CN102772395A - Sustained release preparation containing ambroxol hydrochloride and clenbuterol hydrochloride, and preparation method thereof - Google Patents
Sustained release preparation containing ambroxol hydrochloride and clenbuterol hydrochloride, and preparation method thereof Download PDFInfo
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- CN102772395A CN102772395A CN2011101179320A CN201110117932A CN102772395A CN 102772395 A CN102772395 A CN 102772395A CN 2011101179320 A CN2011101179320 A CN 2011101179320A CN 201110117932 A CN201110117932 A CN 201110117932A CN 102772395 A CN102772395 A CN 102772395A
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- Prior art keywords
- slow
- hydrochloride
- releasing preparation
- preparation
- slow releasing
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- QNVKOSLOVOTXKF-UHFFFAOYSA-N 4-[(2-amino-3,5-dibromophenyl)methylamino]cyclohexan-1-ol;hydron;chloride Chemical compound Cl.NC1=C(Br)C=C(Br)C=C1CNC1CCC(O)CC1 QNVKOSLOVOTXKF-UHFFFAOYSA-N 0.000 title claims abstract description 40
- 229960000985 ambroxol hydrochloride Drugs 0.000 title claims abstract description 40
- OPXKTCUYRHXSBK-UHFFFAOYSA-N clenbuterol hydrochloride Chemical compound Cl.CC(C)(C)NCC(O)C1=CC(Cl)=C(N)C(Cl)=C1 OPXKTCUYRHXSBK-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 229960001399 clenbuterol hydrochloride Drugs 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- 239000003405 delayed action preparation Substances 0.000 title abstract 4
- 239000011230 binding agent Substances 0.000 claims abstract description 12
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 10
- 239000000945 filler Substances 0.000 claims abstract description 7
- 239000002671 adjuvant Substances 0.000 claims abstract description 6
- 239000000314 lubricant Substances 0.000 claims abstract description 5
- 239000003814 drug Substances 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 25
- 239000012729 immediate-release (IR) formulation Substances 0.000 claims description 24
- 239000008187 granular material Substances 0.000 claims description 20
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 18
- 229920002472 Starch Polymers 0.000 claims description 14
- 239000008107 starch Substances 0.000 claims description 14
- 235000019698 starch Nutrition 0.000 claims description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 13
- 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 9
- 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 9
- 239000008101 lactose Substances 0.000 claims description 9
- 235000019359 magnesium stearate Nutrition 0.000 claims description 9
- 239000000463 material Substances 0.000 claims description 9
- 239000000741 silica gel Substances 0.000 claims description 9
- 229910002027 silica gel Inorganic materials 0.000 claims description 9
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 7
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 7
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 7
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 7
- 208000023504 respiratory system disease Diseases 0.000 claims description 7
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 6
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 230000001684 chronic effect Effects 0.000 claims description 6
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 6
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 6
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 6
- DMBUODUULYCPAK-UHFFFAOYSA-N 1,3-bis(docosanoyloxy)propan-2-yl docosanoate Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCCCCCC DMBUODUULYCPAK-UHFFFAOYSA-N 0.000 claims description 5
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 5
- 239000003086 colorant Substances 0.000 claims description 4
- 238000007908 dry granulation Methods 0.000 claims description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 4
- 229960003943 hypromellose Drugs 0.000 claims description 4
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 claims description 4
- 239000004094 surface-active agent Substances 0.000 claims description 4
- 238000005550 wet granulation Methods 0.000 claims description 4
- 229920002125 Sokalan® Polymers 0.000 claims description 3
- 229960001631 carbomer Drugs 0.000 claims description 3
- 229940075507 glyceryl monostearate Drugs 0.000 claims description 3
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 3
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims description 3
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 claims description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 3
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 2
- 239000005995 Aluminium silicate Substances 0.000 claims description 2
- 229920001661 Chitosan Polymers 0.000 claims description 2
- 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 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- 239000001856 Ethyl cellulose Substances 0.000 claims description 2
- 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 2
- 229920002907 Guar gum Polymers 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- 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 2
- 229930006000 Sucrose Natural products 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
- 235000012211 aluminium silicate Nutrition 0.000 claims description 2
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical group [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 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
- 229940045110 chitosan Drugs 0.000 claims description 2
- 238000004132 cross linking Methods 0.000 claims description 2
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 2
- 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 2
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 2
- 229920001249 ethyl cellulose Polymers 0.000 claims description 2
- 229960004667 ethyl cellulose Drugs 0.000 claims description 2
- 239000000665 guar gum Substances 0.000 claims description 2
- 235000010417 guar gum Nutrition 0.000 claims description 2
- 229960002154 guar gum Drugs 0.000 claims description 2
- 239000008172 hydrogenated vegetable oil Substances 0.000 claims description 2
- 239000001341 hydroxy propyl starch Substances 0.000 claims description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 2
- 235000013828 hydroxypropyl starch Nutrition 0.000 claims description 2
- 229950005770 hyprolose Drugs 0.000 claims description 2
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 claims description 2
- 229940037627 magnesium lauryl sulfate Drugs 0.000 claims description 2
- 229940057948 magnesium stearate Drugs 0.000 claims description 2
- HBNDBUATLJAUQM-UHFFFAOYSA-L magnesium;dodecyl sulfate Chemical compound [Mg+2].CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCOS([O-])(=O)=O HBNDBUATLJAUQM-UHFFFAOYSA-L 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims description 2
