CN101352425A - Compound osmotic pump controlled release preparation and preparation method thereof - Google Patents
Compound osmotic pump controlled release preparation and preparation method thereof Download PDFInfo
- Publication number
- CN101352425A CN101352425A CNA200710128956XA CN200710128956A CN101352425A CN 101352425 A CN101352425 A CN 101352425A CN A200710128956X A CNA200710128956X A CN A200710128956XA CN 200710128956 A CN200710128956 A CN 200710128956A CN 101352425 A CN101352425 A CN 101352425A
- Authority
- CN
- China
- Prior art keywords
- controlled release
- preparation
- simvastatin
- label
- release preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 230000003204 osmotic effect Effects 0.000 title claims abstract description 85
- 238000002360 preparation method Methods 0.000 title claims abstract description 50
- 239000003405 delayed action preparation Substances 0.000 title claims description 25
- 150000001875 compounds Chemical class 0.000 title abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 85
- DJQOOSBJCLSSEY-UHFFFAOYSA-N Acipimox Chemical compound CC1=CN=C(C(O)=O)C=[N+]1[O-] DJQOOSBJCLSSEY-UHFFFAOYSA-N 0.000 claims abstract description 80
- 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 77
- 229960002855 simvastatin Drugs 0.000 claims abstract description 77
- 229960003526 acipimox Drugs 0.000 claims abstract description 76
- 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 71
- 238000013270 controlled release Methods 0.000 claims abstract description 24
- 238000000576 coating method Methods 0.000 claims description 86
- 239000011248 coating agent Substances 0.000 claims description 82
- 239000000203 mixture Substances 0.000 claims description 54
- 239000012528 membrane Substances 0.000 claims description 42
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 40
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 38
- 239000000463 material Substances 0.000 claims description 36
- 239000001856 Ethyl cellulose Substances 0.000 claims description 30
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 30
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 30
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 30
- 229920001249 ethyl cellulose Polymers 0.000 claims description 30
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 claims description 30
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 28
- 239000003361 porogen Substances 0.000 claims description 27
- 229920002301 cellulose acetate Polymers 0.000 claims description 25
- -1 hydroxypropyl Chemical group 0.000 claims description 25
- 229920001223 polyethylene glycol Polymers 0.000 claims description 24
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical class OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 22
- 239000002202 Polyethylene glycol Substances 0.000 claims description 22
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 22
- 239000000314 lubricant Substances 0.000 claims description 22
- 239000004014 plasticizer Substances 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 21
- 235000019359 magnesium stearate Nutrition 0.000 claims description 20
- 239000003961 penetration enhancing agent Substances 0.000 claims description 17
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 16
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 16
- 235000002639 sodium chloride Nutrition 0.000 claims description 16
- 239000000945 filler Substances 0.000 claims description 15
- 239000011780 sodium chloride Substances 0.000 claims description 14
- 239000007888 film coating Substances 0.000 claims description 13
- 238000009501 film coating Methods 0.000 claims description 13
- 230000003578 releasing effect Effects 0.000 claims description 13
- 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 12
- 239000000853 adhesive Substances 0.000 claims description 12
- 230000001070 adhesive effect Effects 0.000 claims description 12
- 239000008101 lactose Substances 0.000 claims description 12
- 239000000080 wetting agent Substances 0.000 claims description 11
- 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 10
- 229930195725 Mannitol Natural products 0.000 claims description 10
- 239000000594 mannitol Substances 0.000 claims description 10
- 235000010355 mannitol Nutrition 0.000 claims description 10
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 9
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 9
- 239000005715 Fructose Substances 0.000 claims description 8
- 229930091371 Fructose Natural products 0.000 claims description 8
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 8
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 8
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 8
- PYGXAGIECVVIOZ-UHFFFAOYSA-N Dibutyl decanedioate Chemical compound CCCCOC(=O)CCCCCCCCC(=O)OCCCC PYGXAGIECVVIOZ-UHFFFAOYSA-N 0.000 claims description 7
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 7
- 229930006000 Sucrose Natural products 0.000 claims description 7
- 239000011230 binding agent Substances 0.000 claims description 7
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 7
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 7
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 7
- 239000005720 sucrose Substances 0.000 claims description 7
- 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 6
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 6
- 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 6
- 239000006184 cosolvent Substances 0.000 claims description 6
- 238000005553 drilling Methods 0.000 claims description 6
- 229920000609 methyl cellulose Polymers 0.000 claims description 6
- 239000001923 methylcellulose Substances 0.000 claims description 6
- 235000010981 methylcellulose Nutrition 0.000 claims description 6
- 238000004080 punching Methods 0.000 claims description 6
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 6
- 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 claims description 5
- 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 claims description 5
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 5
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 5
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 5
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 5
- 239000011148 porous material Substances 0.000 claims description 5
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 5
- 239000000600 sorbitol Substances 0.000 claims description 5
- 235000010356 sorbitol Nutrition 0.000 claims description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 4
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 4
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 4
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 4
- 238000007789 sealing Methods 0.000 claims description 4
- 239000001069 triethyl citrate Substances 0.000 claims description 4
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 claims description 4
- 235000013769 triethyl citrate Nutrition 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- 235000021355 Stearic acid Nutrition 0.000 claims description 3
- YBCVMFKXIKNREZ-UHFFFAOYSA-N acoh acetic acid Chemical compound CC(O)=O.CC(O)=O YBCVMFKXIKNREZ-UHFFFAOYSA-N 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- XNGIFLGASWRNHJ-UHFFFAOYSA-N o-dicarboxybenzene Natural products OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 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
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 3
- 229920000053 polysorbate 80 Polymers 0.000 claims description 3
- 239000011347 resin Substances 0.000 claims description 3
- 229920005989 resin Polymers 0.000 claims description 3
- 239000008117 stearic acid Substances 0.000 claims description 3
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims description 2
- RYDFXSRVZBYYJV-TYYBGVCCSA-N (e)-but-2-enedioic acid;sodium Chemical compound [Na].OC(=O)\C=C\C(O)=O RYDFXSRVZBYYJV-TYYBGVCCSA-N 0.000 claims description 2
- 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 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 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
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 2
- 150000001720 carbohydrates Chemical class 0.000 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 235000010980 cellulose Nutrition 0.000 claims description 2
- 229920002678 cellulose Polymers 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 2
- 235000019341 magnesium sulphate Nutrition 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 239000001103 potassium chloride Substances 0.000 claims description 2
- 235000011164 potassium chloride Nutrition 0.000 claims description 2
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 claims description 2
- 229910052939 potassium sulfate Inorganic materials 0.000 claims description 2
- 235000011151 potassium sulphates Nutrition 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 2
- 235000011152 sodium sulphate Nutrition 0.000 claims description 2
- 239000000470 constituent Substances 0.000 claims 1
- 238000001035 drying Methods 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 14
- 235000001968 nicotinic acid Nutrition 0.000 abstract description 4
- 230000009471 action Effects 0.000 abstract description 2
- 230000008901 benefit Effects 0.000 abstract description 2
- 150000002814 niacins Chemical class 0.000 abstract 2
- 239000008194 pharmaceutical composition Substances 0.000 abstract 2
- 231100000053 low toxicity Toxicity 0.000 abstract 1
- 239000003826 tablet Substances 0.000 description 42
- 229940079593 drug Drugs 0.000 description 41
- 239000000243 solution Substances 0.000 description 32
- 238000000034 method Methods 0.000 description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 16
- 239000008187 granular material Substances 0.000 description 15
- 238000003756 stirring Methods 0.000 description 14
- 230000001476 alcoholic effect Effects 0.000 description 13
- 239000008280 blood Substances 0.000 description 13
- 210000004369 blood Anatomy 0.000 description 13
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 12
- 239000007921 spray Substances 0.000 description 12
- 229960004756 ethanol Drugs 0.000 description 11
- 239000007779 soft material Substances 0.000 description 11
- 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
- 235000019197 fats Nutrition 0.000 description 8
- 229920002521 macromolecule Polymers 0.000 description 8
- 239000002609 medium Substances 0.000 description 8
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 7
- 235000021053 average weight gain Nutrition 0.000 description 7
- 230000001186 cumulative effect Effects 0.000 description 7
- 238000005516 engineering process Methods 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
- TZBAVQKIEKDGFH-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound [Cl-].C1=CC=C2SC(C(=O)NCC[NH+](CC)CC)=CC2=C1 TZBAVQKIEKDGFH-UHFFFAOYSA-N 0.000 description 7
