-mentioned mixing is obtained uses the compacting of lift-over compacting machine to form compacting material;
(F) will be the compacting material cross 24 mesh sieves and mill and form the material of having milled;
(G) mixing of materials of will milling forms the amlodipine besylate and atorvastatin calcium granule;
(H) use rotary tablet machine that the amlodipine besylate and atorvastatin calcium granule is pressed into dispersible tablet, make 10000, get final product.
Embodiment 17: the tablet that comprises Atorvastatin calcium liposome and Amlodipine Besylate Tablet
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) | Dosage 4 (mg) |
| The Atorvastatin calcium liposome | ??20.00 | ??40.00 | ??80.00 | ??160.00 |
| Amlodipine Besylate Tablet | ??0.87 | ??1.74 | ??3.47 | ??6.94 |
| Microcrystalline Cellulose | ??9.34 | ??18.69 | ??37.38 | ??74.76 |
| 30 POVIDONE K 30 BP/USP 30 | ??5.00 | ??10.00 | ??20.00 | ??40.00 |
| Carboxymethylstach sodium | ??1.50 | ??3.00 | ??6.00 | ??12.00 |
| Micropowder silica gel | ??0.41 | ??0.82 | ??1.65 | ??3.30 |
| Magnesium stearate | ??0.38 | ??0.75 | ??1.50 | ??3.00 |
| Sheet is heavy | ??37.50 | ??75.00 | ??150.00 | ??300.00 |
Preparation method:
(A) the Atorvastatin calcium liposome is pulverized, crossed 80 mesh sieves;
(B) with Amlodipine Besylate Tablet in 80 ℃ of dryings 6 hours, cross 100 mesh sieves and pulverize, then with the Atorvastatin calcium liposome that has sieved in blender by the equivalent method mix homogeneously that progressively increases;
(C) with microcrystalline Cellulose, 30 POVIDONE K 30 BP/USP 30, carboxymethylstach sodium, micropowder silica gel and magnesium stearate respectively at 80 ℃ of dryings 6 hours, cross 100 mesh sieves and pulverize, then mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer;
(D) will be mix homogeneously Atorvastatin calcium liposome, Amlodipine Besylate Tablet and the microcrystalline Cellulose, 30 POVIDONE K 30 BP/USP 30, carboxymethylstach sodium, micropowder silica gel, magnesium stearate of mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;
(E) measure drug content, it is heavy to calculate sheet, directly makes tablet with rotary tablet machine, makes 10000, and the control tablet hardness is 4.0～10.0kg;
(F) stir with Opadry II and an amount of purified water and make coating solution, the above-mentioned tablet of suppressing is carried out film coating.
Embodiment 18: the granule that comprises Atorvastatin calcium liposome and Amlodipine Besylate Tablet
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) | Dosage 4 (mg) |
| The Atorvastatin calcium liposome | ??20.00 | ??40.00 | ??80.00 | ??160.00 |
| Amlodipine Besylate Tablet | ??0.87 | ??1.74 | ??3.47 | ??6.94 |
| Mannitol | ??17.86 | ??35.71 | ??71.42 | ??142.84 |
| 30 POVIDONE K 30 BP/USP 30 | ??5.00 | ??10.00 | ??20.00 | ??40.00 |
| Sucralose | ??1.25 | ??2.50 | ??5.00 | ??10.00 |
| Strawberry essence | ??0.02 | ??0.05 | ??0.10 | ??0.20 |
| Grain is heavy | ??45.00 | ??90.00 | ??180.00 | ??360.00 |
Preparation method:
(A) the Atorvastatin calcium liposome is pulverized, crossed 80 mesh sieves;
(B) with Amlodipine Besylate Tablet in 60 ℃～80 ℃ dryings 4 hours, cross 100 mesh sieves and pulverize, then with the Atorvastatin calcium liposome that has sieved in blender by the equivalent method mix homogeneously that progressively increases;
(C) with mannitol, sucralose respectively at 60 ℃～80 ℃ dryings 4 hours, cross 80 mesh sieves and pulverize, then mix homogeneously;
(D) will be mix homogeneously Atorvastatin calcium liposome, Amlodipine Besylate Tablet and the mannitol, sucralose of mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;
(E) 30 POVIDONE K 30 BP/USP 30 of getting recipe quantity is dissolved in the 50% an amount of alcoholic solution, makes 50% alcoholic solution of 10% 30 POVIDONE K 30 BP/USP 30, as binding agent;
(F) will be the various supplementary materials of mix homogeneously and the strawberry essence of recipe quantity, add in 50% alcoholic solution of 10% 30 POVIDONE K 30 BP/USP 30 and make soft material, cross 18 mesh sieves and granulate, 55 ℃ of oven dry, 16 order granulate make the amlodipine besylate and atorvastatin calcium granule;
(G) use the granule racking machine to be distributed into granule the amlodipine besylate and atorvastatin calcium granule, make 10000 bags, promptly.