- 239000001923 methylcellulose Substances 0.000 claims description 2
- 229960002900 methylcellulose Drugs 0.000 claims description 2
- 235000010981 methylcellulose Nutrition 0.000 claims description 2
- 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 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical group CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 229940093429 polyethylene glycol 6000 Drugs 0.000 claims description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 2
- 229940068984 polyvinyl alcohol Drugs 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 238000009702 powder compression Methods 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 235000010413 sodium alginate Nutrition 0.000 claims description 2
- 239000000661 sodium alginate Substances 0.000 claims description 2
- 229940005550 sodium alginate Drugs 0.000 claims description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 238000013268 sustained release Methods 0.000 abstract description 8
- 239000012730 sustained-release form Substances 0.000 abstract description 8
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- 150000001875 compounds Chemical class 0.000 description 27
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- HHAGWXCTPQVPJV-UHFFFAOYSA-N N.[Br] Chemical compound N.[Br] HHAGWXCTPQVPJV-UHFFFAOYSA-N 0.000 description 21
- 239000007939 sustained release tablet Substances 0.000 description 20
- 230000000694 effects Effects 0.000 description 17
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- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical group [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 8
- 229960001375 lactose Drugs 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
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- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 208000026435 phlegm Diseases 0.000 description 5
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 4
- 206010011224 Cough Diseases 0.000 description 4
- 206010036790 Productive cough Diseases 0.000 description 4
- 238000010812 external standard method Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 4
- 229920000053 polysorbate 80 Polymers 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000001476 alcoholic effect Effects 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 229960001117 clenbuterol Drugs 0.000 description 3
- 239000012738 dissolution medium Substances 0.000 description 3
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- -1 winnofil Chemical compound 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000005030 aluminium foil Substances 0.000 description 2
- 229960005174 ambroxol Drugs 0.000 description 2
- 230000001088 anti-asthma Effects 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000000924 antiasthmatic agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- STJMRWALKKWQGH-UHFFFAOYSA-N clenbuterol Chemical compound CC(C)(C)NCC(O)C1=CC(Cl)=C(N)C(Cl)=C1 STJMRWALKKWQGH-UHFFFAOYSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000003172 expectorant agent Substances 0.000 description 2
- 230000003419 expectorant effect Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 230000002045 lasting effect Effects 0.000 description 2
- 239000003580 lung surfactant Substances 0.000 description 2
- 210000003097 mucus Anatomy 0.000 description 2
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 238000011003 system suitability test Methods 0.000 description 2
- 239000004925 Acrylic resin Substances 0.000 description 1
- 229920000178 Acrylic resin Polymers 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- 208000018569 Respiratory Tract disease Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 206010044302 Tracheitis Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
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- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000000614 adrenergic beta-2 receptor agonist Substances 0.000 description 1
- 229940124627 adrenergic β2 receptor agonist Drugs 0.000 description 1
- 210000001552 airway epithelial cell Anatomy 0.000 description 1
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- JBDGDEWWOUBZPM-XYPYZODXSA-N ambroxol Chemical compound NC1=C(Br)C=C(Br)C=C1CN[C@@H]1CC[C@@H](O)CC1 JBDGDEWWOUBZPM-XYPYZODXSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
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- 206010006451 bronchitis Diseases 0.000 description 1
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- 210000004081 cilia Anatomy 0.000 description 1
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- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 230000000420 mucociliary effect Effects 0.000 description 1
- 230000000414 obstructive effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
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- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
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- 229960002052 salbutamol Drugs 0.000 description 1
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- 239000011780 sodium chloride Substances 0.000 description 1
- VWDWKYIASSYTQR-YTBWXGASSA-N sodium;dioxido(oxo)azanium Chemical compound [Na+].[O-][15N+]([O-])=O VWDWKYIASSYTQR-YTBWXGASSA-N 0.000 description 1
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Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to a sustained release preparation containing ambroxol hydrochloride and clenbuterol hydrochloride. The preparation comprises a sustained release part and a quick release part, wherein the quick release part comprises clenbuterol hydrochloride, a quick release adjuvant and another pharmaceutic adjuvant, the sustained release part comprises ambroxol hydrochloride, a sustained release adjuvant and another pharmaceutic adjuvant, and the another pharmaceutic adjuvant is one or more selected from the group consisting of a filler, a binder and a lubricant. The invention also relates to a preparation method for the sustained release preparation. The sustained release preparation provided in the invention has the following advantages: the quick release part has fast action, and the sustained release part has a long-acting drug effect.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to a kind of slow releasing preparation that contains ambroxol hydrochloride and clenbuterol hydrochloride, and the method for preparing of said slow releasing preparation.
Background technology
Respiratory system disease is a kind of commonly encountered diseases, frequently-occurring disease, and higher sickness rate is worldwide all arranged, and the trend of increase is arranged, and it is China human mortality's a second largest factor.The cardinal symptom of respiratory system disease is cough, expectoration and asthma, but alternative clinically medicine is also few and onset is slower.
