CN108379588A - 托吡酯组合物 - Google Patents
托吡酯组合物 Download PDFInfo
- Publication number
- CN108379588A CN108379588A CN201810177730.7A CN201810177730A CN108379588A CN 108379588 A CN108379588 A CN 108379588A CN 201810177730 A CN201810177730 A CN 201810177730A CN 108379588 A CN108379588 A CN 108379588A
- Authority
- CN
- China
- Prior art keywords
- sodium
- topiramate
- equivalent
- alkaline
- composition described
- 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
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- KJADKKWYZYXHBB-XBWDGYHZSA-N Topiramic acid Chemical compound C1O[C@@]2(COS(N)(=O)=O)OC(C)(C)O[C@H]2[C@@H]2OC(C)(C)O[C@@H]21 KJADKKWYZYXHBB-XBWDGYHZSA-N 0.000 title claims abstract description 93
- 229960004394 topiramate Drugs 0.000 title claims abstract description 90
- 239000000203 mixture Substances 0.000 title claims abstract description 47
- 239000003381 stabilizer Substances 0.000 claims abstract description 62
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims abstract description 19
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000007864 aqueous solution Substances 0.000 claims abstract description 7
- 239000000725 suspension Substances 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 6
- 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 44
- 239000011734 sodium Substances 0.000 claims description 44
- 229910052708 sodium Inorganic materials 0.000 claims description 44
- CPLXHLVBOLITMK-UHFFFAOYSA-N Magnesium oxide Chemical compound [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims description 40
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical group [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 34
- 239000004299 sodium benzoate Substances 0.000 claims description 34
- 235000010234 sodium benzoate Nutrition 0.000 claims description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 34
- 239000001509 sodium citrate Substances 0.000 claims description 22
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical group O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 22
- 235000011083 sodium citrates Nutrition 0.000 claims description 22
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 21
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 claims description 16
- -1 organic acid alkali metal Chemical class 0.000 claims description 15
- 239000000843 powder Substances 0.000 claims description 15
- 239000000395 magnesium oxide Substances 0.000 claims description 12