Embodiment 19: the oral cavity disintegration tablet that comprises Atorvastatin calcium liposome and Amlodipine Besylate Tablet
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) | Dosage 4 (mg) |
| The Atorvastatin calcium liposome | ??20.00 | ??40.00 | ??80.00 | ??160.00 |
| Amlodipine Besylate Tablet | ??1.74 | ??3.47 | ??6.94 | ??13.88 |
| Microcrystalline Cellulose | ??15.00 | ??30.00 | ??60.00 | ??120.00 |
| Mannitol | ??6.54 | ??13.08 | ??26.16 | ??52.32 |
| 30 POVIDONE K 30 BP/USP 30 | ??5.00 | ??10.00 | ??20.00 | ??40.00 |
| Sodium bicarbonate | ??0.48 | ??0.95 | ??1.90 | ??3.80 |
| Sucralose | ??1.25 | ??2.50 | ??5.00 | ??10.00 |
| Sheet is heavy | ??50.00 | ??100.00 | ??200.00 | ??400.00 |
Preparation method:
(A) the Atorvastatin calcium liposome is pulverized, crossed 80 mesh sieves;
(B) with Amlodipine Besylate Tablet in 80 ℃ of dryings 4 hours, cross 100 mesh sieves and pulverize, then with the Atorvastatin calcium liposome that has sieved in blender by the equivalent method mix homogeneously that progressively increases;
(C) with microcrystalline Cellulose, mannitol, 30 POVIDONE K 30 BP/USP 30, sodium bicarbonate, sucralose respectively at 80 ℃ of dryings 4 hours, cross 100 mesh sieves and pulverize, then mix homogeneously;
(D) will be mix homogeneously Atorvastatin calcium liposome, Amlodipine Besylate Tablet and the microcrystalline Cellulose, mannitol, 30 POVIDONE K 30 BP/USP 30, sodium bicarbonate, sucralose of mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;
(E) 30 POVIDONE K 30 BP/USP 30 of getting recipe quantity is dissolved in the 50% an amount of alcoholic solution, makes 50% alcoholic solution of 10% 30 POVIDONE K 30 BP/USP 30, as binding agent;
(F) will be the various supplementary materials of mix homogeneously, add in 50% alcoholic solution of 10% 30 POVIDONE K 30 BP/USP 30 and make soft material, cross 18 mesh sieves and granulate, 55 ℃ of oven dry, 16 order granulate make the amlodipine besylate and atorvastatin calcium granule;
(G) measure intermediate content, it is heavy to calculate sheet according to assay, is pressed into oral cavity disintegration tablet with rotary tablet machine, makes 10000, promptly.