Clenbuterol hydrochloride is a kind of selective ' beta '3 adrenergic beta 2 receptor agonist of strong effect, can the diastole bronchial smooth muscle, and its bronchiectatic activity is stronger 100 times than salbutamol, and faint to the cardiovascular system influence.Except that relievining asthma, clenbuterol hydrochloride also has the bronchus of enhancing cilia activity ability, promotes sputum to discharge, helps to improve the curative effect of relievining asthma.Clenbuterol hydrochloride is used for the respiratory system disease treatment and has rapid-action, the characteristics such as length, suitable dose is little, toxic and side effects is low of holding time.
Ambroxol hydrochloride is the respiratory mucus regulator of a new generation, has the superior usefulness of eliminating the phlegm, and can reduce airway resistance, thereby reduce mucous adhesive force through increasing the generation and the secretion of pulmonary surfactant, promotes the mucociliary transhipment.The clinical various acute and chronic respiratory tract diseases that are used for expectoration and too much mucus secretion more.Safe in utilization, better tolerance, determined curative effect is reused no drug accumulation.In addition; Ambroxol hydrochloride can also promote pulmonary surfactant to secrete in a large number, and the covering protection airway epithelial cell makes antibacterial can not directly touch the respiratory tract surface; Reduce the danger that infects and promote the phagocytosis of macrophage, play the effect of prevention respiratory tract infection antibacterial.
With the compound preparation that anti-asthmatic clenbuterol hydrochloride and expectorant ambroxol hydrochloride are formed, can bring into play expelling phlegm for arresting cough and antasthmatic effect simultaneously, be used for cough-relieving, reduce phlegm, relieving asthma.The domestic existing listing at present of above-mentioned compound preparation is like compound ambroxol sheet, the special sieve oral liquid of ammonia bromine etc.The shortcoming of these preparations is that it is common compound preparation, and action time is short, needs administration 2～3 times in one day, and patient's compliance is relatively poor; And blood concentration fluctuation, be prone to cause untoward reaction.
Therefore, in order to overcome above-mentioned shortcoming, research has simultaneously relievings asthma and the double effects and have the medicine of slow release effect of eliminating the phlegm, and the lung functions index that is used to improve the patient has crucial meaning particularly for the treatment of chronic respiratory system diseases.
Summary of the invention
The purpose of this invention is to provide a kind of have simultaneously relieving asthma and the double effects and have the compound preparation of slow release effect of eliminating the phlegm.The inventor provides a kind of slow releasing preparation that contains ambroxol hydrochloride and clenbuterol hydrochloride through a large amount of prescription screenings and optimization, and it has, and quick releasing formulation is rapid-action, the characteristics of slow releasing preparation lasting medicine, has accomplished the present invention thus.
One aspect of the present invention relates to a kind of slow releasing preparation; It is made up of slow-released part and immediate release section; Wherein immediate release section contains clenbuterol hydrochloride, rapid release adjuvant and other pharmaceutic adjuvant; Slow-released part contains ambroxol hydrochloride, slow-release auxiliary material and other pharmaceutic adjuvant, and said other pharmaceutic adjuvant is selected from a kind of in filler, binding agent and the lubricant or several.
In the present invention, immediate release section is a kind of quick disintegration-type preparation, can rapid delivery of pharmaceuticals and bring into play drug effect; Slow-released part discharges through framework material control drug slow, makes blood drug level steady.In the present invention, the percentage by weight that clenbuterol hydrochloride accounts for immediate release section is 0.004%-0.1%, is preferably 0.006%-0.04%, and in embodiments of the invention, the consumption of clenbuterol hydrochloride is 10-50 μ g, is about 0.008%-0.032%; The percentage by weight that ambroxol hydrochloride accounts for slow-released part is 7%-80%, is preferably 15%-75%, and in embodiments of the invention, the consumption of ambroxol hydrochloride is 30-90mg, is about 16%-73%.
In one embodiment of the invention, the clenbuterol hydrochloride of immediate release section stripping more than 80% in 45min; In one embodiment of the invention, the ambroxol hydrochloride of slow-released part can continue release in 24 hours, and wherein release in 1 hour is lower than release in 10%, 4 hour between 35-45%, and release in 12 hours is between 60-70%, and release was more than 80% in 20 hours.
In the present invention; Said rapid release adjuvant is mainly disintegrating agent; Its composition and consumption are that this area is conventional to be selected, and include but not limited to a kind of in cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, starch, hydroxypropyl starch and the microcrystalline Cellulose or several.
In the present invention, said slow-release auxiliary material is mainly framework material, and the part by weight of ambroxol hydrochloride and slow-release material is 1: 0.15～1: 4.The composition of said slow-release auxiliary material and content are that this area is conventional to be selected, and it includes but not limited to a kind of in cellulose derivative, carbomer, guar gum, chitosan, polyvinyl alcohol, sodium alginate, octadecanol, glyceryl monostearate, Compritol 888 ATO and the acrylic acid or several.