- 235000012245 magnesium oxide Nutrition 0.000 claims description 12
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 8
- 239000002775 capsule Substances 0.000 claims description 8
- 239000011787 zinc oxide Substances 0.000 claims description 8
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical group [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 claims description 6
- 239000001433 sodium tartrate Substances 0.000 claims description 6
- 229960002167 sodium tartrate Drugs 0.000 claims description 6
- 235000011004 sodium tartrates Nutrition 0.000 claims description 6
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical group [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 239000001632 sodium acetate Substances 0.000 claims description 5
- 235000017281 sodium acetate Nutrition 0.000 claims description 5
- 229940095064 tartrate Drugs 0.000 claims description 5
- 239000000853 adhesive Substances 0.000 claims description 4
- 230000001070 adhesive effect Effects 0.000 claims description 4
- 229910000287 alkaline earth metal oxide Inorganic materials 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 239000007884 disintegrant Substances 0.000 claims description 4
- 239000008187 granular material Substances 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- 150000001447 alkali salts Chemical class 0.000 claims description 3
- 230000021523 carboxylation Effects 0.000 claims description 3
- 238000006473 carboxylation reaction Methods 0.000 claims description 3
- CJCPHVRHJKYIJC-UHFFFAOYSA-N methyl 2-hydroxybenzoate;sodium Chemical compound [Na].COC(=O)C1=CC=CC=C1O CJCPHVRHJKYIJC-UHFFFAOYSA-N 0.000 claims description 3
- 235000021317 phosphate Nutrition 0.000 claims description 3
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 3
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 claims description 3
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 3
- 229960003415 propylparaben Drugs 0.000 claims description 3
- 229960005480 sodium caprylate Drugs 0.000 claims description 3
- BYKRNSHANADUFY-UHFFFAOYSA-M sodium octanoate Chemical compound [Na+].CCCCCCCC([O-])=O BYKRNSHANADUFY-UHFFFAOYSA-M 0.000 claims description 3
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 claims description 2
- 239000001639 calcium acetate Substances 0.000 claims description 2
- 235000011092 calcium acetate Nutrition 0.000 claims description 2
- 229960005147 calcium acetate Drugs 0.000 claims description 2
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000388 diammonium phosphate Inorganic materials 0.000 claims description 2