Embodiment 20: the drop pill that comprises Atorvastatin calcium liposome and Amlodipine Besylate Tablet
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) | Dosage 4 (mg) |
| The Atorvastatin calcium liposome | ??2.000 | ??4.000 | ??8.000 | ??16.000 |
| Amlodipine Besylate Tablet | ??0.174 | ??0.347 | ??0.694 | ??1.388 |
| ??PEG6000 | ??6.026 | ??12.053 | ??24.106 | ??48.212 |
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) | Dosage 4 (mg) |
| Polyoxyethylene sorbitan monoleate | ??0.050 | ??0.100 | ??0.200 | ??0.400 |
| Ball is heavy | ??8.250 | ??16.500 | ??33.000 | ??66.000 |
Preparation method:
(A) the Atorvastatin calcium liposome is pulverized, crossed 80 mesh sieves;
(B) with Amlodipine Besylate Tablet in 80 ℃ of dryings 6 hours, cross 100 mesh sieves and pulverize, then with the Atorvastatin calcium liposome that has sieved in blender by the equivalent method mix homogeneously that progressively increases;
(C) PEG6000 and polyoxyethylene sorbitan monoleate mixing post-heating to 55 ℃～60 ℃ are made fusion;
(D) will be the Atorvastatin calcium liposome of mix homogeneously and Amlodipine Besylate Tablet add to and stir in the fused solution, move in the funnel, 55 ℃～60 ℃ insulations, adjusting dropping funnel size, dimethicone with-20～-5 or liquid paraffin are the cooling phase, and the system of dripping is made 10000 balls, filter, wash, select ball, get final product.Once oral 10 balls, once-a-day.
Embodiment 21: the chewable tablet that comprises Atorvastatin calcium liposome and Amlodipine Besylate Tablet
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) | Dosage 4 (mg) |
| The Atorvastatin calcium liposome | ??20.00 | ??40.00 | ??80.00 | ??160.00 |
| Amlodipine Besylate Tablet | ??1.74 | ??3.47 | ??6.94 | ??13.88 |
| Magnesium stearate | ??0.50 | ??1.00 | ??2.00 | ??4.00 |
| 30 POVIDONE K 30 BP/USP 30 | ??4.50 | ??9.00 | ??18.00 | ??36.00 |
| Microcrystalline Cellulose | ??11.76 | ??23.53 | ??47.06 | ??94.12 |
| 0.5% cochineal solution | ??0.40 | ??0.80 | ??1.60 | ??3.20 |
| 0.25% lemon yellow solution | ??0.40 | ??0.80 | ??1.60 | ??3.20 |
| Sucralose | ??0.50 | ??1.00 | ??2.00 | ??4.00 |
| Mannitol | ??10.0 | ??20.00 | ??40.00 | ??80.00 |
| Strawberry essence | ??0.20 | ??0.40 | ??0.80 | ??1.60 |
| Sheet is heavy | ??50.00 | ??100.00 | ??200.00 | ??400.00 |
Preparation method:
(A) the Atorvastatin calcium liposome is pulverized, crossed 80 mesh sieves;
(B) with Amlodipine Besylate Tablet in 60 ℃ of dryings 8 hours, cross 100 mesh sieves and pulverize, then with the Atorvastatin calcium liposome that has sieved in blender by the equivalent method mix homogeneously that progressively increases;
(C) with magnesium stearate, sucralose, mannitol and microcrystalline Cellulose respectively at 80 ℃ of dryings 6 hours, cross 100 mesh sieves and pulverize, then mix homogeneously;
(D) will be mix homogeneously Atorvastatin calcium liposome, Amlodipine Besylate Tablet and the magnesium stearate, sucralose, mannitol, microcrystalline Cellulose of mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;
(E) 30 POVIDONE K 30 BP/USP 30 of getting recipe quantity is dissolved in the 50% an amount of alcoholic solution, makes 50% alcoholic solution of 10% 30 POVIDONE K 30 BP/USP 30, as binding agent;
(F) will be the various supplementary materials of mix homogeneously and 0.5% cochineal solution, 0.25% lemon yellow solution, the strawberry essence of recipe quantity, add in 50% alcoholic solution of 10% 30 POVIDONE K 30 BP/USP 30 and make soft material, crossing 18 mesh sieves granulates, 60 ℃ of oven dry, 16 order granulate make the amlodipine besylate and atorvastatin calcium granule;
(G) measure intermediate content, it is heavy to calculate sheet according to assay, uses rotary tablet machine that the amlodipine besylate and atorvastatin calcium granule is pressed into chewable tablet, makes 10000, promptly.