In the present invention; The composition of said filler and content are the conventional selection in this area; It includes but not limited to known other material of calcium hydrogen phosphate, Kaolin, lactose, sucrose, mannitol, microcrystalline Cellulose, cellulose powder, winnofil, sorbitol, starch and those skilled in the art, is preferably lactose, microcrystalline Cellulose and starch.
In the present invention; The composition of said binding agent and content are the conventional selection in this area; It includes but not limited to methylcellulose, ethyl cellulose, hyprolose, hypromellose, polyvidone, starch, is preferably hypromellose, polyvidone and starch.
In the present invention; The composition of said lubricant and content are the conventional selection in this area; It includes but not limited to stearic acid, hydrogenated vegetable oil, Compritol 888 ATO, Macrogol 4000, polyethylene glycol 6000, magnesium stearate, magnesium laurylsulfate, Pulvis Talci and micropowder silica gel, is preferably magnesium stearate and micropowder silica gel.
In the present invention, said slow releasing preparation can also contain other excipient, for example a kind of in sweeting agent, coloring agent, correctives and the surfactant or several.
The composition of said sweeting agent, coloring agent, correctives and surfactant and content are the routine of this area and select.In one embodiment of the invention, said coloring agent is an iron oxide red.In one embodiment of the invention, said surfactant is a Tween 80.
In the present invention, the dosage form of said slow releasing preparation can be capsule, tablet or pill etc.; In embodiments of the invention, it is a bilayer tablet.
In embodiments of the invention, the weight ratio of said immediate release section and slow-released part is 1: 1～1: 5.
In one embodiment of the invention, the prescription of immediate release section is:
In one embodiment of the invention, the prescription of immediate release section is:
In one embodiment of the invention, the prescription of immediate release section is:
In one embodiment of the invention, the prescription of slow-released part is:
In one embodiment of the invention, the prescription of slow-released part is:
In one embodiment of the invention, the prescription of slow-released part is:
Another aspect of the present invention relates to the method for preparing of described slow releasing preparation, and it may further comprise the steps:
(1) component of immediate release section is directly mixed or through dry granulation or wet granulation, prepare said immediate release section; The component of slow-released part is directly mixed or through dry granulation or wet granulation, prepare said slow-released part;
(2) immediate release section of step (1) preparation and the powder or the granule of slow-released part are processed double-layer tablet through direct powder compression or granule tabletting.
Of the present inventionly relate in one aspect to the purposes that slow releasing preparation of the present invention is used to prepare treatment chronic respiratory system diseases medicine again.Said chronic respiratory system diseases comprise have cough, chronic tracheitis, chronic bronchitis, bronchial asthma and the chronic obstructive disease of lung of expectoration and SOA.
The beneficial effect of the invention
The present invention has prepared a kind of compound preparation that contains clenbuterol hydrochloride and ambroxol hydrochloride simultaneously, and has had rapid release, slow release effect simultaneously on the basis of the folk prescription of ambroxol hydrochloride and clenbuterol hydrochloride, compound preparation.Wherein the anti-asthmatic clenbuterol hydrochloride can quick acting, rapidly relief of symptoms; The expectorant ambroxol hydrochloride can slowly discharge medicine, makes blood drug level steady, reduces side effect, reduces access times simultaneously, improves patient's compliance.
The specific embodiment
To combine embodiment that embodiment of the present invention are described in detail below, but it will be understood to those of skill in the art that the following example only is used to explain the present invention, and should not be regarded as limiting scope of the present invention.Unreceipted actual conditions person among the embodiment carries out according to the condition of normal condition or manufacturer's suggestion.The unreceipted person of production firm of agents useful for same or instrument, being can be through the conventional products of commercial acquisition.
Embodiment 1: the special sieve double-layer sustained release tablets of low specification compound recipe ammonia bromine
Prescription:
Method for preparing:
Release layer: take by weighing clenbuterol hydrochloride crude drug, lactose, starch, iron oxide red that recipe quantity is crossed 80 mesh sieves, behind the mix homogeneously, add Tween 80; Stir, as binding agent system soft material, required consumption was as the criterion when its consumption was granulated with reality with an amount of 5%PVP aqueous solution; Cross 20 mesh sieves and granulate, in 50 ℃ of baking ovens behind the dry 1h, 18 mesh sieve granulate; Add then that cross-linked carboxymethyl cellulose is received, micropowder silica gel and magnesium stearate, mixing.
Slow release layer: take by weighing recipe quantity and cross the ambroxol hydrochloride crude drug of 80 mesh sieves, lactose, hypromellose (HPMC) K100LV and HPMC K4M, behind the mix homogeneously, add an amount of 5%PVP alcoholic solution as binding agent system soft material; Required consumption was as the criterion when its consumption was granulated with reality; Granulate with 20 mesh sieves, in 50 ℃ of following baking ovens behind the dry 1h, 18 mesh sieve granulate; Add micropowder silica gel and magnesium stearate then, mixing.
Tabletting: the slow release layer granule that takes by weighing recipe quantity earlier with less pressure precompressed once after, insert the release layer granule of recipe quantity again, be pressed into double-layer tablet.