- 239000013557 residual solvent Substances 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 6
- 235000013772 propylene glycol Nutrition 0.000 description 6
- 241000283973 Oryctolagus cuniculus Species 0.000 description 5
- 235000010443 alginic acid Nutrition 0.000 description 5
- 229920000615 alginic acid Polymers 0.000 description 5
- 235000012000 cholesterol Nutrition 0.000 description 5
- 208000029078 coronary artery disease Diseases 0.000 description 5
- 238000013461 design Methods 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 description 4
- 239000000783 alginic acid Substances 0.000 description 4
- 229960001126 alginic acid Drugs 0.000 description 4
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 4
- 239000007948 fast release tablet Substances 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 208000024172 Cardiovascular disease Diseases 0.000 description 3
- 108010010234 HDL Lipoproteins Proteins 0.000 description 3
- 102000015779 HDL Lipoproteins Human genes 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- KSZVHVUMUSIKTC-UHFFFAOYSA-N acetic acid;propan-2-one Chemical compound CC(C)=O.CC(O)=O KSZVHVUMUSIKTC-UHFFFAOYSA-N 0.000 description 3
- 235000014121 butter Nutrition 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 230000003285 pharmacodynamic effect Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 208000035150 Hypercholesterolemia Diseases 0.000 description 2
- 108010007622 LDL Lipoproteins Proteins 0.000 description 2
- 102000007330 LDL Lipoproteins Human genes 0.000 description 2
- 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 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 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 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 210000000577 adipose tissue Anatomy 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 239000003741 agents affecting lipid metabolism Substances 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- 210000002969 egg yolk Anatomy 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- SYKWLIJQEHRDNH-CKRMAKSASA-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@@H](O)C(=O)NCCC(=O)NCCSC(=O)CCCC(O)=O)O[C@H]1N1C2=NC=NC(N)=C2N=C1 SYKWLIJQEHRDNH-CKRMAKSASA-N 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 229960004844 lovastatin Drugs 0.000 description 2
- 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 description 2
- 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 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 229960003512 nicotinic acid Drugs 0.000 description 2
- 239000011664 nicotinic acid Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229960002965 pravastatin Drugs 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 229960004063 propylene glycol Drugs 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000005096 rolling process Methods 0.000 description 2
- HMJIYCCIJYRONP-UHFFFAOYSA-N (+-)-Isradipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1C1=CC=CC2=NON=C12 HMJIYCCIJYRONP-UHFFFAOYSA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical class CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 description 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 108010061435 Enalapril Proteins 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 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
- 235000017858 Laurus nobilis Nutrition 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 241000283977 Oryctolagus Species 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 229940123934 Reductase inhibitor Drugs 0.000 description 1
- 244000125380 Terminalia tomentosa Species 0.000 description 1
- 235000005212 Terminalia tomentosa Nutrition 0.000 description 1
- 108010062497 VLDL Lipoproteins Proteins 0.000 description 1
- BNPSSFBOAGDEEL-UHFFFAOYSA-N albuterol sulfate Chemical compound OS(O)(=O)=O.CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1.CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 BNPSSFBOAGDEEL-UHFFFAOYSA-N 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000002168 brachiocephalic trunk Anatomy 0.000 description 1
- ZDIGNSYAACHWNL-UHFFFAOYSA-N brompheniramine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Br)C=C1 ZDIGNSYAACHWNL-UHFFFAOYSA-N 0.000 description 1
- 229960000725 brompheniramine Drugs 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
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 229940078456 calcium stearate Drugs 0.000 description 1
- 229960000623 carbamazepine Drugs 0.000 description 1
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 1
- 229960004166 diltiazem Drugs 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 description 1
- 229960000873 enalapril Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 201000005577 familial hyperlipidemia Diseases 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000030136 gastric emptying Effects 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- JUMYIBMBTDDLNG-OJERSXHUSA-N hydron;methyl (2r)-2-phenyl-2-[(2r)-piperidin-2-yl]acetate;chloride Chemical compound Cl.C([C@@H]1[C@H](C(=O)OC)C=2C=CC=CC=2)CCCN1 JUMYIBMBTDDLNG-OJERSXHUSA-N 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000031891 intestinal absorption Effects 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 229960004427 isradipine Drugs 0.000 description 1
- 229940037627 magnesium lauryl sulfate Drugs 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- HBNDBUATLJAUQM-UHFFFAOYSA-L magnesium;dodecyl sulfate Chemical compound [Mg+2].CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCOS([O-])(=O)=O HBNDBUATLJAUQM-UHFFFAOYSA-L 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229960001033 methylphenidate hydrochloride Drugs 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- 235000021590 normal diet Nutrition 0.000 description 1
- 238000012946 outsourcing Methods 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229950008882 polysorbate 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
- TUZYXOIXSAXUGO-PZAWKZKUSA-M pravastatin(1-) 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-M 0.000 description 1
- IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 description 1
- 229960001289 prazosin Drugs 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229960003447 pseudoephedrine hydrochloride Drugs 0.000 description 1
- BALXUFOVQVENIU-KXNXZCPBSA-N pseudoephedrine hydrochloride Chemical compound [H+].[Cl-].CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 BALXUFOVQVENIU-KXNXZCPBSA-N 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 210000005181 root of the tongue Anatomy 0.000 description 1
- 238000009666 routine test Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 125000000185 sucrose group Chemical group 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 1
- 229960001685 tacrine Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- 229940057977 zinc stearate Drugs 0.000 description 1
Images
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention provides a new osmotic pump controlled release pharmaceutical composition used for treating hyperlipoidemia and a preparation method thereof, the pharmaceutical composition has a nicotinic acids medicine such as acipimox and the other one estatina medicine such as simvastatin; wherein, the nicotinic acids medicine such as acipimox is a controlled release part, and the estatina medicine such as simvastatin is a quick release part; or both the acipimox and the simvastatin are the controlled release part. The compound osmotic pump preparation of the invention has the advantages of comprehensive action, low toxicity and side effects and convenient use.
Description
Technical field
The invention belongs to drug world, relate to a kind of controlled releasing penetrant pump that contains nicotinic acid class medicine and a kind of statins and preparation method thereof, especially contain compound osmotic pump controlled release preparation of acipimox and simvastatin and preparation method thereof.
Background technology
Along with the continuous development of medical science, people recognize cholesterol, fatty equal size is too high is the basic cause of disease that cardiovascular disease takes place, and hyperlipidemia is that coronary heart disease and hypertensive main hazard factor take place.Therefore, people begin the exploitation of blood lipid regulation medicine as the emphasis of preventing and treating cardiovascular disease.From late 1980s, blood lipid-lowering medicine is released in a large number, and wherein statins is subjected to people's favorable comment, and its clinical efficacy good is that other all kinds of blood lipid regulation medicines institute is incomparable.During the last ten years, finishing of the extensive coronary heart disease control test in several worlds, 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, risen in the whole world by the blood fat revolution that cause in " his spit of fland ".At present, the world of medicine is filled with unbounded confidence in the effect that prevents and treats aspect the cardiovascular disease to fat regulation medicine, transfers the fat therapy will become the main method of 21 century angiocardiopathy preventing.
Simvastatin is a second filial generation Statins lipid-regulation medicine, and the non-activity of this product own, the hydrolyzate after the oral absorption suppress rate-limiting enzyme hydroxyl first glutaryl coenzyme A (HMG-CoA) reductase in the cholesterol building-up process in vivo competitively.Simvastatin (simvastatin) is to have carried out broad research both at home and abroad and at hydroxyl first glutaryl coenzyme A (HMG-CoA) reductase inhibitor of multinational listing, 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, and moderate reduces serum triglyceride level and increases high density lipoprotein level of serum, thus effective atherosis the and coronary heart disease of prevention of arterial.
Acipimox (Acipimox) is a kind of nicotinic acid derivates of synthetic, can suppress the decomposition of fatty tissue, reducing free fatty discharges from fatty tissue, thereby triglyceride reducing (TG) synthesizing in liver, and, make the lowering of concentration of TG and T-CHOL (TC) in the serum by suppressing the synthetic of VLDL and low density lipoprotein, LDL LDL.This product also can suppress the activity of liver fat enzyme, reduces the decomposition of high density lipoprotein (HDL).This medicine oral absorption is rapid, behind the medicine in 2 hours blood drug level be peaking, the half-life is 2 hours.This medicine does not combine with plasma protein, not by metabolism, mainly discharges through urine with original shape.Clinically, acipimox can effectively treat high triglyceride disease (W type), hypercholesterolemia (Ifa type) and high glycerol three vinegar merge hypercholesterolemia (Ilb type), is a kind of lipid regulating agent of safe, effective, better tolerance.