- 235000019838 diammonium phosphate Nutrition 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims description 2
- 229940095060 magnesium tartrate Drugs 0.000 claims description 2
- MUZDLCBWNVUYIR-ZVGUSBNCSA-L magnesium;(2r,3r)-2,3-dihydroxybutanedioate Chemical compound [Mg+2].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O MUZDLCBWNVUYIR-ZVGUSBNCSA-L 0.000 claims description 2
- 235000011056 potassium acetate Nutrition 0.000 claims description 2
- 229960004109 potassium acetate Drugs 0.000 claims description 2
- KYKNRZGSIGMXFH-ZVGUSBNCSA-M potassium bitartrate Chemical compound [K+].OC(=O)[C@H](O)[C@@H](O)C([O-])=O KYKNRZGSIGMXFH-ZVGUSBNCSA-M 0.000 claims description 2
- 239000001508 potassium citrate Substances 0.000 claims description 2
- 229960002635 potassium citrate Drugs 0.000 claims description 2
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 claims description 2
- 235000011082 potassium citrates Nutrition 0.000 claims description 2
- 239000001472 potassium tartrate Substances 0.000 claims description 2
- 229940111695 potassium tartrate Drugs 0.000 claims description 2
- 235000011005 potassium tartrates Nutrition 0.000 claims description 2
- 229960004249 sodium acetate Drugs 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- WGIWBXUNRXCYRA-UHFFFAOYSA-H trizinc;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [Zn+2].[Zn+2].[Zn+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O WGIWBXUNRXCYRA-UHFFFAOYSA-H 0.000 claims description 2
- 239000011746 zinc citrate Substances 0.000 claims description 2
- 235000006076 zinc citrate Nutrition 0.000 claims description 2
- 229940068475 zinc citrate Drugs 0.000 claims description 2
- VRGNUPCISFMPEM-ZVGUSBNCSA-L zinc;(2r,3r)-2,3-dihydroxybutanedioate Chemical compound [Zn+2].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O VRGNUPCISFMPEM-ZVGUSBNCSA-L 0.000 claims description 2
- 240000004307 Citrus medica Species 0.000 claims 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims 1
- 238000005461 lubrication Methods 0.000 claims 1
- 235000015424 sodium Nutrition 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 39
- 239000005022 packaging material Substances 0.000 abstract description 3
- 229920000881 Modified starch Polymers 0.000 description 39
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 38
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 38
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 38
