CN100486572C - Medicament form of tatin class - Google Patents
Medicament form of tatin class Download PDFInfo
- Publication number
- CN100486572C CN100486572C CNB021474842A CN02147484A CN100486572C CN 100486572 C CN100486572 C CN 100486572C CN B021474842 A CNB021474842 A CN B021474842A CN 02147484 A CN02147484 A CN 02147484A CN 100486572 C CN100486572 C CN 100486572C
- Authority
- CN
- China
- Prior art keywords
- statins
- sodium
- dry suspension
- alginate
- acid
- 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.)
- Expired - Fee Related
Links
- 239000003814 drug Substances 0.000 title abstract description 18
- 239000000725 suspension Substances 0.000 claims abstract description 24
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229960002855 simvastatin Drugs 0.000 claims abstract description 21
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 claims abstract description 21
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 claims abstract description 15
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229960004844 lovastatin Drugs 0.000 claims abstract description 14
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 claims abstract description 14
- 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 claims abstract description 7
- 229960002965 pravastatin Drugs 0.000 claims abstract description 7
- 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 claims abstract description 7
- 239000003085 diluting agent Substances 0.000 claims abstract description 6
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 43
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 claims description 43
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 9
- 229920002125 Sokalan® Polymers 0.000 claims description 8
- 229930006000 Sucrose Natural products 0.000 claims description 8
- 239000005720 sucrose Substances 0.000 claims description 7
- 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 claims description 6
- 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 claims description 6
- 229960005370 atorvastatin Drugs 0.000 claims description 6
- 239000000741 silica gel Substances 0.000 claims description 6
- 229910002027 silica gel Inorganic materials 0.000 claims description 6
- 235000010265 sodium sulphite Nutrition 0.000 claims description 6
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 6
- FJLGEFLZQAZZCD-MCBHFWOFSA-N (3R,5S)-fluvastatin Chemical compound C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)=C1C1=CC=C(F)C=C1 FJLGEFLZQAZZCD-MCBHFWOFSA-N 0.000 claims description 5
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 5
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 5
- 229960005070 ascorbic acid Drugs 0.000 claims description 5
- 239000011668 ascorbic acid Substances 0.000 claims description 5
- 229960001631 carbomer Drugs 0.000 claims description 5
- 229960003765 fluvastatin Drugs 0.000 claims description 5
- 235000010413 sodium alginate Nutrition 0.000 claims description 5
- 239000000661 sodium alginate Substances 0.000 claims description 5
- 229940005550 sodium alginate Drugs 0.000 claims description 5
- 239000000375 suspending agent Substances 0.000 claims description 5
- 239000005995 Aluminium silicate Substances 0.000 claims description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 4
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 4
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 4
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 4
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 claims description 4
- 239000004373 Pullulan Substances 0.000 claims description 4
- 229920001218 Pullulan Polymers 0.000 claims description 4
- 244000269722 Thea sinensis Species 0.000 claims description 4
- 235000010443 alginic acid Nutrition 0.000 claims description 4
- 229920000615 alginic acid Polymers 0.000 claims description 4
- 235000012211 aluminium silicate Nutrition 0.000 claims description 4
- 239000003963 antioxidant agent Substances 0.000 claims description 4
- 230000003078 antioxidant effect Effects 0.000 claims description 4