At present, the research tendency in this field is that the lipid regulating agent of two kinds of different mechanism of action is made compound preparation, thereby makes effect for reducing fat more comprehensive, also can bring into play synergism simultaneously, heightens the effect of a treatment, and reduces toxic and side effects.U.S. Pat 526030SA discloses the compositions of HMG-COA reductase inhibitor pravastatin and nicotinic acid and derivant thereof, specifically disclosing specification is the preparation of compositions of pravastatin 5mg, 10mg, 20mg, 40mg and acipimox 750mg, but does not have to disclose the pharmacological experimental data of its beneficial effect and best proportioning.Chinese patent application CN1425374A discloses acipimox and lovastatin compositions, disclosed ratio is that the weight ratio of acipimox and lovastatin is 25～50: 1, preferred ratio is 25: 1 or 37.5: 1, but does not relate to the best proportioning and the corresponding pharmacological experimental data of acipimox and simvastatin compound recipe.
The osmotic pumps technology was the model of control drug administration carrier since coming out from the seventies in 20th century always, and U.S. Alza company has at first developed osmotic pump tablet in 1970, with this class preparation name into
System or OROS
TMTechnology.Existing more than ten launch since nineteen eighty-three, for example the Oros preparation of medicines such as prazosin, Carclura, verapamil, methylphenidate hydrochloride, Isradipine, nifedipine, pseudoephedrine hydrochloride, salbutamol sulfate, carbamazepine, brompheniramine, enalapril, diltiazem, tacrine mostly is medication in day product once.Osmotic pump tablet is the maximum characteristics of release in vivo, except that evenly constant, its rate of releasing drug is not subjected to the influence in gastrointestinal tract variable factor such as wriggling, pH, gastric emptying time etc., and is applicable to the medicine of the various dissolubility of preparation, is ideal a kind of in the controlled release formulations for oral administration up to now.
Summary of the invention
The objective of the invention is the prescription design by a series of science, a kind of osmotic pump controlled-release medicinal composition of new treatment hyperlipemia be provided, its advantage be effect comprehensively, toxic and side effects is low and easy to use.This medicine contains the nicotinic acid class and the statins of special ratios, for example acipimox and simvastatin, because two medicine mechanism of action differences, it will be more comprehensive forming after the compositions effect for reducing fat, and two medicines have share synergism, and its effect for reducing fat obviously is better than the folk prescription of same dose; In addition, by the consumption of simvastatin in the choose reasonable compositions, make compositions effectively not have obvious toxic and side effects again in the blood fat reducing level.Prior, by animal experiment study, we find to use the prepared osmotic pump controlled release tablet of osmotic pumps preparation method provided by the invention, in the atheromatous plaque process of prevention and treatment rabbit, embody pharmacodynamic action unexpectedly.This compositions only needed medication once on 1st simultaneously, and medication is convenient, and this will improve patient's compliance greatly.
The ratio of described nicotinic acid class medicine and statins was from 5: 1～100: 1, and wherein nicotinic acid class medicine is an acipimox, and statins is a simvastatin, and its ratio was preferably 5: 1～50: 1 from 5: 1～100: 1, most preferably 10: 1～30: 1.
Because compound preparation is designed to be administered once in one day, the half-life of acipimox is shorter, only is 2h, and its minimum effective blood drug concentration is 0.2ug/ml.Common quick releasing formulation is difficult in and keeps effective blood drug level in the dosing interval, be difficult to make compound medicine to produce better synergism, adopt the osmotic pump controlled-releasing technology, the back medicine of taking medicine is discharged stably at gastrointestinal tract, medicine makes the rate-limiting step of drug absorption from the rate of release of osmotic pumps, by intestinal absorption, keeps stable blood drug level, in most times of single administration, make acipimox and the good synergism of statins deposits yields.
Simvastatin is eliminated about 2～3h of half-life, be longer than acipimox slightly, bibliographical information, therefore simvastatin is a prodrug, and its metabolite still has activity in vivo, has adopted acipimox (controlled release part) and simvastatin in osmotic pumps to form the double speed release (accompanying drawing 1 of immediate release section outside semipermeable membrane, 2) and simvastatin and acipimox all be wrapped in design (accompanying drawing 3 in the semipermeable membrane, 4), asymmetric pair of chamber double speed of the three-layer tablet core that also adopts in addition discharges design (accompanying drawing 5,6).
For achieving the above object, the inventor is in technical elementary osmotic pump, two-chamber osmotic pump and the micropore permeation pump technology of having adopted of osmotic pumps, the selection space of having enriched dosage form greatly.Have following three kinds of forms:
(1) make label by nicotinic acid class medicine and penetration enhancer, filler, lubricant, and one deck contains the film-coat of the film coating of semi-permeable character of macromolecule filming material, plasticizer and porogen and statins and binding agent composition;
Or (2) by nicotinic acid class medicine, statins, penetration enhancer, filler, and the label that lubricant is formed, and one deck contains the film coating of the semi-permeable character of macromolecule filming material, plasticizer and porogen;
Or (3) are by containing nicotinic acid class medicine layer, containing the three-layer tablet core that statins layer and sealing coat are formed, also comprise penetration enhancer in the label simultaneously, filler, lubricant, two surface curvature differences of label, wherein nicotinic acid class medicine layer surface is that curvature is bigger, statins laminar surface curvature is less, reach the film coating that one deck contains the semi-permeable character of macromolecule filming material, plasticizer and porogen, and/or form by the isolated film clothing that macromolecular material is formed;
The film coating one or both sides of above-mentioned semi-permeable character have small delivery aperture, or meet water dissolution formation micropore by the porogen in the semi-transparent coating membrane, and medicine discharges from aperture or micropore.
Above-mentioned nicotinic acid class medicine is an acipimox, and statins is a simvastatin.
On the used macromolecule filming material of semipermeable membrane, two kinds of film materials of cellulose acetate and ethyl cellulose have mainly been studied.Wherein cellulose acetate is the normal both at home and abroad osmotic pump controlled-releasing film material that adopts, because the present domestic cellulose acetate that does not also have the pharmaceutic adjuvant level, we are to the ethyl cellulose extensive studies, curve when having obtained release in vitro curve suitable with cellulose acetate and body giving drugs into nose.Ethyl cellulose character is stable than cellulose acetate, and domestic existing pharmaceutic adjuvant level ethyl cellulose, more have practical value for the present invention, and ethyl cellulose is dissolved in ethanol, acetone-the ethanol-water system that in carrying out the sustained release coating process, needn't use cellulose acetate to use, acetone belongs to restriction and uses solvent, needs strict control residual quantity for the acetone that uses in the pharmaceutical production technology.In addition, because the acetone boiling point is low, volatile, in the coating process, blast potential danger when having increased use easily.Therefore the ethyl cellulose that adopts among the present invention prepares the method for osmotic pumps, obviously is better than cellulose acetate in industrialized great production, has the using value of reality.
What adopt among the present invention program (3) is the two controlled-release technology (accompanying drawings 5 of two-chamber osmotic pump, 6), utilize osmotic pumps release principle, the drug release hole in the different apertures of adopting is regulated the rate of releasing drug of acipimox and simvastatin, wherein the acipimox face directly is 0.4-1.0mm, preferred 0.5mm, the simvastatin face directly is 0.5-1.5, preferred 0.8mm.The rate of releasing drug of simvastatin can be controlled at 8h release about 90%, avoid multiple dose administration to cause accumulating of medicine.Adopt the asymmetric configuration design of label simultaneously, acipimox laminar surface curvature is bigger, and A Xintating laminar surface curvature is less.Since in the coating process because symmetric figure label rolling in coating pan is not completely random, the small curve face is difficult for rolling and makes the deep camber face more probabilities be arranged up, thereby accept coating, the clothing film that its surface is formed is thicker, thereby the permeation rate of the clothing film in dispose procedure is slower, rate of releasing drug slow (the permeable speed of the rate of releasing drug of normal conditions shape osmotic pump tablet and semipermeable membrane is directly proportional), the drug release hole different with the aperture cooperates, and passable obtains better double speed controlled-release effect.In addition, employing is asymmetric can be so that discern the two sides to punch respectively.In the technical scheme of the present invention, when the compressed cores process, adopt three laminate machine tablettings, adopt the drift of different curvature, obtain the two sides of different curvature, for example, dash to deep concave type dashes down, be the acipimox part, curvature is bigger, and the upper strata is that dimple form dashes, and is the simvastatin part, and curvature is less.Can more easily distinguish the two sides of different pharmaceutical like this, thereby beat the hole in different apertures exactly.