Embodiment 2: the special sieve double-layer sustained release tablets of middle specification compound recipe ammonia bromine
Prescription:
Method for preparing:
Release layer: take by weighing clenbuterol hydrochloride crude drug, lactose, microcrystalline Cellulose, iron oxide red that recipe quantity is crossed 80 mesh sieves, behind the mix homogeneously, add Tween 80; Stir, as binding agent system soft material, required consumption was as the criterion when its consumption was granulated with reality with an amount of 3%HPMC aqueous solution; 20 mesh sieves are granulated, in 50 ℃ of baking ovens behind the dry 1h, and 18 mesh sieve granulate; Add polyvinylpolypyrrolidone, micropowder silica gel and magnesium stearate then, mixing.
Slow release layer: take by weighing ambroxol hydrochloride crude drug, lactose, carbomer and Compritol 888 ATO that recipe quantity is crossed 80 mesh sieves, behind the mix homogeneously, add an amount of 5%PVP alcoholic solution as binding agent system soft material; Required consumption was as the criterion when its consumption was granulated with reality; Granulate with 20 mesh sieves, in 50 ℃ of following baking ovens behind the dry 1h, 18 mesh sieve granulate; Add micropowder silica gel and magnesium stearate then, mixing.
Tabletting: the slow release layer granule that takes by weighing recipe quantity earlier with less pressure precompressed once after, insert the release layer granule of recipe quantity again, be pressed into double-layer tablet.
Embodiment 3: the special sieve double-layer sustained release tablets of high standard compound recipe ammonia bromine
Prescription:
Annotate: 10% starch slurry is the binding agent in these article, and required consumption was as the criterion when its consumption was granulated with reality.
Method for preparing:
Release layer: take by weighing clenbuterol hydrochloride crude drug, lactose, starch, iron oxide red that recipe quantity is crossed 80 mesh sieves, behind the mix homogeneously, add Tween 80; Stir, be made as the binding agent soft material with an amount of 10% starch slurry, required consumption was as the criterion when its consumption was granulated with reality; 20 mesh sieves are granulated, in 50 ℃ of baking ovens behind the dry 1h, and 18 mesh sieve granulate; Add low-substituted hydroxypropyl cellulose, micropowder silica gel and magnesium stearate then, mixing.
Slow release layer: take by weighing ambroxol hydrochloride crude drug, lactose, acrylic resin and glyceryl monostearate that recipe quantity is crossed 80 mesh sieves, behind the mix homogeneously, adding an amount of 5%PVP alcoholic solution is binding agent system soft material; Required consumption was as the criterion when its consumption was granulated with reality; Granulate with 20 mesh sieves, in 50 ℃ of following baking ovens behind the dry 1h, 18 mesh sieve granulate; Add micropowder silica gel and magnesium stearate then, mixing.
Tabletting: the slow release layer granule that takes by weighing recipe quantity earlier with less pressure precompressed once after, insert the release layer granule of recipe quantity again, be pressed into double-layer tablet.
Test Example 1: content assaying method, determination of related substances method and the dissolution determination method of immediate release section clenbuterol hydrochloride in the special sieve double-layer sustained release tablets of compound recipe ammonia bromine
Measure with reference to HPLC (two appendix V of Chinese Pharmacopoeia version in 2010 D).
Chromatographic condition and system suitability test: using octadecylsilane chemically bonded silica to be filler, is mobile phase with 1.7% dioctylis sulfosuccinas natricus methanol solution-water-acetic acid (700: 300: 100), and the detection wavelength is 296nm.Number of theoretical plate calculates by the clenbuterol hydrochloride peak should be lower than 1000.
Determination: get these article, remove slow-released part, porphyrize; Precision takes by weighing in right amount, adds the mobile phase dissolving and quantitatively dilutes the solution of processing hydrochloric approximately clenbuterol 0.1 μ g among every 1ml, filters; Precision is measured subsequent filtrate 20 μ l, injects chromatograph of liquid, the record chromatogram; It is an amount of that precision takes by weighing the clenbuterol hydrochloride reference substance in addition, also quantitatively is diluted to the solution that contains 20 μ g clenbuterol hydrochlorides among every 1ml approximately with 0.1mol/L HCl dissolving, as reference substance solution, measures with method.By the content of external standard method, should be the 90.0-110.0% of labelled amount with the calculated by peak area clenbuterol hydrochloride.
The determination of related substances method: get these article, remove slow-released part, porphyrize, precision takes by weighing in right amount, adds the mobile phase dissolving and quantitatively dilutes the solution of processing hydrochloric clenbuterol 100 μ g among every 1ml, as need testing solution.Precision is measured 1ml, puts in the 100ml measuring bottle, is diluted to scale with mobile phase, shakes up, as contrast solution.According to chromatographic condition under the assay item, precision is measured contrast solution 20 μ l and is injected chromatograph of liquid, regulates instrumental sensitivity, makes the peak height of main constituent chromatographic peak be about 20% of monitor full scale.Precision is measured need testing solution and each 20 μ l of contrast solution; According to chromatographic condition under the assay item; Inject chromatograph of liquid respectively; The record chromatogram is to 3 times of main composition retention time, in the need testing solution chromatogram if any impurity peaks, each impurity peak area with must not be greater than 2 times (2.0%) of contrast solution main peak area.