- 235000006708 antioxidants Nutrition 0.000 claims description 4
- 239000002270 dispersing agent Substances 0.000 claims description 4
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 4
- 229940071826 hydroxyethyl cellulose Drugs 0.000 claims description 4
- -1 hydroxypropyl Chemical group 0.000 claims description 4
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 claims description 4
- 150000008442 polyphenolic compounds Chemical class 0.000 claims description 4
- 235000013824 polyphenols Nutrition 0.000 claims description 4
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 4
- 229940068984 polyvinyl alcohol Drugs 0.000 claims description 4
- 235000019423 pullulan Nutrition 0.000 claims description 4
- 235000010352 sodium erythorbate Nutrition 0.000 claims description 4
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium erythorbate Chemical compound [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 claims description 4
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims description 4
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 claims description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- 241000220324 Pyrus Species 0.000 claims description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 3
- 235000010489 acacia gum Nutrition 0.000 claims description 3
- 239000001785 acacia senegal l. willd gum Substances 0.000 claims description 3
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 claims description 3
- 239000008103 glucose Substances 0.000 claims description 3
- 239000003292 glue Substances 0.000 claims description 3
- 235000021017 pears Nutrition 0.000 claims description 3
- 239000004584 polyacrylic acid Substances 0.000 claims description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 claims description 2
- LKAPTZKZHMOIRE-KVTDHHQDSA-N (2s,3s,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolane-2-carbaldehyde Chemical compound OC[C@H]1O[C@H](C=O)[C@@H](O)[C@@H]1O LKAPTZKZHMOIRE-KVTDHHQDSA-N 0.000 claims description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 2
- FEBUJFMRSBAMES-UHFFFAOYSA-N 2-[(2-{[3,5-dihydroxy-2-(hydroxymethyl)-6-phosphanyloxan-4-yl]oxy}-3,5-dihydroxy-6-({[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}methyl)oxan-4-yl)oxy]-3,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl phosphinite Chemical compound OC1C(O)C(O)C(CO)OC1OCC1C(O)C(OC2C(C(OP)C(O)C(CO)O2)O)C(O)C(OC2C(C(CO)OC(P)C2O)O)O1 FEBUJFMRSBAMES-UHFFFAOYSA-N 0.000 claims description 2
- OPAORDVBZRVVNQ-RNQWEJQRSA-N 4-[(z,2r)-4-(4-hydroxy-3-methoxyphenyl)-2,3-dimethylbut-3-enyl]-2-methoxyphenol Chemical compound C1=C(O)C(OC)=CC(C[C@@H](C)C(\C)=C/C=2C=C(OC)C(O)=CC=2)=C1 OPAORDVBZRVVNQ-RNQWEJQRSA-N 0.000 claims description 2
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 claims description 2
- 229920001817 Agar Polymers 0.000 claims description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- 229920002101 Chitin Polymers 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- CIWBSHSKHKDKBQ-MVHIGOERSA-N D-ascorbic acid Chemical compound OC[C@@H](O)[C@@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-MVHIGOERSA-N 0.000 claims description 2
- 239000004375 Dextrin Substances 0.000 claims description 2
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- 229920000896 Ethulose Polymers 0.000 claims description 2
- 239000001859 Ethyl hydroxyethyl cellulose Substances 0.000 claims description 2
- 244000286663 Ficus elastica Species 0.000 claims description 2
- 108010010803 Gelatin Proteins 0.000 claims description 2
- 229920001503 Glucan Polymers 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 claims description 2
- 229920001612 Hydroxyethyl starch Polymers 0.000 claims description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 2
- 229920000161 Locust bean gum Polymers 0.000 claims description 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 229920000881 Modified starch Polymers 0.000 claims description 2
- HDSBZMRLPLPFLQ-UHFFFAOYSA-N Propylene glycol alginate Chemical compound OC1C(O)C(OC)OC(C(O)=O)C1OC1C(O)C(O)C(C)C(C(=O)OCC(C)O)O1 HDSBZMRLPLPFLQ-UHFFFAOYSA-N 0.000 claims description 2