- 239000008108 microcrystalline cellulose Substances 0.000 description 38
- 229940016286 microcrystalline cellulose Drugs 0.000 description 38
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 37
- 239000008101 lactose Substances 0.000 description 37
- 229920002472 Starch Polymers 0.000 description 35
- 229940032147 starch Drugs 0.000 description 35
- 239000008107 starch Substances 0.000 description 35
- 235000019698 starch Nutrition 0.000 description 35
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 33
- 229910000019 calcium carbonate Inorganic materials 0.000 description 19
- 239000011122 softwood Substances 0.000 description 18
- 229960001375 lactose Drugs 0.000 description 17
- 230000015556 catabolic process Effects 0.000 description 16
- 238000006731 degradation reaction Methods 0.000 description 16
- 235000017557 sodium bicarbonate Nutrition 0.000 description 16
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 16
- 229940097017 topiramate 100 mg Drugs 0.000 description 16
- 239000012535 impurity Substances 0.000 description 14
- LUVOJBWJNHWVNG-UHFFFAOYSA-N [Na].[Na].[Na].OC(=O)CC(O)(C(O)=O)CC(O)=O Chemical compound [Na].[Na].[Na].OC(=O)CC(O)(C(O)=O)CC(O)=O LUVOJBWJNHWVNG-UHFFFAOYSA-N 0.000 description 12
- 239000002245 particle Substances 0.000 description 12
- 238000004090 dissolution Methods 0.000 description 11
- 239000008213 purified water Substances 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical group NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 9
- 238000005303 weighing Methods 0.000 description 8
- 239000011248 coating agent Substances 0.000 description 7
- 238000000576 coating method Methods 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 7
- 238000004806 packaging method and process Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 230000006641 stabilisation Effects 0.000 description 6
- 238000011105 stabilization Methods 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 3
- 229920001903 high density polyethylene Polymers 0.000 description 3
- 239000004700 high-density polyethylene Substances 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000011812 mixed powder Substances 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000011975 tartaric acid Substances 0.000 description 3
- 235000002906 tartaric acid Nutrition 0.000 description 3
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 239000004368 Modified starch Substances 0.000 description 2
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