Dissolution method: get these article; With reference to dissolution method (2010 editions two X C three therapeutic methods of traditional Chinese medicine of Chinese Pharmacopoeia), be dissolution medium with the hydrochloric acid solution 200ml of 0.1mol/L, rotating speed is that per minute 100 changes; Operation in accordance with the law; In the time of 45 minutes, get solution with 0.45 μ m membrane filtration, subsequent filtrate is as need testing solution.It is an amount of that precision takes by weighing the clenbuterol hydrochloride reference substance in addition, also quantitatively is diluted to the solution that contains 0.1 μ g among every 1ml approximately with 0.1mol/L HCl dissolving, as reference substance solution.According to chromatographic condition under the assay item, get reference substance solution and need testing solution 20 μ l, inject chromatograph of liquid respectively, the record chromatogram by the medicine stripping quantity of external standard method with the calculated by peak area clenbuterol hydrochloride, should be not less than 80% of labelled amount.
Test Example 2: content assaying method, determination of related substances method and the drug release determination method of slow-released part ambroxol hydrochloride in the special sieve double-layer sustained release tablets of compound recipe ammonia bromine
Measure with reference to HPLC (two appendix V of Chinese Pharmacopoeia version in 2010 D).
Chromatographic condition and system suitability test: use octadecylsilane chemically bonded silica to be filler, (regulating pH value to 7.0 with phosphoric acid)-acetonitrile (50: 50) is a mobile phase with the 0.01mol/L ammonium dibasic phosphate solution; The detection wavelength is 248nm.Number of theoretical plate calculates by the ambroxol hydrochloride peak should be not less than 3000.
Determination: get these article, remove immediate release section, porphyrize; Precision takes by weighing in right amount, adds the mobile phase dissolving and quantitatively dilutes the solution of processing about ambroxol-hydrochloride-containing 30 μ g among every 1ml, filters; Precision is measured subsequent filtrate 20 μ l, injects chromatograph of liquid, the record chromatogram.It is an amount of that precision takes by weighing the ambroxol hydrochloride reference substance in addition, adds the solution that the mobile phase dissolving also quantitatively is diluted to about ambroxol-hydrochloride-containing 30 μ g among every 1ml, measures with method.By the content of external standard method, should be the 95.0-105.0% of labelled amount with the calculated by peak area ambroxol hydrochloride.
The determination of related substances method: get these article, remove immediate release section, porphyrize, precision takes by weighing in right amount, adds the mobile phase dissolving and quantitatively dilutes the solution of processing ambroxol-hydrochloride-containing 1mg among every 1ml, as need testing solution.All the other steps are with the determination of related substances method in the experimental example 1.
Drug release determination method: get these article,, adopt the device of dissolution method (two appendix VC of Chinese Pharmacopoeia version in 2010), (get sodium chloride 2g with the sodium chloride salt acid solution with reference to drug release determination method (2010 editions two X D first methods of Chinese Pharmacopoeia); Add water and dissolve in right amount, add hydrochloric acid 7ml, be diluted with water to 1000ml; PH value is 1.2) 1000ml is release medium, rotating speed is that per minute 50 changes, operation in accordance with the law; In the time of 1 hour, to get solution 10ml and filter, filtrating is as need testing solution (1); Changing with phosphate buffer (get potassium dihydrogen phosphate 6.805g, add 1mol/L sodium hydroxide solution 22.4ml, add water and make into 1000ml, pH value is 6.8) 1000ml immediately is release medium.Continue operation in accordance with the law, and clock continuously, in the time of 4,12 and 24 hours, get solution 5ml respectively and filter, and in time in process container, replenish release medium 5ml.Each precision is measured subsequent filtrate 2ml, puts respectively in the 10ml measuring bottle, adds release medium and is diluted to scale, shakes up, as need testing solution (2), (3) and (4).Precision is measured need testing solution 20 μ l, injects chromatograph of liquid, the record chromatogram.It is an amount of that precision takes by weighing the ambroxol hydrochloride reference substance in addition, adds the solution that the mobile phase dissolving also quantitatively is diluted to about ambroxol-hydrochloride-containing 10 μ g among every 1ml, measures with method.External standard method is with the release degree of calculated by peak area ambroxol hydrochloride, should be respectively below 10% 1,4,12,24 hour burst size, 35%-45%, more than the 60%-70% and 80%.
Test Example 3: the dissolution test of the special sieve double-layer sustained release tablets of compound recipe ammonia bromine
With the special sieve double-layer sustained release tablets of the compound recipe ammonia bromine of prescription among the embodiment 2 and prepared, be dissolution medium with 0.1mol/L HCl 500ml, per minute 100 changes, and according to the dissolution of clenbuterol hydrochloride in the method mensuration slow release layer of Test Example 1, the result sees table 1.
The clenbuterol hydrochloride dissolution determination result of the special sieve double-layer sustained release tablets of table 1 compound recipe ammonia bromine
Annotate: RSD is relative standard deviation (relative standard diviation).
It is thus clear that 45 minutes clenbuterol hydrochloride stripping of these article three lot sample article shows that all more than 80% the clenbuterol hydrochloride in the special sieve double-layer sustained release tablets of this compound recipe ammonia bromine can rapid release.