- 229920002305 Schizophyllan Polymers 0.000 claims description 2
- 244000275012 Sesbania cannabina Species 0.000 claims description 2
- UQZIYBXSHAGNOE-USOSMYMVSA-N Stachyose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@H](CO[C@@H]2[C@@H](O)[C@@H](O)[C@@H](O)[C@H](CO)O2)O1 UQZIYBXSHAGNOE-USOSMYMVSA-N 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- 240000004584 Tamarindus indica Species 0.000 claims description 2
- 235000004298 Tamarindus indica Nutrition 0.000 claims description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 229960004308 acetylcysteine Drugs 0.000 claims description 2
- 239000008272 agar Substances 0.000 claims description 2
- 229940072056 alginate Drugs 0.000 claims description 2
- 239000000783 alginic acid Substances 0.000 claims description 2
- 229960001126 alginic acid Drugs 0.000 claims description 2
- 150000004781 alginic acids Chemical class 0.000 claims description 2
- 229940087168 alpha tocopherol Drugs 0.000 claims description 2
- 239000004411 aluminium Substances 0.000 claims description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 2
- 229910052782 aluminium Inorganic materials 0.000 claims description 2
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 claims description 2
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 claims description 2
- 235000010407 ammonium alginate Nutrition 0.000 claims description 2
- 239000000728 ammonium alginate Substances 0.000 claims description 2
- KPGABFJTMYCRHJ-YZOKENDUSA-N ammonium alginate Chemical compound [NH4+].[NH4+].O1[C@@H](C([O-])=O)[C@@H](OC)[C@H](O)[C@H](O)[C@@H]1O[C@@H]1[C@@H](C([O-])=O)O[C@@H](O)[C@@H](O)[C@H]1O KPGABFJTMYCRHJ-YZOKENDUSA-N 0.000 claims description 2
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- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
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- TWNIBLMWSKIRAT-VFUOTHLCSA-N levoglucosan Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@H]2CO[C@@H]1O2 TWNIBLMWSKIRAT-VFUOTHLCSA-N 0.000 claims description 2
- 235000010420 locust bean gum Nutrition 0.000 claims description 2
- 239000000711 locust bean gum Substances 0.000 claims description 2
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- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
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- GGHPAKFFUZUEKL-UHFFFAOYSA-M sodium;hexadecyl sulfate Chemical compound [Na+].CCCCCCCCCCCCCCCCOS([O-])(=O)=O GGHPAKFFUZUEKL-UHFFFAOYSA-M 0.000 description 1
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- 235000010491 tara gum Nutrition 0.000 description 1
- 239000000213 tara gum Substances 0.000 description 1
- 235000012756 tartrazine Nutrition 0.000 description 1
- GMMAPXRGRVJYJY-UHFFFAOYSA-J tetrasodium 4-acetamido-5-hydroxy-6-[[7-sulfonato-4-[(4-sulfonatophenyl)diazenyl]naphthalen-1-yl]diazenyl]naphthalene-1,7-disulfonate Chemical compound [Na+].[Na+].[Na+].[Na+].OC1=C2C(NC(=O)C)=CC=C(S([O-])(=O)=O)C2=CC(S([O-])(=O)=O)=C1N=NC(C1=CC(=CC=C11)S([O-])(=O)=O)=CC=C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 GMMAPXRGRVJYJY-UHFFFAOYSA-J 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- UJMBCXLDXJUMFB-UHFFFAOYSA-K trisodium;5-oxo-1-(4-sulfonatophenyl)-4-[(4-sulfonatophenyl)diazenyl]-4h-pyrazole-3-carboxylate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-UHFFFAOYSA-K 0.000 description 1
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- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A dried suspension of tatin medicines is prepared from the active component chosen from lovastatin, simvastatin, pravastatin, etc and the carrier containing diluent or disperser, suspending aid, antioxidizing agent, chelating agent, flowing aid, flavouring and color correcting agent through proportionally mixing, granulating or pulverizing, and sieving. Its advantage is high solubility.
Description
The present invention relates to the novel form of statins, is that an amount of statins of a kind of usefulness loads the dry suspension that system becomes.