Above-mentioned single chamber/asymmetric pair chamber laser boring osmotic pump tablet and single chamber/asymmetric pair of chamber micro-porous osmotic pump tablet have following three kinds of forms:
(1) make label by acipimox and penetration enhancer, filler, lubricant, and one deck contains the film-coat of the film coating of semi-permeable character of macromolecule filming material, plasticizer and porogen and simvastatin and binding agent composition;
Main prescription is formed (by 1000)
Label is formed:
Acipimox 100～300g
Filler 3～10g
Lubricant 3～10g
Semipermeable membrane:
The simvastatin coatings:
Adhesive 3～30g
Make 1000
Or (2) by acipimox, simvastatin, penetration enhancer, filler, and the label that lubricant is formed, and one deck contains the film coating of the semi-permeable character of macromolecule filming material, plasticizer and porogen;
Main prescription is formed (by 1000)
Label is formed:
Acipimox 100～300g
Adhesive 3～30g
Filler 3～10g
Lubricant 3～10g
Semipermeable membrane
Make 1000
Or (3) are by containing the acipimox layer, containing the three-layer tablet core that simvastatin layer and sealing coat are formed, also comprise penetration enhancer in the label simultaneously, filler, lubricant, two surface curvature differences of label, wherein acipimox medicine layer surface is that curvature is bigger, simvastatin medicine layer surface curvature is less, reach the film coating that one deck contains the semi-permeable character of macromolecule filming material, plasticizer and porogen, and/or form by the isolated film clothing that macromolecular material is formed;
Main prescription is formed (by 1000)
The acipimox layer:
Acipimox 100～300g
Lubricant 3～10g
Filler 3～10g
Sealing coat: 20～100g
The simvastatin layer:
Other adjuvants:
Adhesive 3～30g
Make 1000
The controlled releasing penetrant pump of above-mentioned three kinds of forms, if desired, the isolated film clothing of all can the outsourcing macromolecular material forming.
The film coating one or both sides of above-mentioned semi-permeable character have small delivery aperture, or meet water dissolution formation micropore by the porogen in the semi-transparent coating membrane, and medicine discharges from aperture or micropore.
Above-mentioned label contains principal agent, penetration enhancer, adhesive, lubricant, contains filmogen, porogen and plasticizer in the semipermeable membrane, and the immediate release drug layer contains medicine, adhesive, plasticizer, antitackiness agent.
For laser boring type osmotic pumps, porogen is 5%～45% of a coating membrane weight, and is preferred 15%～35%, and semipermeable membrane is 3%～15% of a label weight, preferred 5%～8%.
For the pore type osmotic pumps, porogen is 10%～50% of a coating membrane weight, and is preferred 35%～45%, and semipermeable membrane is 3%～15% of a label weight, preferred 5%～8%.
To above-mentioned osmotic pump controlled release tablet, wherein said porogen, can be glycerol, propylene glycol, Polyethylene Glycol, sucrose, mannitol, lactose, sodium chloride, sorbitol, hydroxypropyl cellulose, methylcellulose, hydroxypropyl methylcellulose, the mixture of solable matters such as polyvinylpyrrolidone or above-mentioned material is preferably Polyethylene Glycol (molecular weight 2000～6000) or hydroxypropyl cellulose and hydroxypropyl methylcellulose.
Above-mentioned osmotic pump controlled release tablet, wherein said filmogen can be the mixture of cellulose acetate, ethyl cellulose, crylic acid resin, cellulose acetate acetate, hydroxypropyl methylcellulose acetate, polyvinyl alcohol or above-mentioned material.Be preferably cellulose acetate and ethyl cellulose.
Above-mentioned osmotic pump controlled release tablet, wherein said penetration enhancer can be sucrose, sorbitol, mannitol, glucose, lactose, fructose for low molecule saccharide; Inorganic salts is one or more of sodium chloride, potassium chloride, magnesium sulfate, potassium sulfate, sodium sulfate, is preferably fructose, lactose, sodium chloride and mannitol.
Above-mentioned osmotic pump controlled release tablet comprises plasticizer in the wherein said semipermeable membrane.Wherein, described plasticizer can be glycerol, and the mixture of propylene glycol, Polyethylene Glycol, triethyl citrate, dibutyl sebacate, phthalic acid ester or above-mentioned material is preferably dibutyl sebacate, diethyl phthalate and Polyethylene Glycol.
Above-mentioned osmotic pump controlled release tablet can also comprise filler in the wherein said label, comprises the mixture of lactose, microcrystalline Cellulose, calcium hydrogen phosphate, Powderd cellulose or above-mentioned material.
Above-mentioned osmotic pump controlled release tablet can also comprise permeation-promoter in the wherein said label.Wherein, described permeation-promoter can be the mixture of one or more compositions in microcrystalline Cellulose, alginic acid, alginate, propylene glycol alginic acid ester, the Polyethylene Glycol, is preferably microcrystalline Cellulose, alginic acid or propylene glycol alginic acid ester and polyoxyethylene.
Above-mentioned osmotic pump controlled release tablet, the adhesive of wherein said label are polyvinylpyrrolidone, the mixture of hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, methylcellulose, ethyl cellulose or above-mentioned material etc.
Above-mentioned osmotic pump controlled release tablet, the wetting agent of label are the mixed solution of water, ethanol or above-mentioned material etc.
Above-mentioned osmotic pump controlled release tablet can also comprise lubricant in the wherein said label.Wherein, described lubricant, can be preferably magnesium stearate for the mixture of one or more compositions in magnesium stearate, calcium stearate, zinc stearate, glyceryl monostearate, sodium stearyl fumarate, polyoxyethylene monostearate, single Laurel sucrose acid ester, sodium laurylsulfate, magnesium laurylsulfate, Stepanol MG, the Pulvis Talci.
Above-mentioned osmotic pump controlled release tablet, wherein said semipermeable membrane comprises filmogen, plasticizer, porogen.Filmogen comprises: the mixture of cellulose acetate, ethyl cellulose, crylic acid resin, cellulose acetate acetate, hydroxypropyl methylcellulose acetate, polyvinyl alcohol or above-mentioned material.Plasticizer comprises glycerol, the mixture of propylene glycol, Polyethylene Glycol, triethyl citrate, dibutyl sebacate, phthalic acid ester or above-mentioned material.The mixture of solable matters such as porogen comprises glycerol, propylene glycol, Polyethylene Glycol, sucrose, mannitol, sorbitol, lactose, sodium chloride, hydroxypropyl cellulose, methylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone or above-mentioned material.
Above-mentioned osmotic pump controlled release tablet, the film-coat layer that wherein said statins and adhesive are formed is the immediate release drug layer, comprises statins, adhesive, lubricant, cosolvent.The ratio of statins and adhesive was preferably 1: 0.5～1: 3 from 1: 0.1～1: 10.Adhesive comprises polyvinylpyrrolidone, the mixture of hydroxypropyl emthylcellulose, hydroxypropyl cellulose, methylcellulose or above-mentioned material.Lubricant comprises the mixture of magnesium stearate, Pulvis Talci PEG, stearic acid, fumaric acid sodium or above-mentioned material.Cosolvent comprises Polyethylene Glycol, sodium lauryl sulphate, Polysorbate, polyoxyethylene hydrogenated Oleum Ricini, the mixture of Tween-80 or above-mentioned material, preferably sodium dodecyl sulfate, Tween-80 are wherein by 1000, cosolvent 3～10g, lubricant 3～10g.
Above-mentioned osmotic pump controlled release tablet can also comprise plasticizer in the wherein said immediate release drug layer, can be for getting one or more mixture in triethyl citrate, dibutyl sebacate, phthalate, the Polyethylene Glycol.
Adjuvants such as above-mentioned penetration enhancer, filler, cosolvent, filmogen, plasticizer and lubricant can be determined according to pharmaceutical properties, dosage form design requirement, releasing effect and concrete the application.To those skilled in the art, can determine its suitable consumption by routine test.
In addition, if desired, can also be at semipermeable membrane outer wrapping isolated film clothing layer.Can select pharmaceutically conventional macromolecule membrane coating material for use, for example Opadry
Film-coated technique by routine carries out coating.
Description of drawings:
Accompanying drawing 1 contains the structural representation of release layer osmotic pump preparation
Accompanying drawing 2 contains the structural representation of release layer osmotic pump preparation
The structural representation of accompanying drawing 3 osmotic pump preparations
The structural representation of accompanying drawing 4 osmotic pump preparations
5 asymmetric pairs of chamber laser boring of accompanying drawing type osmotic pumps sketch map;
6 asymmetric pairs of chambers of accompanying drawing pore type osmotic pumps sketch map;
Accompanying drawing 7 embodiment 1 acipimox release profiles (n=6)
Accompanying drawing 8 embodiment 1 simvastatin stripping curve (n=6);
Accompanying drawing 9 embodiment 2 acipimox release profiles (n=6)
Accompanying drawing 10 embodiment 2 simvastatin stripping curves (n=6)
Accompanying drawing 11 embodiment 3 acipimox osmotic pumps release profiles (n=6);
Accompanying drawing 12 embodiment 3 simvastatin stripping curves (n=6)
Accompanying drawing 13 embodiment 4 acipimox osmotic pumps release profiles (n=6)
Accompanying drawing 14 embodiment 4 simvastatin stripping curves (n=6)
Accompanying drawing 15 embodiment 5 acipimoxs/simvastatin osmotic pumps release profiles (n=6)
Accompanying drawing 16 embodiment 6 acipimoxs/simvastatin osmotic pumps release profiles (n=6)
Accompanying drawing 17 embodiment 7 acipimoxs/simvastatin osmotic pumps release profiles (n=6)
Simvastatin/acipimox the osmotic pump tablet and blood drug level one time graph (n=6) of acipimox fast-release tablet in the begle dog of accompanying drawing 18 embodiment 3 preparations
The specific embodiment
Further explain and describe content of the present invention by the following examples.Described embodiment only in order to help to understand content of the present invention, should not be understood that the qualification to purport of the present invention and protection domain.Following examples 1～7 are the best preparation method of osmotic pumps dosage form, and embodiment 8 is a pharmacodynamics test.