Test Example 4: the release degree test of the special sieve double-layer sustained release tablets of compound recipe ammonia bromine
With the special sieve double-layer sustained release tablets of the compound recipe ammonia bromine of prescription among the embodiment 2 and prepared, be dissolution medium with pH6.8 phosphate buffer 900ml, per minute 100 changes, and according to the release profiles of ambroxol hydrochloride in the method mensuration slow release layer of Test Example 2, the result sees table 2.
The ambroxol hydrochloride drug release determination result of the special sieve double-layer sustained release tablets of table 2 compound recipe ammonia bromine
It is thus clear that the release in 1 hour of these article three lot sample article ambroxol hydrochlorides is lower than release in 10%, 4 hour between 35%-45%, release in 12 hours is between 60%-70%, and release in 20 hours has tangible slow release effect more than 80%.
Above-mentioned dissolution shows with release degree result of the test; The special sieve double-layer sustained release tablets of compound recipe ammonia bromine of the present invention has that quick releasing formulation is rapid-action, the advantage of slow releasing preparation lasting medicine; After it can play clenbuterol hydrochloride and reaches effective blood drug concentration fast, ambroxol hydrochloride continued to keep the effect of stable effective blood drug concentration.
Test Example 5: the stability test of the special sieve double-layer sustained release tablets of compound recipe ammonia bromine
With the special sieve double-layer sustained release tablets of the compound recipe ammonia bromine of prescription among the embodiment 2 and prepared is that object carries out accelerated test, and test specimen packs with PTP aluminium foil and PVC hardboard bubble eye.Sustained-release double-layer tablet through packing carries out accelerated test under 40 ± 2 ℃ of high temperature, relative humidity RH 75 ± 5% conditions; In sampling in 1,2,3,6 month; Measure the content and the related substance of sustained-release double-layer tablet principal agent clenbuterol hydrochloride and ambroxol hydrochloride respectively according to the method for Test Example 1 and 2; And clenbuterol hydrochloride is through the release degree of 45 minutes dissolution and ambroxol hydrochloride warp 1 hour, 4 hours, 12 hours and 20 hours, and the result compares with 0 month data, and the result sees table 3 and table 4.Wherein 45 minutes dissolution of (1) clenbuterol hydrochloride warp should be not less than 80% of labelled amount, and content should be the 90.0-110.0% of labelled amount, and related substance must not be greater than 2.0%; (2) the release degree of ambroxol hydrochloride should be release in 1 hour be lower than release in 10%, 4 hour between the 35%-45%, release in 12 hours between the 60%-70%, release in 20 hours is more than 80%; Content should be the 95.0-105.0% of labelled amount, and related substance must not be greater than 2.0%.
The special sieve double-layer sustained release tablets of table 3 compound recipe ammonia bromine accelerated test clenbuterol hydrochloride immediate release section result
Annotate: related substance is not deducted solvent peak
The special sieve double-layer sustained release tablets of table 4 compound recipe ammonia bromine accelerated test ambroxol hydrochloride sustained-release partial results
It is thus clear that; After the special sieve double-layer sustained release tablets of compound recipe ammonia bromine packs with the bubble eye of PTP aluminium foil and PVC hardboard; 40 ℃ of temperature, relative humidity 75% condition held is after 6 months, content and the related substance and the quality investigation indexs such as dissolution and release degree of the clenbuterol hydrochloride immediate release section of sample and ambroxol hydrochloride sustained-release part; Compare with 0 month data, significance does not all take place change.Prove that the special sieve double-layer sustained release tablets of this compound recipe ammonia bromine is stable.
In a word, the special sieve double-layer sustained release tablets of compound recipe ammonia bromine provided by the invention good stability, and its release layer can rapid delivery of pharmaceuticals, have rapid-action, the effect of relief of symptoms rapidly; And the slow release layer Chinese medicine slowly discharges, and can reduce patient's medicining times, improves compliance.
Although the specific embodiment of the present invention has obtained detailed description, it will be understood to those of skill in the art that.According to disclosed all instructions, can carry out various modifications and replacement to those details, these change all within protection scope of the present invention.Four corner of the present invention is provided by accompanying claims and any equivalent thereof.
Claims (10)
1. slow releasing preparation; It is made up of slow-released part and immediate release section; Wherein immediate release section contains clenbuterol hydrochloride, rapid release adjuvant and other pharmaceutic adjuvant; Slow-released part contains ambroxol hydrochloride, slow-release auxiliary material and other pharmaceutic adjuvant, and said other pharmaceutic adjuvant is selected from a kind of in filler, binding agent and the lubricant or several.
2. the slow releasing preparation of claim 1, wherein to account for the percentage by weight of immediate release section be 0.004%-0.1% to clenbuterol hydrochloride; Wherein to account for the percentage by weight of slow-released part be 7%-80% to ambroxol hydrochloride.
3. the slow releasing preparation of claim 1, wherein said rapid release adjuvant are selected from a kind of in cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, starch, hydroxypropyl starch and the microcrystalline Cellulose or several.
4. the slow releasing preparation of claim 1, wherein said slow-release auxiliary material are selected from a kind of in cellulose derivative, carbomer, guar gum, chitosan, polyvinyl alcohol, sodium alginate, octadecanol, glyceryl monostearate, Compritol 888 ATO and the acrylic acid or several.