Dyslipidemia is meant that blood cholesterol and content of triglyceride are too high, easily causes cardiovascular and cerebrovascular disease.By studies show that more than 10 years that statins is carried out, statins can be prevented and treated cardiovascular and cerebrovascular disease effectively by reducing serum cholesterol level.The statins mechanism of action is energy competitive inhibition HMG-CoA reductase (this enzyme is the rate-limiting enzyme in the cholesterol biosynthetic process), cause hepatocyte inner cholesterol content to lower, thereby the increase of cell cultured supernatant Surface L DL expression of receptor, promote LDL (low density lipoprotein, LDL) and LDL precursor from circulation, to remove.Statins can suppress the synthetic Apolipoprotein B-100 of liver and reduce the synthetic and secretion of being rich in the triglyceride lipoprotein.The cholesterol of human body 70% is synthetic by self, and " his spit of fland " reduces blood cholesterol level by synthesizing of blocking-up body inner cholesterol, therefore is described as revolutionary discovery.During the last ten years, what several international extensive coronary heart disease controls highly visible were tested finishes, confirm that statins can reduce evidence of coronary heart diseases and mortality rate, and the atheromatous plaque development that has formed is slowed down, even go down, thereby broken the irreversible traditional view of coronary heart disease." statins " makes may cause acute myocardial infarction, worsen the unstability atheromatous plaque stabilisation increase the weight of angina pectoris or sudden death, reduces these arteria coronaria serious consequence that syndrome caused of fighting to some extent." his spit of fland " not only reduces the coronary heart disease death rate, also significantly reduces apoplexy, reduces general mortality rate.The appearance in " his spit of fland " makes the mankind that the reliable active drug of prevention coronary heart disease arranged.
Annual 1000 ten thousand people in the whole world die from the cardiovascular diseases, and these digital 2005 with double.The data that China Ministry of Public Health is announced shows, Beijing area coronary heart disease death rate 1973 was to increase to 62.0/10 ten thousand in 21.7/10 ten thousand, 1986, had almost increased by 2 times.So far had 14 years again in the past, this numeral is still continuing to increase, and is high.Hyperlipemia tends to cause many cardiovascular and cerebrovascular diseases such as atherosclerosis, coronary heart disease, also usually follows diabetes, fatty liver, nephrotic syndrome etc.Along with the raising of China's economic development and living standards of the people, coronary heart disease will become the No.1 killer of new century harm China's numerous people health and life, become the principal element of China resident cause of death.
Since first statins lovastatin of the whole world in 1987 obtained the drugs approved by FDA listing, the Statins new drug constantly was pushed out.2000, the annual sales of fat regulation medicine reached 15,900,000,000 dollars, became world's second largest medicine classification, and wherein the global marketing volume of statins reaches more than 120 hundred million dollars, was the main force of fat regulation medicine.The statins kind of China's listing has Luo Huaning (lovastatin tablet), lovastatin, Teroltrat (lovastatin tablet); Simvastatin (simvastatin sheet), Jing Bishuxin (simvastatin sheet), pravastatin sheet (Sino-U.S. executes in Shanghai expensive precious pharmaceutical Co. Ltd and produces); Atorvastatin, fluvastatin have synthesis material, but yet there are no the production listing in China as crude drug and preparation.The at present domestic producer that other produces statins has Yan'an, Shanghai, Beijing University's dimension letter, capital, Zhejiang new, the auspicious nation in Zhejiang, and Hainan Province's clever pharmacy in sea, southwestern synthesis pharmaceutical, the sky, Shandong reaches Pharmaceutical, and pharmacy, those enlightening Pharmaceuticaies of Guangdong etc. are given birth to by Changzhou China.Domesticly mainly contain the drop pills of simvastatin of Huhehaote City normal celestial movement medicine new technology development company exploitation, the simvastatin chewable tablet of the general living health approach in simvastatin capsule, the Nanjing of Zhejiang Jing Xin pharmaceutical factory development development corporation, Ltd. development etc. in other dosage forms of the statins that grinds.The make an uproar lovastatin capsule of sub-pharmaceutical factory exploitation of Guangxi Gold has been produced listing.