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- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 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 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 239000004411 aluminium Substances 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
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- 239000002585 base Substances 0.000 description 2
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- 229940095672 calcium sulfate Drugs 0.000 description 2
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- 238000005469 granulation Methods 0.000 description 2
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- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
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- 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 description 1
- OQUFOZNPBIIJTN-UHFFFAOYSA-N 2-hydroxypropane-1,2,3-tricarboxylic acid;sodium Chemical compound [Na].OC(=O)CC(O)(C(O)=O)CC(O)=O OQUFOZNPBIIJTN-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical class OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical class OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
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- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明涉及以特殊物理形状为特征的医用配制品,具体涉及含有托吡酯的组合物及其制备方法。本发明的托吡酯组合物,包括托吡酯和碱性稳定剂,碱性稳定剂的水溶液或混悬液的pH值为7.0~10,碱性稳定剂可溶于水或其与硫酸反应生成的硫酸盐可溶于水。本发明的组合物可以提高托吡酯的稳定性,可以耐受更高水分,使得组合物的包装材料可选范围扩大;也不影响组合物制备片剂的硬度。
Description
技术领域
本发明涉及以特殊物理形状为特征的医用配制品,还涉及含有有机有效成分的医药配制品,该有机有效成分用于治疗心血管疾病。更具体涉及含有托吡酯的组合物及其制备方法。
背景技术
托吡酯是一个由氨基磺酸酯取代单糖的新型抗癫痫药物。在对体外培养的神经细胞元进行电生理和生化研究中发现托吡酯的抗癫痫作用有三个机制:1.托吡酯可阻断神经元持续去极化导致的反复电位发放,此作用与使用托吡酯后的时间密切相关,表明托吡酯可以阻断钠通道;2.托吡酯可以增加γ-氨基丁酸(GABA)激活GABAA受体的频率,加强氯离子内流,表明托吡酯可增强抑制性中枢神经递质的作用;3.托吡酯可降低谷氨酸AMPA受体的活性,表明托吡酯可降低兴奋性中枢神经递质的作用。
托吡酯(topiramate)化学名为:2,3:4,5-双-O-(1-甲基亚乙基)-β-D-吡喃果糖氨基磺酸,分子式C12H21NO8S,结构式如下
Janssen公司研制的托吡酯片已由西安杨森于2005年开始在中国地产化,商品名为:妥泰(Topamax),规格25mg和100mg。原研的托吡酯(Topamax)制剂包括托吡酯片、托吡酯胶囊、托吡酯分散胶囊(sprinkle capsule),其中托吡酯片含有的辅料包括乳糖、预胶化淀粉、羧甲淀粉钠等;托吡酯分散胶囊其实采用空白丸芯(蔗糖、淀粉)上药,然后再包裹醋酸纤维素衣膜,服用时将药物颗粒分散在食物或饮料中,避免略带苦味的药物快速释放影响儿童服药,对儿童有较好的顺应性。同时外包衣膜对药物稳定性也有保护作用。
然而由于各种原因,即使专利过期多年,十余年来尚无仿制药上市。
但是托吡酯对湿热不稳定,会发生降解。托吡酯片剂的降解容易通过物理外观的变化(片剂颜色变为棕色、黑点或黑色)和通过形成的杂质氨基磺酸盐、硫酸盐来检测,所述硫酸盐可以通过本领域普通技术人员已知的标准技术容易地检测到(李继, 李霞, 罗晶,等. 离子色谱法测定托吡酯原药中氨基磺酸盐和硫酸盐[J]. 中国医药工业杂志, 2015,46(2):197-199.)。另外的指标如有关物质(主要为杂质A,2,3,4,5-双-O-(1-甲基亚乙基)-β-D-吡喃果糖)参考托吡酯片国家药品标准(WS1-(X-070)-2006Z)测定。
为了保持片剂质量,因此托吡酯片剂(西安杨森)已经被包装到含有干燥剂的高密度聚乙烯(HDPE)瓶和包含干燥剂的泡罩包装中。经过一段时间的稳定性测试表明,这种包装中的片剂已经在各种温度,湿度和光照条件下保存。然而,泡罩包装比目前销售的包装中使用的HDPE瓶具有优势,其重量轻,储存更方便,快速取用,取用不影响其他未取用片剂,因此是托吡酯片剂的优选包装形式。