Embodiment 22: the monolayer tablet that comprises Atorvastatin calcium liposome and Amlodipine Besylate Tablet
Preparation method:
(I) granulation of Atorvastatin calcium liposome particles:
(A) the Atorvastatin calcium liposome is crossed 80 mesh sieves, pulverize;
(B) with 30 POVIDONE K 30 BP/USP 30, microcrystalline Cellulose, micropowder silica gel, magnesium stearate and carboxymethylstach sodium respectively at 80 ℃ of dryings 4 hours, cross 100 mesh sieves and pulverize, then mix homogeneously;
The Atorvastatin calcium liposome that (C) will sieve and the 30 POVIDONE K 30 BP/USP 30, microcrystalline Cellulose, micropowder silica gel, magnesium stearate, carboxymethylstach sodium of mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;
(D) mixed powder that above-mentioned mixing is obtained uses the compacting of lift-over compacting machine to form compacting material;
(E) will be the compacting material cross 18 mesh sieves and mill and form the material of having milled;
(F) mixing of materials of will milling forms the Atorvastatin calcium liposome particles, and is standby;
(II) the particulate granulation of Amlodipine Besylate Tablet:
(G) with Amlodipine Besylate Tablet in 80 ℃ of dryings 4 hours, cross 80 mesh sieves and pulverize;
(H) with 30 POVIDONE K 30 BP/USP 30, calcium carbonate, micropowder silica gel, magnesium stearate and carboxymethylstach sodium respectively at 80 ℃ of dryings 4 hours, cross 100 mesh sieves and pulverize, then mix homogeneously;
(I) Amlodipine Besylate Tablet that will sieve and the 30 POVIDONE K 30 BP/USP 30, calcium carbonate, micropowder silica gel, magnesium stearate, carboxymethylstach sodium of mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;
(J) 30 POVIDONE K 30 BP/USP 30 usefulness 50% ethanol of recipe quantity is made 10% 30 POVIDONE K 30 BP/USP 30 alcoholic solution, make adhesive and use;
(K) will be the various supplementary materials of mix homogeneously, add in 50% alcoholic solution of 10% 30 POVIDONE K 30 BP/USP 30 and make soft material, cross 18 mesh sieves and granulate, 60 ℃ of oven dry, 16 order granulate make the Amlodipine Besylate Tablet granule, and are standby;
(III) be pressed into the monolayer tablet:
(L) with the Atorvastatin calcium liposome particles that makes and Amlodipine Besylate Tablet granule in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;
(M) measure intermediate content, it is heavy to calculate sheet according to assay, is pressed into the monolayer tablet with rotary tablet machine, makes 10000, promptly.