Make a general survey of the dosage form of domestic and international statins, the kind of listing is mainly based on tablet, capsule at present, there are deficiencies such as taking difficulty in patient such as old man, child and other dysphagia crowd to dysphagia, and still there are these deficiencies in existing other dosage form such as drop pill etc.Because the easy oxidation of statins, should not make particulate matter or powder, according to statins in the relatively poor and water-fast characteristics of water stability, through repetition test, we are unexpected to find to adopt new technology and Statins is made the patient that the particulate matter that is easy to take or Powdered dry suspension help dysphagia takes, and said preparation has advantage and steady qualities such as clothes are convenient, drug dissolution is fast.In addition, because the use of adjuvants such as dry suspension process seasoning regulating QI, drug smell is better, and the patient is more acceptant to novel formulation.Therefore, purpose one of the present invention provides a kind of new good preparation of statins, and purpose two is for providing the preparation method of statins dry suspension, and purpose three is for providing a kind of simvastatin dry suspension and prescription prescription and preparation method.
Statins disclosed by the invention is mainly lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin and based on the compound preparation of statins.Be mainly the complex that the chemical compound that increases the statins drug effect and Statins principal agent are formed based on the compound preparation of statins, the compound preparation of Statins principal agent and nicotinic acid composition for example, its drug effect is better than using separately the curative effect of his spit of fland medicine.Statins dosage is 5-80mg, and for example the lovastatin common dose is respectively 10mg, 20mg, 30mg, 40mg, 80mg; Simvastatin common dose 5mg, 10mg, 20mg, 40mg, pravastatin common dose 10mg, 20mg, 30mg, 40mg, atorvastatin common dose 10mg, 20mg, 30mg, 40mg, fluvastatin common dose 10mg, 20mg, 30mg, 40mg.His medicine material source, spit of fland can be synthetic, semi-synthetic or extracts refining from mold fermentation liquid or from natural drug.
Dry suspension disclosed by the invention meets pertinent regulations under the dry suspension item that second appendix of 2000 editions Chinese Pharmacopoeias record; Be characterized in that medicine and suitable carrier make powder or granular substance, face the time spent and add the water jolting and can be dispersed into suspension for oral liquid preparation.Above-mentioned dry suspension carrier mainly comprises diluent or dispersant, suspending agent, antioxidant, intercalating agent, fluidizer, correctives, rectifys toner etc.Wherein diluent or dispersant are sucrose, lactose, glucose, sugar alcohol, mannitol, mountain plough alcohol, D-xylose, xylitol, compressible sugar, maltose, lactulose, newborn pears alcohol, stachyose, pregelatinized Starch, water solublity dextrin, polyvinyl alcohol and mixture separately etc.; The consumption of diluent is generally 50-99%; Above-mentioned suspending agent is mainly hydroxypropyl emthylcellulose, tragcanth, arabic gum, hydroxyethyl-cellulose, carbomer, carbomer, micropowder silica gel, methylcellulose, hetastarch sodium, sodium alginate, polyvinylpyrrolidone, gelatin, ethylhydroxyethylcellulose, chitin, chitose, kaolin, sesbania gum, tara gum, Ficus elastica, Furcellaran, kaolin, carrageenin, glue is drawn in red match, tamarind gum, pectin, POLY-karaya, alginic acid, propylene glycol alginate, sodium alginate, potassium alginate, ammonium alginate, calcium alginate, Ai Lansheng, colloidality silicon dioxide, hydroxyethylmethyl-cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, xanthan gum, aluminium-magnesium silicate, sodium starch glycol, scleroglucan, glucosan, aluminium stearate, double stearic acid aluminium, agar, Pullulan, the acetyl group Pullulan, microbial alginate, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinyl alcohol, polyvinyl methyl ethermaleic anhydride, sodium polyacrylate, polyacrylic acid, polyvidone, locust bean gum etc., the consumption of suspending agent is generally 0.1-20%; Above-mentioned antioxidant mainly contains sodium sulfite, sodium sulfite, sodium sulfite, sodium formaldehyde sulphoxylate, sodium thiosulfate, 1-ascorbic acid, d-ascorbic acid, acetylcysteine, cysteine hydrochloride, thioglycerol, thiourea, thioglycolic acid, ascorbic acid, cetylate, butylated hydroxyarisol (BHA), dibenzylatiooluene (BHT), nor-pair of hydrogen guaiaretic acid (NDGA), propyl