Drug release determination method of the present invention is release medium referring to two appendix XD first methods of Chinese Pharmacopoeia version in 2005 with water.
Embodiment 1
Label is formed:
Acipimox 100g
NaCl 50g
PVPk30 2.5g
Magnesium stearate 3g
Coating membrane is formed:
Cellulose acetate 6g
Macrogol 4000 1.5g
Diethyl phthalate 1g
The immediate release drug layer is formed:
Simvastatin 10g
HPMC?6cp 6g
Pulvis Talci 1g
Isolated film clothing layer:
Opadry II
Make 1000 by being prepared as follows method: the preparation of (1) label is got sodium chloride and is pulverized, crossing 100 mesh sieves, with the acipimox mix homogeneously, is wetting agent with 70% alcoholic solution that contains 8%PVPk30, the system soft material, cross 20 mesh sieves and granulate, 45 ℃ of oven dry 2h, granulate, add magnesium stearate, mixing, tabletting adopts 1000 of conventional pressed-disc technique compactings.(2) label coating: get cellulose acetate, add acetone 280ml, stir and make dissolving; In addition taking polyethylene glycol is put in the measuring bottle of 50ml, adds 20ml water and makes after its dissolving 100ml ethanol again, mix homogeneously, join in the above-mentioned 280ml cellulose acetate acetone soln, the limit edged stirs, and Polyethylene Glycol is all dissolved, add diethyl phthalate and shake up, make coating solution.The above-mentioned label that makes is put in the coating machine, and logical hot blast maintains the temperature between 35～45 ℃, sprays into the semipermeable membrane coating solution.Average coating weightening finish 5% after coating is finished, is positioned over heat treatment 12h in 40 ℃ the environment, and volatilizes residual solvent, adopts laser-beam drilling machine that the osmotic pump tablet that makes is carried out the single face punching, and the release hole count is 1, and the aperture is 0.5mm.The osmotic pump tablet that has openning hole is carried out immediate release drug layer coating, the above-mentioned osmotic pump tablet that makes is put in the coating machine, logical hot blast maintains the temperature between 35～45 ℃, sprays into immediate release drug layer coating solution.Press the weightening finish of simvastatin cubage coating, with identical operations bag contagion gown layer, average weight gain 2% promptly again.Adopt two appendix XD first methods of Chinese Pharmacopoeia version in 2000 to measure the release of said preparation, wherein the release medium of acipimox and simvastatin is water, and rotating speed is 100 rev/mins, and acipimox cumulative release curve is seen Fig. 7, and the simvastatin stripping curve is seen Fig. 8.
Change the cellulose acetate in the above-mentioned technological operation into the equivalent ethyl cellulose, acetone makes equivalent ethanol into, and all the other operations are the same, and products obtained therefrom release and result of extraction are suitable.
Label is formed:
Acipimox 150g
Fructose 45g
Lactose 45g
PVPk30 5g
Magnesium stearate 5g
Coating membrane is formed:
Cellulose acetate 8g
Macrogol 4000 2g
Dibutyl sebacate 2g
The immediate release drug layer is formed:
Simvastatin 10g
HPMC?6cp 6g
Sodium lauryl sulphate 2g
Titanium dioxide 1g
Pulvis Talci 0.5g
Make 1000 by being prepared as follows method: the preparation of (1) label is got sodium chloride and is pulverized, crossing 100 mesh sieves, with the acipimox mix homogeneously, is wetting agent with 70% alcoholic solution that contains 8%PVPk30, the system soft material, cross 20 mesh sieves and granulate, 45 ℃ of oven dry 2h, granulate, add magnesium stearate, mixing, tabletting adopts 1000 of conventional pressed-disc technique compactings.(2) label coating: get cellulose acetate, add acetone 280ml, stir and make dissolving; In addition taking polyethylene glycol is put in the measuring bottle of 50ml, adds 20ml water and makes after its dissolving 100ml ethanol again, mix homogeneously, join in the above-mentioned 280ml cellulose acetate acetone soln, the limit edged stirs, and Polyethylene Glycol is all dissolved, add dibutyl sebacate and shake up, make coating solution.The above-mentioned label that makes is put in the coating machine, and logical hot blast maintains the temperature between 35～45 ℃, sprays into the semipermeable membrane coating solution.Average coating weightening finish 5% after coating is finished, is positioned over heat treatment 12h in 40 ℃ the environment, and volatilizes residual solvent, adopts laser-beam drilling machine that the osmotic pump tablet that makes is carried out the single face punching, and the release hole count is 1, and the aperture is 0.5mm.The osmotic pump tablet that has openning hole is carried out immediate release drug layer coating, the above-mentioned osmotic pump tablet that makes is put in the coating machine, logical hot blast maintains the temperature between 35～45 ℃, sprays into immediate release drug layer coating solution.Cut down the weightening finish of cubage coating by atropic, average weight gain 2% promptly.Adopt two appendix XD first methods of Chinese Pharmacopoeia version in 2000 to measure the release of said preparation, wherein the release medium of acipimox and simvastatin is a water, and rotating speed is 100 rev/mins, and acipimox cumulative release curve is seen Fig. 9, and the simvastatin stripping curve is seen Figure 10.
Change the cellulose acetate in the above-mentioned technological operation into the equivalent ethyl cellulose, acetone makes equivalent ethanol into, and all the other operations are the same, and products obtained therefrom release and result of extraction are suitable.
Embodiment 3
Label is formed:
Acipimox 200g
NaCl 90g
PVP
k30 5g
Magnesium stearate 5g
Coating membrane is formed:
Ethyl cellulose 12g
HPMC6cp 2g
Macrogol 4000 1g
The immediate release drug layer is formed:
Simvastatin 10g
HPMC
6cp 6g
Pulvis Talci 1g
Isolated film clothing layer:
Opadry II
Make 1000 by being prepared as follows method: the preparation of (1) label is got sodium chloride and is pulverized, crossing 100 mesh sieves, with the acipimox mix homogeneously, is wetting agent with 50% alcoholic solution that contains 5%HPMC6cp, the system soft material, cross 20 mesh sieves and granulate, 5 ℃ of oven dry 2h, granulate, add magnesium stearate, mixing, tabletting adopts 1000 of conventional pressed-disc technique compactings.(2) label coating: get ethyl cellulose, add ethanol 320ml, stir and make dissolving; Taking polyethylene glycol and HPMC put in the measuring bottle of 100ml in addition, add to join in the above-mentioned 320ml ethyl cellulose alcoholic solution after 80ml water makes its dissolving again, and the limit edged stirs, and Dissolve things inside all dissolves, and makes coating solution.The above-mentioned label that makes is put in the coating machine, and logical hot blast maintains the temperature between 35～45 ℃, sprays into the semipermeable membrane coating solution.Average coating weightening finish 5% after coating is finished, is positioned over the 12h of heat place in 40 ℃ the environment, and volatilizes residual solvent, adopts laser-beam drilling machine that the osmotic pump tablet that makes is carried out the single face punching, and the release hole count is 1, and the aperture is 0.5mm.The osmotic pump tablet that has openning hole is carried out immediate release drug layer coating, the above-mentioned osmotic pump tablet that makes is put in the coating machine, logical hot blast maintains the temperature between 35～45 ℃, sprays into immediate release drug layer coating solution.Cut down the weightening finish of cubage coating by atropic, with identical operations bag contagion gown layer, average weight gain 1% promptly again.Adopt two appendix XD first methods of Chinese Pharmacopoeia version in 2000 to measure the release of said preparation, wherein the release medium of acipimox is a water, and rotating speed is 100 rev/mins, and the dissolution medium of simvastatin is a water, rotating speed is 100 rev/mins, and acipimox cumulative release curve is seen Figure 11.The simvastatin stripping curve is seen Figure 12.Simvastatin/acipimox the osmotic pump tablet of the method preparation of employing embodiment 3 and the contrast test that the acipimox fast-release tablet has carried out begle dog single-dose, the result as shown in figure 18, the acipimox osmotic pump tablet has partly shown good controlled release preparation feature, blood drug level is held stationary in 24h, and be higher than effective blood drug concentration (0.2 μ g/ml) all the time, and the quick releasing formulation of same dose blood drug level when 12h just approaches 0.The relative bioavailability of osmotic pump preparation is 108.17%, with the fast-release tablet bioequivalence.With delay merchant (Rs) value of fast-release tablet be 2.89, demonstrate stronger controlled-release function.