Embodiment 23: the bilayer tablet that comprises Atorvastatin calcium liposome and Levamlodipine besylate
Preparation method:
(I) the particulate granulation of Levamlodipine besylate:
(A) with Levamlodipine besylate in 80 ℃ of dryings 6 hours, cross 80 mesh sieves and pulverize;
(B) with 30 POVIDONE K 30 BP/USP 30, calcium carbonate, micropowder silica gel, magnesium stearate and carboxymethylstach sodium respectively at 80 ℃ of dryings 6 hours, cross 100 mesh sieves and pulverize, then mix homogeneously;
(C) 30 POVIDONE K 30 BP/USP 30 of the Levamlodipine besylate that will sieve and mix homogeneously, calcium carbonate, micropowder silica gel, magnesium stearate, carboxymethylstach sodium in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;
(D) mixed powder that above-mentioned mixing is obtained uses the compacting of lift-over compacting machine to form compacting material;
(E) will be the compacting material cross 18 mesh sieves and mill and form the material of having milled;
(F) mixing of materials of will milling forms the Levamlodipine besylate granule, and is standby;
(G) measure Levamlodipine besylate granule intermediate content, calculate packing weight according to assay;
(II) granulation of Atorvastatin calcium liposome particles:
(H) the Atorvastatin calcium liposome being crossed 80 mesh sieves pulverizes;
(I) with 30 POVIDONE K 30 BP/USP 30, microcrystalline Cellulose, micropowder silica gel, magnesium stearate and carboxymethylstach sodium respectively at 80 ℃ of dryings 6 hours, cross 100 mesh sieves and pulverize, then mix homogeneously;
The 30 POVIDONE K 30 BP/USP 30 of the Atorvastatin calcium liposome that (J) will sieve and mix homogeneously, microcrystalline Cellulose, micropowder silica gel, magnesium stearate, carboxymethylstach sodium in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;
(K) mixed powder that above-mentioned mixing is obtained uses the compacting of lift-over compacting machine to form compacting material;
(L) will be the compacting material cross 18 mesh sieves and mill and form the material of having milled;
(M) mixing of materials of will milling forms the Atorvastatin calcium liposome particles, and is standby;
(N) measure Atorvastatin calcium liposome particles intermediate content, calculate packing weight according to assay;
(III) be pressed into bilayer tablet:
(0) last, use double-deck rotary tablet machine that the Atorvastatin calcium liposome particles is pressed into ground floor, subsequently the Levamlodipine besylate granule is pressed into the second layer, make 10000, this bilayer tablet can randomly carry out film coating.
Embodiment 24: the mensuration of envelop rate
Get the atorvastatin liposome of embodiment 1～5 preparation, the total content that high performance liquid chromatography detects atorvastatin is M, selects for use column chromatography to separate liposome.
Get 1.5g sephadex G-50, soak swelling more than 12 hours with the pH6.8 phosphate buffer, pack in the chromatographic column (200mm * 10mm), with above-mentioned phosphate buffer flushing balance, get the atorvastatin plastid that embodiment 1～5 makes, add water and make dissolving, make the solution that contains atorvastatin 10mg among every 1ml approximately, get solution 1.0ml respectively, add the chromatographic column top, with above-mentioned phosphate buffer 50ml eluting, flow velocity 1.2ml/min, the eluent of collecting adds rupture of membranes agent (ethanol: 50ml benzyl alcohol=8: 1), mixing, the content M1 of high performance liquid chromatography detection atorvastatin.
Envelop rate %=M1/M * 100%.
Investigate 0,3,6,24 month respectively, result such as following table:
Obviously, the above embodiment of the present invention only is for example of the present invention clearly is described, and is not to be qualification to embodiments of the present invention.For those of ordinary skill in the field, can also make other changes in different forms on the basis of the above description.Here need not also can't give exhaustive to all embodiments.And these belong to conspicuous variation or the change that spirit of the present invention extended out and still are among protection scope of the present invention.
Claims (10)
1. an atorvastatin liposome is characterized in that, described atorvastatin liposome is made up of atorvastatin or its pharmaceutically acceptable salt and phospholipid, and wherein the weight of phospholipid is atorvastatin or its pharmaceutically acceptable salt 1～10 times.
2. atorvastatin liposome as claimed in claim 1 is characterized in that, described atorvastatin or its pharmaceutically acceptable salt are preferably Atorvastatin calcium.
3. as claim 1,2 each described atorvastatin liposomees, it is characterized in that described phospholipid is selected from one or more in hydrogenated soy phosphatidyl choline, soybean lecithin, Ovum Gallus domesticus Flavus lecithin, hydrogenated yolk lecithin, two stearic acid lecithin, two palmitic acid lecithin, two myristic acid lecithin, EPG, egg yolk lecithin acyl serine, the egg yolk lecithin acyl inositol.