gallate, α-tocopherol, tea polyphenols, sodium isoascorbate etc., and common dose is 0.001-1.0%; Above-mentioned fluidizer (lubricant, antiplastering aid) mainly contains refining hydrogenated vegetable oil, politef, polyethylene glycols, sodium lauryl sulphate, Stepanol MG, ethanedioic acid, Fumaric acid, micropowder silica gel, kaolin, hargil, magnesium carbonate, magnesium hydroxide complex, light magnesium oxide, Aluminium Hydroxide glue gel etc., and usual amounts is 0-10%; Above-mentioned aromatic is mainly Oleum Caryophylli, Cardamom oil, aniseed oil, wintergreen oil, Semen Myristicae oil, Oleum Cinnamomi, Fructus Coriandri oil, Oleum Rosae Rugosae, bitter orange oil, oil of rosemary, Oleum Anisi Stellati, Fructus Citri Limoniae oil, citrus seed oil, Oleum Menthae Rotundifoliae, Eucalyptus oil, caraway oil, Oleum menthae, Oleum menthae, Oleum lavandula angustifolia, butanoic acid, geraniol, citronellol, L-menthol, clovenic acid, octanal, cinnamic aldehyde etc., and its dosage is 0-2%; Dry suspension also can add the suspensoid that the pigment coloring agent is made different colours in addition, as shellac color, monascorubin, carmine, beet red, carthamin, Gardenia Yellow, Rhizoma Curcumae Longae and curcumin, β-carotene (phylloerythrin), caramel, chlorophyll, the canthaxanthin purine, sodium iron chlorophyllin, sodium copper chlorophyllin, erythrosine, Rose Bengal, Ponceaux, red No. 40 of food coloring, food coloring redness 106 (Xylene Red), amaranth, azorubine, sunset yellow, tartrazines, yellow No. 5 of food coloring, D C Yellow No. 10, bright blue FCF, patent Isatis indigotica Fort (Indigofera tinctoria L, Baphicanthus cusia (nees) Brem. Polygonum tinctorium Ait) pharynx fat, fast green FCF, viride nitens, bright black BN etc., usual amounts is 0-0.5%.
Dry suspension preparation method of the present invention can be that principal agent directly adopts suitable method mixing as ways such as employing mechanical lapping crushing screenings with carrier, and packing promptly behind the mixing; Can sieve with principal agent with melting way processing backs and carrier mixing such as molten, packing promptly; Also can be to sieve packing promptly behind principal agent and the carrier mixed pelletization.Correctives, coloring agent can adopt dissolvings such as The suitable solvent such as dehydrated alcohol, is sprayed to do in the outstanding agent; Consider the easy oxidation of statins, packaging material must the lucifuge sealing.When having ready conditions, but the nitrogen-filled seal packing.With the simvastatin is that its preparation technology of example is as follows: get sucrose, pulverize, cross 80 mesh sieves, and 50 ℃ of following oven dryings 4 hours, standby; Take by weighing simvastatin by recipe quantity, add among the PEG-6000 that has melted, stir rapidly and make dissolving, add the about 400g of standby sucrose and stir, cooling is pulverized, and gets medicinal mixture, and is standby; Get hypromellose, tea polyphenols, the micropowder silica gel mixing, equivalent increase progressively with the cane sugar powder mixing after with the said medicine mixture, pulverize, mixing, packing, promptly.This product character is white or off-white color powder, and it is sweet to distinguish the flavor of.Compare with the simvastatin standard substance, the test sample main peak is consistent with the HPLC chromatogram retention time of reference substance main peak.Test sample is carried out the inspection of lovastatin and related substance, and the result is up to specification; Test sample is carried out settling volume ratio, moisture content, content uniformity and health examination, and the result all meets pertinent regulations under 2000 editions two appendix dry suspension items of Chinese Pharmacopoeia.Compare with the simvastatin reference substance solution, adopt the HPLC method that test sample is carried out assay, press one point external standard method and calculate content, content is the 90%-110% of labelled amount as a result, and is up to specification.Record dissolution determination method " slurry method " and 24 editions simvastatin tablet dissolution determinations of American Pharmacopeia condition with reference to 2000 editions two ones of Chinese Pharmacopoeias: dissolution medium be pH value be 7.0 contain 0.5% sodium hexadecyl sulfate alcohol 0.01M sodium radio-phosphate,P-32 solution, medium volume 900ml, rotating speed 50rpm, 37 ℃ ± ℃ of temperature, time is 30min, the dissolution that carries out test sample dissolution determination and former dosage form simvastatin sheet is compared, and this product dry suspension dissolution rate is better than the simvastatin sheet as a result.