Embodiment 4
Label is formed:
Acipimox 250g
Lactose 60g
Sucrose 90g
PVPk30 5g
Magnesium stearate 5g
Coating membrane is formed:
Ethyl cellulose 12g
HPMC6cp 3g
Macrogol 4000 2.5g
The immediate release drug layer is formed:
Simvastatin 10g
HPMC6cp 6g
Pulvis Talci 1g
Isolated film clothing layer:
The common stomach dissolution type film-coat of Ai Leyi
Make 1000 by being prepared as follows method: the preparation of (1) label is got sodium chloride and is pulverized, crossing 100 mesh sieves, with the acipimox mix homogeneously, is wetting agent with 50% alcoholic solution that contains 5%HPMC6cp, the system soft material, cross 20 mesh sieves and granulate, 5 ℃ of oven dry 2h, granulate, add magnesium stearate, mixing, tabletting adopts 1000 of conventional pressed-disc technique compactings.(2) label coating: get ethyl cellulose, add ethanol 320ml, stir and make dissolving; Taking polyethylene glycol and HPMC put in the measuring bottle of 100ml in addition, add to join in the above-mentioned 320ml ethyl cellulose alcoholic solution after 80ml water makes its dissolving again, and the limit edged stirs, and Dissolve things inside all dissolves, and makes coating solution.The above-mentioned label that makes is put in the coating machine, and logical hot blast maintains the temperature between 35～45 ℃, sprays into the semipermeable membrane coating solution.Average coating weightening finish 5% after coating is finished, is positioned over heat treatment 12h in 40 ℃ the environment, and volatilizes residual solvent.Micro-porous osmotic pump tablet is carried out immediate release drug layer coating, the above-mentioned osmotic pump tablet that makes is put in the coating machine, logical hot blast maintains the temperature between 35～45 ℃, sprays into immediate release drug layer coating solution.Cut down the weightening finish of cubage coating by atropic, with identical operations bag contagion gown layer, average weight gain 2% promptly again.Adopt two appendix XD first methods of Chinese Pharmacopoeia version in 2000 to measure the release of said preparation, wherein the release medium of acipimox is a water, and rotating speed is 100 rev/mins, and the dissolution medium of acipimox is a water, rotating speed is 100 rev/mins, and acipimox cumulative release curve is seen Figure 13.The simvastatin stripping curve is seen Figure 14.
Double-deck label is formed:
The acipimox part:
Acipimox 280g
Fructose 115g
PVPk30 4g
Magnesium stearate 3g
The simvastatin part:
Simvastatin 10g
PEG4000 20g
Mannitol 60g
PVPk30 2g
Sodium stearyl fumarate 1g
The intermediate layer part:
Polyvinyl alcohol 20g
Ethyl cellulose 20g
Coating membrane is formed:
Ethyl cellulose 12g
HPMC 2g
Macrogol 4000 2.5g
Diethyl phthalate 1g
Isolated film clothing layer:
Opadry II
As shown in Figure 2, make 1000 by being prepared as follows method: the preparation of (1) label is got sodium chloride and is pulverized, crossing 100 mesh sieves, with the acipimox mix homogeneously, is wetting agent with 50% alcoholic solution that contains 5%HPMC6cp, the system soft material, cross 20 mesh sieves and granulate, 45 ℃ of oven dry 2h, 20 mesh sieve granulate, add magnesium stearate, mixing; With simvastatin, PEG4000, the mannitol mix homogeneously of recipe quantity, be wetting agent with 70% the alcoholic solution that contains 5%PVPk30, the system soft material is crossed 20 mesh sieves and is granulated, 45 ℃ of oven dry 2h, 20 mesh sieve granulate add the magnesium stearate mix homogeneously; Get the polyvinyl alcohol and the ethyl cellulose of recipe quantity, dehydrated alcohol system soft material, 20 sieve series grains, 50 ℃ of oven dry 2h, three laminate machine tablettings dash to deep concave type dashes down, are the acipimox part, and the upper strata is that dimple form dashes, and is the simvastatin part.(2) label coating: get ethyl cellulose, add ethanol 320ml, stir and make dissolving; Taking polyethylene glycol and HPMC put in the measuring bottle of 100ml in addition, add to join in the above-mentioned 320ml ethyl cellulose alcoholic solution after 80ml water makes its dissolving again, and the limit edged stirs, and Dissolve things inside all dissolves, and makes coating solution.The above-mentioned label that makes is put in the coating machine, and logical hot blast maintains the temperature between 35～45 ℃, sprays into the semipermeable membrane coating solution.Average coating weightening finish 5% after coating is finished, is positioned over heat treatment 12h in 40 ℃ the environment, and volatilizes residual solvent.Use laser-beam drilling machine and will carry out two-sided punching, the acipimox face directly is 0.5mm, and the simvastatin face directly is 0.8mm.With identical operations bag contagion gown layer, average weight gain 2% promptly.Adopt two appendix XD first methods of Chinese Pharmacopoeia version in 2005 to measure the release of said preparation, wherein acipimox and simvastatin all are release medium with water, 100 rev/mins of rotating speeds.The cumulative release curve is seen accompanying drawing 15.
Embodiment 6
Double-deck label is formed:
The acipimox part:
Acipimox 300g
Fructose 140g
PVPk30 4.5g
Magnesium stearate 3g
The simvastatin part:
Simvastatin 10g
PEG4000 15g
Mannitol 70g
PVPk30 2g
Magnesium stearate 1g
The intermediate layer part:
Polyvinyl alcohol 20g
Ethyl cellulose 20g
Coating membrane is formed:
Cellulose acetate 12g
Macrogol 4000 2.5g
Diethyl phthalate 1g
Isolated film clothing layer:
Opadry II
As shown in Figure 3, make 1000 by being prepared as follows method: the preparation of (1) label is got sodium chloride and is pulverized, crossing 100 mesh sieves, with the acipimox mix homogeneously, is wetting agent with 50% alcoholic solution that contains 5%HPMC6cp, the system soft material, cross 20 mesh sieves and granulate, 45 ℃ of oven dry 2h, 20 mesh sieve granulate, add magnesium stearate, mixing; With simvastatin, PEG4000, the mannitol mix homogeneously of recipe quantity, be wetting agent with 70% the alcoholic solution that contains 5%PVPk30, the system soft material is crossed 20 mesh sieves and is granulated, 45 ℃ of oven dry 2h, 20 mesh sieve granulate add the magnesium stearate mix homogeneously; Get the polyvinyl alcohol and the ethyl cellulose of recipe quantity, dehydrated alcohol system soft material, 20 mesh sieves are granulated, 50 ℃ of oven dry 2h, three laminate machine tablettings dash to deep concave type dashes down, are the acipimox part, and the upper strata is that dimple form dashes, and is the simvastatin part.(2) label coating: get cellulose acetate, add acetone 280ml, stir and make dissolving; In addition taking polyethylene glycol is put in the measuring bottle of 50ml, adds 20ml water and makes after its dissolving 100ml ethanol again, mix homogeneously, join in the above-mentioned 280ml cellulose acetate acetone soln, the limit edged stirs, and Polyethylene Glycol is all dissolved, add diethyl phthalate and shake up, make coating solution.The above-mentioned label that makes is put in the coating machine, and logical hot blast maintains the temperature between 35～45 ℃, sprays into the semipermeable membrane coating solution.Average coating weightening finish 6% after coating is finished, is positioned over heat treatment 12h in 40 ℃ the environment, and volatilizes residual solvent.With the pore type osmotic pumps bag contagion gown layer of preparation, adopt Opadry II type film coating powder, inlet temperature is 45 ℃, and the sheet bed tempertaure is 30 ℃, and average weight gain 2% is promptly.Adopt two appendix XD first methods of Chinese Pharmacopoeia version in 2005 to measure the release of said preparation, wherein the release medium of acipimox and simvastatin release is a water, and rotating speed is 100 rev/mins.The cumulative release curve is seen accompanying drawing 16.