4. a method for preparing each described atorvastatin liposome of claim 1 to 3 is characterized in that, described preparation method comprises:
(1) phospholipid of atorvastatin or its pharmaceutically acceptable salt and 1～10 times is dissolved in 1～20 times the organic solvent, mix homogeneously, recording volume filters, and evaporation is removed organic solvent and is made immobilized artificial membrane, drying;
(2) the adding pH value is 6.5～10.0 buffer, soaked 1～2 hour, and high-speed stirred, after 5～20 minutes,, concentration dissolved with same buffer to wherein slowly dripping is the 30 POVIDONE K 30 BP/USP of 0.5～1.0mg/ml
30Solution, and supply buffer to original volume;
(3) filtering with microporous membrane that is 0.8 μ m with above-mentioned liposome turbid liquor diameter, filtrate lyophilization or spray drying with obtaining promptly get the atorvastatin liposome.
5. a pharmaceutical composition is characterized in that, is made up of each described atorvastatin liposome of claim 1 to 4 and pharmaceutically acceptable carrier.
6. a pharmaceutical composition is characterized in that, is made up of each described atorvastatin liposome of claim 1 to 4 and amlodipine or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
7. pharmaceutical composition as claimed in claim 6 is characterized in that, described atorvastatin liposome is preferably the Atorvastatin calcium liposome, and described amlodipine or its pharmaceutically acceptable salt are preferably Amlodipine Besylate Tablet.
8. the tablet, capsule, chewable tablet, oral cavity disintegration tablet, drop pill, granule or the dispersible tablet that comprise each described atorvastatin liposome of claim 1 to 7.
9. method for preparing claim 5,8 each described pharmaceutical compositions is characterized in that described preparation method comprises:
(A) the atorvastatin liposome is pulverized, sieved;
(B) with diluent, in disintegrating agent, add disintegrating agent, binding agent, fluidizer, lubricant, dissolubility promoter and carry out drying respectively, the pulverizing of sieving;
(C) diluent that will sieve, in disintegrating agent, fluidizer, dissolubility promoter mix homogeneously in blender;
The atorvastatin liposome that (D) will sieve and the above-mentioned adjuvant of mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;
(E) adhesive water or ethanol water are made 2～15% bonding solution, do to bind and use;
(F) incite somebody to action the various supplementary materials of mix homogeneously, add to bind in the solution and make soft material, the granulation of sieving, oven dry, granulate makes atorvastatin liposome particles I;
(G) will add disintegrating agent, lubricant and atorvastatin liposome particles I in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases, make atorvastatin liposome particles II, standby;
(H) drug content among the mensuration atorvastatin liposome particles II, the calculating sheet is heavy or grain is heavy;
(I) use rotary tablet machine that atorvastatin liposome particles II is pressed into tablet or dispersible tablet, perhaps use the capsule subpackage machine that atorvastatin liposome particles II is distributed into capsule.