Advantages such as dry suspension of the present invention and existing capsule, tablet, drop pill etc. relatively have taking convenience, and the medicine stripping is fast, the crowd who helps dysphagia takes.In addition, because dry suspension is rectified the use of adjuvants such as gas through flavoring, drug smell is better, and the patient is more acceptant to novel formulation.
Below for realizing prescription of the present invention and process:
Embodiment 1:
Prescription: lovastatin 20g
Tragcanth 5g
Sodium isoascorbate 1g
Micropowder silica gel 20g
Method for making: get lovastatin and tragcanth, sodium isoascorbate, micropowder silica gel mixing, mix pulverizing with sucrose (60 ℃ drying 4 hours) again, cross 65 mesh sieves, packing promptly.
Embodiment 2
Method for making: get simvastatin, hydroxypropyl emthylcellulose, tea polyphenols, magnesium stearate and grind mixing, spray into again behind the flavoring orange oil essence with sucrose (60 ℃ drying 4 hours) and mixes pulverizing, mistake 65 mesh sieves, packing is promptly.
Embodiment 3
Method for making: get pravastatin, arabic gum, butylated hydroxyarisol, light magnesium oxide mixing, get mixture 1; Aniseed oil adds ethanol 2ml, and dissolving adds glucose 10g and disperses, and mixes with mixture 1, adds residue sucrose mixing to the pulverizer, mistake 65 mesh sieves, and packing is promptly.
Embodiment 4
Method for making: get atorvastatin and put in the molten molten Polyethylene Glycol, stir, cooling with the abundant mixing of carbomer, 1-ascorbic acid, ethanedioic acid, D-xylose (60 ℃ drying 4 hours), is pulverized, and crosses 65 mesh sieves, and packing promptly.
Embodiment 5
Method for making: get simvastatin in molten molten polyvinylidene 6000, stir, add sodium sulfite 1g, make mixing, cooling; With Gardenia Yellow, polyacrylic acid, newborn pears alcohol mixing, pulverize, cross 65 mesh sieves, packing is promptly.
Embodiment 6
Method for making: get lovastatin and put in the molten molten Polyethylene Glycol, stir, cooling, with nicotinic acid, sodium alginate, thiourea, ethanedioic acid, mountain plough alcohol (60 ℃ drying 4 hours) be mixing fully, pulverizes, and crosses 65 mesh sieves, and packing is promptly.
Claims (8)
1, Statins dry suspension, it is made up of statins, antioxidant and carrier, and the dosage of described statins is 5-80mg, and described statins is lovastatin, simvastatin, pravastatin, atorvastatin or fluvastatin.
2, Statins dry suspension according to claim 1, wherein said carrier are diluent or dispersant, suspending agent, intercalating agent, fluidizer, correctives, rectify toner.
3, Statins dry suspension according to claim 2, wherein said diluent or dispersant are sucrose, lactose, glucose, sugar alcohol, mannitol, sorbitol, D-xylose, xylitol, maltose, lactulose, newborn pears alcohol, stachyose, pregelatinized Starch, water solublity dextrin, polyvinyl alcohol and mixture separately.