Embodiment 7
Label is formed:
Acipimox 350g
Simvastatin 10g
Lactose 80g
Fructose 80g
PVPk30 3g
Sodium stearyl fumarate 4g
Coating membrane is formed:
Ethyl cellulose 12g
HPMC6cp 3g
Macrogol 4000 1.5g
Isolated film clothing layer:
Opadry II
Make 1000 by being prepared as follows method: lactose is got in the preparation of (1) label and fructose is pulverized, and crosses 100 mesh sieves, with acipimox and simvastatin mix homogeneously, to contain 5%PVP
K3050% alcoholic solution be wetting agent, the system soft material is crossed 20 mesh sieves and is granulated, 5 ℃ of oven dry 2h, granulate adds sodium stearyl fumarate, mixing, tabletting adopts 1000 of conventional pressed-disc technique compactings.(2) label coating: get ethyl cellulose, add ethanol 320ml, stir and make dissolving; Taking polyethylene glycol and HPMC put in the measuring bottle of 100ml in addition, add to join in the above-mentioned 320ml ethyl cellulose alcoholic solution after 80ml water makes its dissolving again, and the limit edged stirs, and Dissolve things inside all dissolves, and makes coating solution.The above-mentioned label that makes is put in the coating machine, and logical hot blast maintains the temperature between 35～45 ℃, sprays into the semipermeable membrane coating solution.Average coating weightening finish 5% after coating is finished, is positioned over heat treatment 12h in 40 ℃ the environment, and volatilizes residual solvent, adopts laser-beam drilling machine that the osmotic pump tablet that makes is carried out the single face punching, and the release hole count is 1, and the aperture is 0.5mm.The osmotic pump tablet that has openning hole is carried out contagion gown layer coating, the above-mentioned osmotic pump tablet that makes is put in the coating machine, logical hot blast maintains the temperature between 35～45 ℃, sprays into contagion gown layer coating solution, and average weight gain 1% promptly.Adopt two appendix XD first methods of Chinese Pharmacopoeia version in 2000 to measure the release of said preparation, wherein the release medium of acipimox and simvastatin is water, and rotating speed is 100 rev/mins, and acipimox and simvastatin cumulative release curve are seen Figure 17.
Example 8 acipimox simvastatin compound osmotic pump preparations are to the influence of model rabbit atheromatous plaque
1. the foundation of animal model and grouping
Select 24 of between twenty and fifty new zealand rabbits, be divided into 3 groups at random.8 of model control group are raised with normal diet, take blank tablet in addition; 8 of ordinary preparation groups are raised with high lipid food (5g/kg cholesterol and 150g/kg yolk powder), take acipimox simvastatin compound recipe conventional tablet (containing acipimox 250g, simvastatin 10g) in addition; 8 of osmotic pump preparation groups are raised with high lipid food (5g/kg cholesterol and 150g/kg yolk powder), take osmotic pump controlled release tablet prepared among the embodiment 4 in addition.The mouth medication administration is adopted in this experiment, and administration is all carried out after the animal feed, can directly tablet be filled in rabbit root of the tongue place and allow it swallow, successive administration 80 days, 1 slice/day of pharmaceutical dosage.The single cage of animal is raised, and drinking-water is not limit, and free diet is about every feed every day 150g.
2. pharmacodynamic result is observed and date processing
After real face finishes, adopt depletion method to put to death all animals, cut aorta and make progress to left neck and innominate artery 1cm from the heart root, peel off adventitial connective tissue, cut open from the stringer of film side, and take pictures, the form of perusal atheromatous plaque with digital camera.With the tremulous pulse image of German Leica image analyzer processing atherosclerotic plaque, analyze the plaque area size.
With reference to the grade scale that atheromatous plaque forms, respectively organize size, the area of the atheromatous plaque of rabbit, analysis result is as shown in Figure 1.The atherosclerosis grade scale is as follows:
0 grade: intimal surface is smooth, and no butter changes, and does not promptly have speckle;
0.5 level: inner membrance has extensive milky butter to change, but does not have the speckle that protrudes in the surface;
1 grade: sure butter speckle is arranged, and area is less than 3mm;
2 grades: plaque area is greater than 3mm;
3 grades: have the more speckle that varies in size to merge in flakes, the area of big speckle is greater than 3mm;
4 grades: endarterium is almost all covered by speckle.
Fig. 1 respectively organizes the atherosclerotic classification of rabbit
# and model control group compare, p＜0.01; # and ordinary preparation group compare, p＜0.05
Claims (29)
1. a controlled releasing penetrant pump that contains nicotinic acid class medicine and a kind of statins is characterized in that, has following composition:
(1) make label by nicotinic acid class medicine and penetration enhancer, filler, lubricant, and one deck contains the film-coat of the film coating of semi-permeable character of filmogen, plasticizer and porogen and statins and binding agent composition;
Or (2) by nicotinic acid class medicine, statins, penetration enhancer, filler, and the label that lubricant is formed, and one deck contains the film coating of the semi-permeable character of filmogen, plasticizer and porogen;
Or (3) are by containing nicotinic acid class medicine layer, containing the three-layer tablet core that statins layer and sealing coat are formed, also comprise penetration enhancer in the label simultaneously, filler, lubricant, two surface curvature differences of label, wherein nicotinic acid class medicine layer surface is that curvature is bigger, statins laminar surface curvature is less, reach the film coating that one deck contains the semi-permeable character of filmogen, plasticizer and porogen, and/or form by the isolated film clothing that macromolecular material is formed;
The film coating one or both sides of above-mentioned semi-permeable character have small delivery aperture, or meet water dissolution formation micropore by the porogen in the semi-transparent coating membrane, and medicine discharges from aperture or micropore.
2. the described controlled release preparation of claim 1 is characterized in that, described active constituents of medicine is a kind of to be nicotinic acid class medicine, and a kind of is statins, and the ratio of its nicotinic acid class medicine and statins was from 5: 1～100: 1.
3. the described controlled release preparation of claim 1 is characterized in that, described nicotinic acid class medicine is an acipimox, and statins is a simvastatin, its ratio 5: 1～50: 1.
4. the described controlled release preparation of claim 1 is characterized in that, described nicotinic acid class medicine is an acipimox, and statins is a simvastatin, and its ratio was from 10: 1～30: 1.
5. the described controlled release preparation of claim 1, it is characterized in that described penetration enhancer is selected from low molecule saccharide and comprises that sucrose, sorbitol, mannitol, glucose, lactose, fructose and inorganic salts comprise one or more of sodium chloride, potassium chloride, magnesium sulfate, potassium sulfate, sodium sulfate.
6. the described controlled release preparation of claim 1 is characterized in that, described filler comprises the mixture of lactose, microcrystalline Cellulose, calcium hydrogen phosphate, Powderd cellulose or above-mentioned material.
7. the described controlled release preparation of claim 1 is characterized in that, the binding agent of label is a polyvinylpyrrolidone, the mixture of hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, methylcellulose, ethyl cellulose or above-mentioned material.
8. the described controlled release preparation of claim 1 is characterized in that, the wetting agent of label is the mixed solution of water, ethanol or above-mentioned material.
9. the described controlled release preparation of claim 1 is characterized in that, the lubricant of label is the mixture of magnesium stearate, Pulvis Talci, stearic acid, Polyethylene Glycol, sodium lauryl sulphate, sodium stearyl fumarate or above-mentioned material.
10. the described controlled release preparation of claim 1 is characterized in that, semipermeable membrane comprises filmogen, plasticizer, porogen.
11. the described controlled release preparation of claim 10 is characterized in that, filmogen comprises the mixture of cellulose acetate, ethyl cellulose, crylic acid resin, cellulose acetate acetate, hydroxypropyl methylcellulose acetate, polyvinyl alcohol or above-mentioned material.
12. the described controlled release preparation of claim 10 is characterized in that plasticizer mainly comprises glycerol, the mixture of propylene glycol, Polyethylene Glycol, triethyl citrate, dibutyl sebacate, phthalic acid ester or above-mentioned material.
13. the described controlled release preparation of claim 10, it is characterized in that, the mixture of solable matters such as porogen comprises glycerol, propylene glycol, Polyethylene Glycol, sucrose, mannitol, sorbitol, lactose, sodium chloride, hydroxypropyl cellulose, methylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone or above-mentioned material.
14. the described controlled release preparation of claim 1 is characterized in that, the film-coat layer that statins and binding agent are formed comprises statins, binding agent, lubricant, cosolvent.
15. the described controlled release preparation of claim 14 is characterized in that the ratio of statins and adhesive was from 1: 0.1～1: 10.
16. the described controlled release preparation of claim 15 is characterized in that, the ratio of statins and adhesive is preferably 1: 0.5～and 1: 3.
17. the described controlled release preparation of claim 14 is characterized in that binding agent comprises polyvinylpyrrolidone, the mixture of hydroxypropyl emthylcellulose, methylcellulose or above-mentioned material.
18. the described controlled release preparation of claim 14 is characterized in that, lubricant comprises the mixture of magnesium stearate, Pulvis Talci PEG, stearic acid, fumaric acid sodium or above-mentioned material.
19. the described controlled release preparation of claim 14 is characterized in that cosolvent comprises the mixture of sodium lauryl sulphate, Tween-80 or above-mentioned material.