10. a method for preparing each described pharmaceutical composition of claim 6 to 8 is characterized in that, described preparation method comprises:
(A) the atorvastatin liposome is pulverized, sieved;
(B) amlodipine or its pharmaceutically acceptable salt are carried out drying, the pulverizing of sieving, then with the atorvastatin liposome that has sieved in blender by the equivalent method mix homogeneously that progressively increases;
(C) with diluent, in disintegrating agent, add disintegrating agent, binding agent, fluidizer, lubricant, dissolubility promoter and carry out drying respectively, the pulverizing of sieving;
(D) diluent that will sieve, in disintegrating agent, fluidizer, dissolubility promoter mix homogeneously in blender;
(E) will be mix homogeneously atorvastatin liposome, amlodipine or its pharmaceutically acceptable salt and the above-mentioned adjuvant of mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;
(F) adhesive water or ethanol water are made 2～15% bonding solution, do to bind and use;
(G) incite somebody to action the various supplementary materials of mix homogeneously, add to bind in the solution and make soft material, the granulation of sieving, oven dry, granulate makes amlodipine besylate and atorvastatin granule I;
(H) will add disintegrating agent, lubricant and amlodipine besylate and atorvastatin granule I in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases, make amlodipine besylate and atorvastatin granule II, standby;
(I) two drug contents among the mensuration amlodipine besylate and atorvastatin granule II, the calculating sheet is heavy or grain is heavy;
(J) use rotary tablet machine that amlodipine besylate and atorvastatin granule II is pressed into tablet or dispersible tablet, perhaps use the capsule subpackage machine that amlodipine besylate and atorvastatin granule II is distributed into capsule.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010172783A CN101804029A (en) | 2010-05-15 | 2010-05-15 | Atorvastatin liposome and preparation method thereof, and medicine composition containing atorvastatin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010172783A CN101804029A (en) | 2010-05-15 | 2010-05-15 | Atorvastatin liposome and preparation method thereof, and medicine composition containing atorvastatin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101804029A true CN101804029A (en) | 2010-08-18 |
Family
ID=42606092
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201010172783A Pending CN101804029A (en) | 2010-05-15 | 2010-05-15 | Atorvastatin liposome and preparation method thereof, and medicine composition containing atorvastatin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101804029A (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102008440A (en) * | 2010-12-02 | 2011-04-13 | 海南美大制药有限公司 | Solid preparation of atorvastatin calcium liposome |
| CN102028658A (en) * | 2010-12-02 | 2011-04-27 | 陶灵刚 | Solid preparation containing rosuvastain calcium liposome |
| CN102133187A (en) * | 2011-03-18 | 2011-07-27 | 海南美大制药有限公司 | Pravastatin sodium liposome solid preparation |
| CN102423482A (en) * | 2011-11-17 | 2012-04-25 | 南京瑞尔医药有限公司 | The preparation method of compound amlodipine lisinopril tablet |
| CN102552143A (en) * | 2011-12-31 | 2012-07-11 | 海口南陆医药科技有限公司 | Medicine composition containing pravastatin sodium fenofibrate liposome and preparation method of medicine composition |
| CN102614182A (en) * | 2012-03-02 | 2012-08-01 | 海南美大制药有限公司 | Solid preparation of compound ammonia phenol renin medicine composition liposome |
| CN108042507A (en) * | 2017-12-25 | 2018-05-18 | 北京颐方生物科技有限公司 | A kind of more twenty alcohol microballoons and preparation method and application |
| GB2624171A (en) * | 2022-11-08 | 2024-05-15 | Novumgen Ltd | An orally disintegrating tablet containing atorvastatin and process of preparing the same |
-
2010
- 2010-05-15 CN CN201010172783A patent/CN101804029A/en active Pending
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102028658A (en) * | 2010-12-02 | 2011-04-27 | 陶灵刚 | Solid preparation containing rosuvastain calcium liposome |
| CN102028658B (en) * | 2010-12-02 | 2012-03-21 | 陶灵刚 | Solid preparation containing rosuvastain calcium liposome |