普通的泡罩包装为铝-塑包装,鱼泡眼采用聚氯乙烯(PVC)材料,其对水汽具有一定渗透性,不能充分保护对水分敏感的片剂。因此制造商和包装者通过提供除了片剂腔以外的其他材料(例如干燥剂)的空腔来提高泡罩包装的稳定性能。例如,EP0466068A描述了一种泡罩包装,其中每个药片腔与一个干燥剂腔连接。类似地,FR 2593152A描述了一种泡罩包装,其中多个片剂腔室与一个干燥剂腔室连接。加入干燥剂会增加成本,有可能造成干燥剂误服的安全事件。
WO0189445A公开了一种托吡酯片的稳定包装,采用铝-铝泡罩作为内包材,以避免采用高密度聚乙烯塑料瓶装需加入干燥剂的缺点,但是即便如此,也需要高温干燥包衣后的片剂以控制片剂的水分不大于1.4%,当片剂水分为1.8%时,在40℃/75% RH下 5个月时片剂即不合格。过度干燥包衣后片剂增加工序和能耗,铝铝泡罩包装材料成本增加,包装速率也较慢,影响生产成本。
WO2006/097946公开了含有重量比为5%-35%托吡酯和25%-70%喷雾干燥甘露醇颗粒的托吡酯片剂,该片剂通过直接压片法制备,此方法制备的片剂容易出现裂片现象、含量均匀度差。
CN103417501A公开了一种含有预胶化淀粉的托吡酯组合物,采用干法制粒制备,以改善含量均匀性、制粒粘结性,并提高其稳定些。
CN105326814A公开了托吡酯缓释制剂及其制备方法,缓释颗粒包括托吡酯、稳定剂、缓释包衣材料等,采用流化床制粒和包衣。稳定剂选自氢氧化钙、碳酸钙、碳酸氢钠、碳酸镁、葡甲胺、硅酸铝镁。这些稳定剂性质差异较大,无规律可循,实施例采用的仅为碳酸钙,检测结果仅为有关物质,其他如性状、硫酸盐、氨基磺酸盐、对片剂硬度的影响等指标并无测试。
因此现有技术尝试采用控制水分、控制包装形式、制备工艺、以及加入碳酸钙等来促使托吡酯稳定,多数未有全面的质量测试对比。
发明内容
本发明所要解决的技术问题是,提供一种稳定的托吡酯组合物。同时提供一种组合物的制备方法。还提供该组合物在制备各种固体制剂中的用途。
托吡酯组合物,包括托吡酯和碱性稳定剂,碱性稳定剂的水溶液或混悬液的pH值为7.0~10.0,碱性稳定剂可溶于水或其与硫酸反应生成的硫酸盐可溶于水。碱性稳定剂可溶于水或其与硫酸反应生成的硫酸盐可溶于水的定义是按照中国药典规定属于略溶以上,即溶解度不小于1g/100ml,包括略溶、溶解、易溶、极易溶解。
pH值太高,使托吡酯发生碱降解。
碱性稳定剂有溶于水,不溶于水,测量其水溶液或混悬液的pH值,混悬液可采用直接测定或滤过后测定。碱性稳定剂由于本身是弱碱,不同厂家和批次的产品,其水溶液或混悬液pH有变化。默认的pH为中国药典规定浓度下限度范围的中值。
中值计算举例为,磷酸氢二钠,收载于中国药典2015年版四部,测定方法为:取本品1.0g,加水20ml溶解后,依法测定(通则0631),pH值应为9.0〜9. 4。此时其重量比浓度为5%,其pH值定义为下限9.0与上限9.4的中值9.2。
碱性稳定剂不同浓度的pH值不同,一般浓度范围为1%-10%(重量比),以标准中规定的浓度为准,标准优选顺序为中国药典、他国药典、其他公开标准。
托吡酯组合物,碱性稳定剂的水溶液或混悬液的pH值优选为7.5~9.0,最优选7.5~8.5。
表1 代表性碱性稳定剂的pH值
名称 | 阳离子 | 价态 | pH值中值 | pH值范围(浓度) |
辛酸钠 | 钠 | 1 | 9.2 | 8.0-10.5 |
苯甲酸钠 | 钠 | 1 | 8.5 | 8-9 |
枸橼酸钠 | 钠 | 3 | 8.5 | <10(5%) |
轻质氧化镁 | —— | 2 | 9 | 8-10 |
氧化锌 | —— | 2 | 8.5 | 8-9(10%) |
酒石酸钠 | 钠 | 2 | 8 | 7-9 |
羟苯丙酯钠 | 钠 | 1 | 10 | 9.5-10.5 |
羟苯甲酯钠 | 钠 | 1 | 10 | 9.5-10.5 |
硼砂 | 钠 | 2 | 9.3 | 9.0-9.6 |
羧甲纤维素钠 | 钠 | 1 | 7.2 | 6.5-8.0(1%) |
羧甲纤维素钙 | 钙 | 2 | 7.5 | <9 |
羧甲淀粉钠 | 钠 | 1 | 6 | 5.5-7.5 |
碳酸氢钠 | 钠 | 1 | 8 | <8.6(1%) |
碳酸氢钾 | 钾 | 1 | 8 | <8.6(1%) |
碳酸钠 | 钠 | 2 | 11.6 | —— |
醋酸钠 | 钠 | 1 | 8.3 | 7.5-9.2(3%) |
磷酸氢二钠 | 钠 | 2 | 9.2 | 9.0-9.4(5%) |
磷酸氢二钾 | 钾 | 2 | 9.0 | 8.5-9.6(5%) |
磷酸氢二铵 | 铵 | 2 | 7.8 | 7.6-8.2 |
葡甲胺 | —— | —— | 11 | 11(1%) |
羧甲纤维素钠、羧甲淀粉钠、碳酸钠pH值范围就不在7.5~10.0范围内;辛酸钠、羟苯丙酯钠、羟苯甲酯钠、硼砂、磷酸氢二钠pH值范围就不在7.5~9范围内。
除了关注碱性稳定剂的pH值,还要关注其热稳定性,比如碳酸氢盐在受热情况下,生成碳酸盐,使得pH值升高,导致托吡酯稳定性降低,如碳酸氢钠在50℃开始分解,对于温度超过60℃不再是优选。本发明一个实施例说明了这种情况。
本身受热产气或者与酸反应产气的碱性稳定剂,也有可能使组合物制备的片剂硬度下降,因此,如果组合物最终制剂为片剂,则不优选受热产气或者与酸反应产气的碱性稳定剂;作为其他如颗粒剂、胶囊剂,则并无禁忌。
碱性稳定剂选自碱土金属氧化物、有机酸碱金属或碱土金属盐、无机酸碱金属盐,碱土金属氧化物选自氧化镁、氧化锌;有机酸碱金属或碱土金属盐选自三价枸橼酸盐、二价酒石酸盐、C1-C8一元羧酸盐、苯甲酸盐、对羟基苯甲酸酯盐;无机酸盐选自二价磷酸盐。