20. the described controlled release preparation of claim 1 is characterized in that, described isolated film clothing layer comprises Opadry.
21. the preparation method of the described controlled release preparation of claim 1, it is characterized in that, the semipermeable membrane THICKNESS CONTROL is at 0.05mm～0.30mm, places drying baker dry coated tablet after coating finishes, then on coated tablet with the laser single face small delivery aperture that to make a call to a diameter be 0.4mm～1.2mm.
22. the described controlled release preparation of claim 1, acipimox and simvastatin all in osmotic pumps as the controlled release part, it is characterized in that, for double speed discharges osmotic pump preparation, use laser-beam drilling machine and will carry out two-sided punching, the acipimox face directly is 0.4-1.0mm, and the simvastatin face directly is 0.5-1.5mm.
23. the osmotic pump preparation of described acipimox of claim 21 and simvastatin compound recipe is characterized in that, the acipimox face directly is 0.5mm, and the simvastatin face directly is 0.8mm.
24. the osmotic pump preparation of claim 21 or 22 arbitrary described acipimoxs and simvastatin compound recipe is characterized in that the label two sides has different curvature.
25. the preparation method of the osmotic pump preparation of claim 21 or 22 arbitrary described acipimoxs and simvastatin compound recipe is characterized in that, label adopts three laminate machine tablettings, down towards dashing for deep concave type, be the acipimox part, the upper strata is that dimple form dashes, and is the simvastatin part.
26. the described osmotic pump preparation of claim 1 is characterized in that, for the pore type osmotic pumps, porogen is 10%～50% of a coating membrane weight, and semipermeable membrane is 3%～15% of a label weight.
27. the described osmotic pump preparation of claim 26 is characterized in that, for the pore type osmotic pumps, porogen is that the ratio of coating membrane weight is preferably 35%～45%, and semipermeable membrane is that the ratio of label weight is preferably 5%～8%.
28. the described osmotic pump preparation of claim 1 is characterized in that, for laser boring type osmotic pumps, porogen is 5%～45% of a coating membrane weight, and semipermeable membrane is 3%～15% of a label weight.
29. the described osmotic pump preparation of claim 28 is characterized in that, for laser boring type osmotic pumps, porogen is that the ratio of coating membrane weight is preferably 15%～35%, and semipermeable membrane is that the ratio of label weight is preferably 5%～8%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710128956XA CN101352425B (en) | 2007-07-27 | 2007-07-27 | Compound osmotic pump controlled release preparation and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710128956XA CN101352425B (en) | 2007-07-27 | 2007-07-27 | Compound osmotic pump controlled release preparation and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101352425A true CN101352425A (en) | 2009-01-28 |
| CN101352425B CN101352425B (en) | 2010-11-10 |
Family
ID=40305600
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200710128956XA Active CN101352425B (en) | 2007-07-27 | 2007-07-27 | Compound osmotic pump controlled release preparation and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101352425B (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102018682A (en) * | 2009-09-15 | 2011-04-20 | 北京天衡药物研究院 | Osmotic pump controlled-release tablet and preparation method thereof |
| CN102198112A (en) * | 2010-03-26 | 2011-09-28 | 北京天衡药物研究院 | Osmotic pump type controlled release tablets and preparation method thereof |
| CN102458360A (en) * | 2009-05-01 | 2012-05-16 | 阿普塔利斯医药科技公司 | Orally disintegrating tablet composition containing combination of high dose and low dose drug |
| CN102512398A (en) * | 2012-01-12 | 2012-06-27 | 合肥立方制药股份有限公司 | Simvastatin osmotic pump preparation and preparation method thereof |
| CN111346067A (en) * | 2020-03-11 | 2020-06-30 | 广东科泰鼎润药业科技有限公司 | Controlled release preparation of guanfacine and preparation method thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1205934C (en) * | 2003-01-20 | 2005-06-15 | 鲁南制药股份有限公司 | Composition for treating hyperlipemia |
| CN1307996C (en) * | 2004-04-01 | 2007-04-04 | 山东新时代药业有限公司 | Composition for treating hyperlipemia |
-
2007
- 2007-07-27 CN CN200710128956XA patent/CN101352425B/en active Active
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102458360A (en) * | 2009-05-01 | 2012-05-16 | 阿普塔利斯医药科技公司 | Orally disintegrating tablet composition containing combination of high dose and low dose drug |
| CN102018682A (en) * | 2009-09-15 | 2011-04-20 | 北京天衡药物研究院 | Osmotic pump controlled-release tablet and preparation method thereof |
| CN102198112A (en) * | 2010-03-26 | 2011-09-28 | 北京天衡药物研究院 | Osmotic pump type controlled release tablets and preparation method thereof |
| CN102512398A (en) * | 2012-01-12 | 2012-06-27 | 合肥立方制药股份有限公司 | Simvastatin osmotic pump preparation and preparation method thereof |
| CN102512398B (en) * | 2012-01-12 | 2013-05-01 | 合肥立方制药股份有限公司 | Simvastatin osmotic pump preparation and preparation method thereof |
| CN111346067A (en) * | 2020-03-11 | 2020-06-30 | 广东科泰鼎润药业科技有限公司 | Controlled release preparation of guanfacine and preparation method thereof |
| CN111346067B (en) * | 2020-03-11 | 2022-05-17 | 广东科泰鼎润药业科技有限公司 | Controlled release preparation of guanfacine and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101352425B (en) | 2010-11-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101352426B (en) | Osmotic pump controlled release preparation composition and preparation thereof | |
| US4927640A (en) | Controlled release beads having glass or silicon dioxide core | |
| JP5563731B2 (en) | Controlled release formulation of opioid and non-opioid analgesics | |
| JP5315055B2 (en) | Mitigation of alcohol-induced dose dumping for opioid sustained release oral dosage forms. | |
| RU2420268C2 (en) | Method of programmed floating delivery | |
| CN101466384B (en) | Osmotic Drug Delivery Systems Containing Release-Enhancing Agents | |
| CN101375869B (en) | Slow/controlled release pellet composition containing ginkgo leaf extracts and preparation method thereof | |
| JP2003509354A (en) | Formulation and method for providing effective reboxetine treatment once a day | |
| MXPA06001548A (en) | Uniform delivery of topiramate over prolonged period of time with enhanced dispersion formulation. | |
| CN101352425B (en) | Compound osmotic pump controlled release preparation and preparation method thereof | |
| CN101385729B (en) | Osmotic pump controlled release preparation composition for treating hyperlipemia and preparation method thereof | |
| CN101385731B (en) | Osmotic pump controlled release preparation composition for treating hyperlipemia and preparation method thereof | |
| WO2001078681A1 (en) | Drug delivery system for avoiding pharmacokinetic interaction between drugs and method thereof | |
| CN101385718B (en) | Osmotic pump preparation composition for treating hyperlipemia | |
| WO2008083561A1 (en) | Oral pharmaceutical composition of glycyrrhizin or its salts and the preparation method thereof | |
| CN101385719B (en) | Osmotic pump preparation composition for treating hyperlipemia | |
| CN101385730B (en) | Osmotic pump controlled release preparation composition for treating hyperlipemia and preparation method thereof | |
| CN102028668B (en) | Simvastatin osmotic pump controlled-release tablet | |
| CN101269056B (en) | Metoprolol salt oral administration impulse pellet preparation | |
| CN101351202A (en) | Method of reducing alcohol-induced dose dumping of opioid sustained release oral dosage forms | |
| CN117679382A (en) | Mycophenolate mofetil gastric adhesion osmotic pump controlled release tablet and preparation method thereof | |
| Patel | Formulation and evaluation of ranolazine sustained release tablets by hot melt coating technique | |
| Borole | FORMULATION, DEVELOPMENT AND EVALUATION OF FLOATING-PULSATILE DRUG DELIVERY SYSTEM OF NIFEDIPINE | |
| HK1141226B (en) | Isosorbide mononitrate osmotic pump type controlled-release formulation and preparation method thereof | |
| HK11494A (en) | New drug preparation with controlled release of the active compound, and a method for the manufacture thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Assignee: Lunan Beite Pharmaceutical Co., Ltd. Assignor: Lunan Pharmaceutical Group Co., Ltd. Contract record no.: 2010370000512 Denomination of invention: Compound osmotic pump controlled release preparation and preparation method thereof License type: Exclusive License Open date: 20090128 Record date: 20100909 |
|
| GR01 | Patent grant | ||
| EC01 | Cancellation of recordation of patent licensing contract |
Assignee: Lunan Beite Pharmaceutical Co., Ltd. Assignor: Lunan Pharmaceutical Group Co., Ltd. Contract record no.: 2010370000512 Date of cancellation: 20131016 |
|
| LICC | Enforcement, change and cancellation of record of contracts on the licence for exploitation of a patent or utility model |