| CN102008440A (en) * | 2010-12-02 | 2011-04-13 | 海南美大制药有限公司 | Solid preparation of atorvastatin calcium liposome |
| CN102133187B (en) * | 2011-03-18 | 2012-06-27 | 海南美大制药有限公司 | Pravastatin sodium liposome solid preparation |
| CN102133187A (en) * | 2011-03-18 | 2011-07-27 | 海南美大制药有限公司 | Pravastatin sodium liposome solid preparation |
| CN102423482B (en) * | 2011-11-17 | 2013-09-25 | 南京瑞尔医药有限公司 | preparation method of compound amlodipine-lisinopril tablets |
| CN102423482A (en) * | 2011-11-17 | 2012-04-25 | 南京瑞尔医药有限公司 | The preparation method of compound amlodipine lisinopril tablet |
| CN102552143A (en) * | 2011-12-31 | 2012-07-11 | 海口南陆医药科技有限公司 | Medicine composition containing pravastatin sodium fenofibrate liposome and preparation method of medicine composition |
| CN102552143B (en) * | 2011-12-31 | 2017-09-15 | 海口南陆医药科技股份有限公司 | Pharmaceutical composition of the fenofibrate liposome containing pravastatin sodium and preparation method thereof |
| CN102614182A (en) * | 2012-03-02 | 2012-08-01 | 海南美大制药有限公司 | Solid preparation of compound ammonia phenol renin medicine composition liposome |
| CN102614182B (en) * | 2012-03-02 | 2013-05-29 | 海南美大制药有限公司 | Solid preparation of compound ammonia phenol renin medicine composition liposome |
| CN108042507A (en) * | 2017-12-25 | 2018-05-18 | 北京颐方生物科技有限公司 | A kind of more twenty alcohol microballoons and preparation method and application |
| CN108042507B (en) * | 2017-12-25 | 2020-06-30 | 北京颐方生物科技有限公司 | Policosanol microsphere and preparation method and application thereof |
| GB2624171A (en) * | 2022-11-08 | 2024-05-15 | Novumgen Ltd | An orally disintegrating tablet containing atorvastatin and process of preparing the same |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101804029A (en) | Atorvastatin liposome and preparation method thereof, and medicine composition containing atorvastatin | |
| AU2006295440B2 (en) | Capsule formulation of pirfenidone and pharmaceutically acceptable excipients | |
| US7741374B1 (en) | Methods of use of fenofibric acid | |
| CN102204920A (en) | Solid preparation of sodium aspirin and sodium pravastatin medicinal composition | |
| JP2005501051A (en) | Pharmaceutical composition of amlodipine and atorvastatin | |
| CN103002883A (en) | Pharmaceutical formulation in the form of a bilayer tablet comprising an HMG-CoA reductase inhibitor and irbesartan | |
| CN102579350A (en) | Pidotimod liposome solid preparation | |
| AU2013365715B2 (en) | A pharmaceutical composition containing candesartan cilexetil and amlodipine | |
| CN101810580A (en) | Valsartan liposome, preparation method thereof and medicinal composition containing same | |
| CA2764172A1 (en) | A thrombin receptor antagonist and clopidogrel fixed dose tablet | |
| CN102018708A (en) | Pharmaceutical composition containing amlodipine and atorvastatin magnesium | |
| CN101816640A (en) | Prasugrel liposome solid preparation | |
| CN102008469B (en) | Method for preparing telmisartan amlodipine tablets | |
| CN101433539A (en) | Therapeutic compositions containing amlodipine niacin and rosuvastatin medicament | |
| ES2387913T3 (en) | Combination preparations of salts of O-acetylsalicylic acid | |
| CN102000075A (en) | Novel pharmaceutical composite containing amlodipine and atorvastatin calcium anhydride | |
| CN102579346A (en) | Liposome solid preparation of benazepril/hydrochlorothiazide medicine combination | |
| CN102552143A (en) | Medicine composition containing pravastatin sodium fenofibrate liposome and preparation method of medicine composition | |
| TWI651101B (en) | Bilayer composite tablet formulation comprising atorvastatin, irbesartan and magnesium carbonate | |
| WO2009110010A2 (en) | Stable oral dosage form | |
| CN102028658B (en) | Solid preparation containing rosuvastain calcium liposome | |
| CN102038682A (en) | Pharmaceutical composition containing amlodipine and atorvastatin calcium solvate | |
| CN106310273A (en) | Quadruple antihypertensive drug composition | |
| CN101862329A (en) | Amlodipine besylate and atorvastatin calcium medicine compound liposome solid preparation | |
| AU2013201986B2 (en) | Capsule Formulation Of Pirfenidone And Pharmaceutically Acceptable Excipients |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20100818 |