4; Statins dry suspension according to claim 2, wherein said suspending agent are hydroxypropyl emthylcellulose; tragcanth; arabic gum; hydroxyethyl-cellulose; carbomer; carbomer; micropowder silica gel; methylcellulose; hetastarch sodium; sodium alginate; polyvinylpyrrolidone; gelatin; ethylhydroxyethylcellulose; chitin; chitose; sesbania gum; Ficus elastica; Furcellaran; kaolin; carrageenin; glue is drawn in red match; tamarind gum; pectin; POLY-karaya; alginic acid; propylene glycol alginate; sodium alginate; potassium alginate; ammonium alginate; calcium alginate; Ai Lansheng; colloidality silicon dioxide; hydroxyethylmethyl-cellulose; hydroxyethyl-cellulose; hydroxypropyl cellulose; xanthan gum; aluminium-magnesium silicate; sodium starch glycol; scleroglucan; glucosan; aluminium stearate; double stearic acid aluminium; agar; Pullulan; the acetyl group Pullulan; microbial alginate; sodium carboxymethyl cellulose; carboxymethylcellulose calcium; polyvinyl alcohol; polyvinyl methyl ethermaleic anhydride; sodium polyacrylate; polyacrylic acid; locust bean gum.
5, Statins dry suspension according to claim 1, wherein said antioxidant are sodium sulfite, sodium sulfite, sodium formaldehyde sulphoxylate, sodium thiosulfate, 1-ascorbic acid, D-ascorbic acid, acetylcysteine, cysteine hydrochloride, thioglycerol, thiourea, thioglycolic acid, ascorbic acid, cetylate, butylated hydroxyarisol, dibenzylatiooluene, the nor-pair of hydrogen guaiaretic acid, propyl gallate, alpha-tocopherol, tea polyphenols, sodium isoascorbate.
6, Statins dry suspension according to claim 1, wherein said statins is a lovastatin, and its dosage is 10mg, 20mg or 40mg.
7, Statins dry suspension according to claim 1, wherein said statins is a simvastatin, and its dosage is 5mg, 10mg or 20mg.
8, Statins dry suspension according to claim 1, wherein said statins is pravastatin, atorvastatin or fluvastatin, and its dosage is 10mg, 20mg or 40mg.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021474842A CN100486572C (en) | 2002-11-04 | 2002-11-04 | Medicament form of tatin class |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021474842A CN100486572C (en) | 2002-11-04 | 2002-11-04 | Medicament form of tatin class |
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| CN1498612A CN1498612A (en) | 2004-05-26 |
| CN100486572C true CN100486572C (en) | 2009-05-13 |
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| WO2007125339A1 (en) * | 2006-04-26 | 2007-11-08 | Rosemont Pharmaceuticals Ltd | Liquid oral compositions |
| CN101766807B (en) * | 2008-12-26 | 2013-06-19 | 成都地奥九泓制药厂 | Injection packaging preparation of thymosin alpha1 microspheres |
| CN102309452B (en) * | 2011-09-14 | 2013-01-23 | 海南美大制药有限公司 | Fluvastatin sodium liposome solid preparation |
| CN102406922B (en) * | 2011-12-05 | 2014-01-08 | 江西信尔诚动物药业有限公司 | Compound long-acting norfloxacin nicotinate suspension for livestock and preparation method thereof |
| CN104096213A (en) * | 2013-04-07 | 2014-10-15 | 长春海悦药业有限公司 | Pharmaceutical composition containing brain protein hydrolysate and preparation thereof |
| CN108096212B (en) * | 2017-12-25 | 2020-06-09 | 河北科技大学 | Preparation method of drug microspheres with hydroxyethyl starch 200/0.5 as carrier |
| CN110812326B (en) * | 2019-11-04 | 2022-04-22 | 黑龙江省农业科学院畜牧兽医分院 | Simvastatin suspension emulsion and preparation method and application thereof |
-
2002
- 2002-11-04 CN CNB021474842A patent/CN100486572C/en not_active Expired - Fee Related
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| CN1498612A (en) | 2004-05-26 |
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