5. the slow releasing preparation of claim 1, wherein said filler is selected from calcium hydrogen phosphate, Kaolin, lactose, sucrose, mannitol, microcrystalline Cellulose, cellulose powder, winnofil, sorbitol, starch; Said binding agent is selected from methylcellulose, ethyl cellulose, hyprolose, hypromellose, polyvidone, starch; Said lubricant is selected from stearic acid, hydrogenated vegetable oil, Compritol 888 ATO, Macrogol 4000, polyethylene glycol 6000, magnesium stearate, magnesium laurylsulfate, Pulvis Talci and micropowder silica gel.
6. each slow releasing preparation of claim 1-5, it also contains a kind of in sweeting agent, coloring agent, correctives and the surfactant or several.
7. each slow releasing preparation of claim 1-6, it is a bilayer tablet.
8. the slow releasing preparation of claim 7, wherein the weight ratio of immediate release section and slow-released part is 1: 1～1: 5.
9. the method for preparing of claim 7 or 8 slow releasing preparation, it may further comprise the steps:
(1) component of immediate release section is directly mixed or through dry granulation or wet granulation, prepare said immediate release section; The component of slow-released part is directly mixed or through dry granulation or wet granulation, prepare said slow-released part;
(2) immediate release section of step (1) preparation and the powder or the granule of slow-released part are processed double-layer tablet through direct powder compression or granule tabletting.
10. each slow releasing preparation of claim 1-8 is used to prepare the purposes of treatment chronic respiratory system diseases medicine.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105326839A (en) * | 2015-11-05 | 2016-02-17 | 国药集团国瑞药业有限公司 | Medicinal composition containing ambroxol hydrochloride and application of medicinal composition |
| CN111346063A (en) * | 2020-03-13 | 2020-06-30 | 南京嘉晨医药科技有限公司 | Chewable tablet containing ambroxol hydrochloride and clenbuterol hydrochloride and preparation method thereof |
| CN115137695A (en) * | 2021-03-29 | 2022-10-04 | 成都倍特药业股份有限公司 | Ammoniumbromoterio liquid preparation and preparation method thereof |
| CN115350150A (en) * | 2022-09-23 | 2022-11-18 | 海门普适医药有限公司 | Stable oral solution of ambroxol and preparation method thereof |
| CN115531337A (en) * | 2022-10-17 | 2022-12-30 | 南京康川济医药科技有限公司 | Compound ambroxol Luo Huanshi tablet and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101084912A (en) * | 2007-07-02 | 2007-12-12 | 山东省医药工业研究所 | Compound ambroxol hydrochloride sustained-release tablet and preparation method thereof |
| CN101244049A (en) * | 2007-02-14 | 2008-08-20 | 中国科学院上海药物研究所 | Clenbuterol hydrochloride double-layer sustained-release tablet and preparation method thereof |
| CN101288658A (en) * | 2008-05-16 | 2008-10-22 | 北京正大绿洲医药科技有限公司 | Compound ambroxol sustained-release drop pills and preparation method thereof |
| CN101756947A (en) * | 2008-10-29 | 2010-06-30 | 天津金世制药有限公司 | Compound solid preparation for treating asthma |
-
2011
- 2011-05-09 CN CN2011101179320A patent/CN102772395A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101244049A (en) * | 2007-02-14 | 2008-08-20 | 中国科学院上海药物研究所 | Clenbuterol hydrochloride double-layer sustained-release tablet and preparation method thereof |
| CN101084912A (en) * | 2007-07-02 | 2007-12-12 | 山东省医药工业研究所 | Compound ambroxol hydrochloride sustained-release tablet and preparation method thereof |
| CN101288658A (en) * | 2008-05-16 | 2008-10-22 | 北京正大绿洲医药科技有限公司 | Compound ambroxol sustained-release drop pills and preparation method thereof |
| CN101756947A (en) * | 2008-10-29 | 2010-06-30 | 天津金世制药有限公司 | Compound solid preparation for treating asthma |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105326839A (en) * | 2015-11-05 | 2016-02-17 | 国药集团国瑞药业有限公司 | Medicinal composition containing ambroxol hydrochloride and application of medicinal composition |
| CN111346063A (en) * | 2020-03-13 | 2020-06-30 | 南京嘉晨医药科技有限公司 | Chewable tablet containing ambroxol hydrochloride and clenbuterol hydrochloride and preparation method thereof |
| CN115137695A (en) * | 2021-03-29 | 2022-10-04 | 成都倍特药业股份有限公司 | Ammoniumbromoterio liquid preparation and preparation method thereof |
| CN115350150A (en) * | 2022-09-23 | 2022-11-18 | 海门普适医药有限公司 | Stable oral solution of ambroxol and preparation method thereof |
| CN115531337A (en) * | 2022-10-17 | 2022-12-30 | 南京康川济医药科技有限公司 | Compound ambroxol Luo Huanshi tablet and preparation method thereof |
| CN115531337B (en) * | 2022-10-17 | 2024-01-26 | 南京康川济医药科技有限公司 | Compound ambroxol sustained release tablet and preparation method thereof |
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