氧化镁在中国药典的标准名称为轻质氧化镁,在本发明叙述中,两者为相同物质。
枸橼酸为三元酸,三价枸橼酸盐指3羧基均成盐;酒石酸为二元酸,二价酒石酸盐指酒石酸的2个羧酸均成盐;C1-C8一元羧酸为甲酸、乙酸(醋酸)、辛酸等。
三价枸橼酸盐优选枸橼酸钠、枸橼酸钾、枸橼酸镁和枸橼酸锌;二价酒石酸盐选自酒石酸钠、酒石酸钾、酒石酸镁和酒石酸锌;C1-C8一元羧酸盐选自醋酸钠、醋酸钾、醋酸钙、辛酸钠;苯甲酸盐为苯甲酸钠;对羟基苯甲酸酯盐选自羟苯丙酯钠、羟苯甲酯钠;二价磷酸盐选自磷酸氢二钠、磷酸氢二钾、磷酸氢二铵。
碱性稳定剂优选氧化镁、氧化锌、磷酸氢二钠、枸橼酸钠、苯甲酸钠、酒石酸钠、醋酸钠。
优选的碱性稳定剂与托吡酯的摩尔比为2%~20%。
优选的碱性稳定剂与托吡酯的摩尔比为5%~15%。
为了使托吡酯组合用于制备各种制剂,托吡酯组合物,其还包含一种或多种填充剂、粘合剂、崩解剂或润滑剂。
合适的填充剂包括,例如:乳糖、蔗糖、淀粉、改性淀粉、甘露醇、山梨醇、无机盐(如磷酸氢钙)、纤维素衍生物(例如微晶纤维素、纤维素)、 硫酸钙、木糖醇和乳糖醇。
合适的粘合剂包括例如:聚乙烯吡咯烷酮、乳糖、淀粉、改性淀粉、糖、阿拉伯树胶、黄芪胶、瓜尔胶、果胶、蜡粘合剂、微晶纤维素、甲基纤维素、羧甲基纤维素、羟丙基甲基纤维素、羟乙基纤维素、羟丙基纤维素、明胶和海藻酸钠。
合适的崩解剂包括例如:交联羧甲基纤维素钠、交联聚维酮、、淀粉羟基乙酸钠、玉米淀粉、微晶纤维素、羟丙基甲基纤维素和羟丙基纤维素。
合适的润滑剂包括例如:硬脂酸镁、硬脂酸、棕榈酸、硬脂酸钙、滑石、巴西棕榈蜡、氢化植物油、矿物油、聚乙二醇和硬脂富马酸钠。
还可以加入其它助流剂二氧化硅。
托吡酯组合物的方法,包括把碱性稳定剂粉碎成细粉加入到组合物中的步骤或溶于水后加入到组合物中后干燥的步骤。细粉指通过100目筛的比例不少于95%。
托吡酯组合物的应用,用于制备胶囊剂、片剂、颗粒剂等固体制剂。
可以在片剂上包衣。常用包衣材料为胃溶型包衣预混剂。
本发明的组合物可以提高托吡酯的稳定性,可以耐受更高水分,使得组合物的包装材料可选范围扩大;也不影响组合物制备片剂的硬度。
具体实施方式
实施例中水分采用水分测定仪(奥豪斯,MB-35)测定(80℃,AUTO);硬度采用片剂脆碎度硬度测定仪(上海黄海药检仪器有限公司 CJY-2C型)测定。
实施例1——碱性稳定剂比较
制备方法
托吡酯组合物的制备方法主要步骤包括:
(1)将包括托吡酯、微晶纤维素、乳糖、预胶化淀粉、碱性稳定剂、崩解剂的原辅料粉碎过筛,混合均匀,制得混合粉。
(2)向混合粉中加入纯化水捏合制软材,过24目筛制得湿颗粒。
(3)湿颗粒经干燥,过24目筛整粒,制得干颗粒。
(4)干颗粒、助流剂、润滑剂混合均匀后压片、包衣。
碱性稳定剂样品处方及制备方法
表2
用量(每片份) | 处方1 | 处方2 | 处方3 | 处方4 |
托吡酯 | 100mg | 100mg | 100mg | 100mg |
微晶纤维素 | 70mg | 64.7mg | 59.4mg | 54.2mg |
乳糖 | 123.4mg | 123.4mg | 123.4mg | 123.4mg |
磷酸氢二钠 | 0mg | 5.3mg(5%当量) | 10.6mg(10%当量) | 15.8mg(15%当量) |
预胶化淀粉 | 15mg | 15mg | 15mg | 15mg |
羧甲淀粉钠 | 9.6mg | 9.6mg | 9.6mg | 9.6mg |
制备方法:称取处方量的托吡酯、微晶纤维素、乳糖、预胶化淀粉、羧甲淀粉钠混合均匀,加入适量纯化水,捏合制软材,过24目筛制湿颗粒,60℃常压干燥至水分1.5~2.0%和≤1%。
表3
用量(每片份) | 处方5 | 处方6 | 处方7 |
托吡酯 | 100mg | 100mg | 100mg |
微晶纤维素 | 65.7mg | 61.3mg | 57mg |
乳糖 | 123.4mg | 123.4mg | 123.4mg |
枸橼酸钠 | 4.3mg(5%当量) | 8.7mg(10%当量) | 13.0mg(15%当量) |
预胶化淀粉 | 15mg | 15mg | 15mg |
羧甲淀粉钠 | 9.6mg | 9.6mg | 9.6mg |
制备方法:称取处方量的托吡酯、微晶纤维素、乳糖、枸橼酸钠、预胶化淀粉、羧甲淀粉钠混合均匀,加入适量纯化水,捏合制软材,过24目筛制湿颗粒,60℃常压干燥至水分1.5~2.0%和≤1%。
表4
用量(每片份) | 处方8 | 处方9 | 处方10 |
托吡酯 | 100mg | 100mg | 100mg |
微晶纤维素 | 69.4mg | 68.8mg | 68.2mg |
乳糖 | 123.4mg | 123.4mg | 123.4mg |
轻质氧化镁 | 0.6mg(5%当量) | 1.2mg(10%当量) | 1.8mg(15%当量) |
预胶化淀粉 | 15mg | 15mg | 15mg |
羧甲淀粉钠 | 9.6mg | 9.6mg | 9.6mg |
制备方法:称取处方量的托吡酯、微晶纤维素、乳糖、轻质氧化镁、预胶化淀粉、羧甲淀粉钠混合均匀,加入适量纯化水,捏合制软材,过24目筛制湿颗粒,60℃常压干燥至水分1.5~2.0%和≤1%。
表5
用量(每片份) | 处方11 | 处方12 | 处方13 |
托吡酯 | 100mg | 100mg | 100mg |
微晶纤维素 | 67.9mg | 65.8mg | 63.6mg |
乳糖 | 123.4mg | 123.4mg | 123.4mg |
苯甲酸钠 | 2.1mg(5%当量) | 4.2mg(10%当量) | 6.4mg(15%当量) |
预胶化淀粉 | 15mg | 15mg | 15mg |
羧甲淀粉钠 | 9.6mg | 9.6mg | 9.6mg |
制备方法:称取处方量的托吡酯、微晶纤维素、乳糖、苯甲酸钠、预胶化淀粉、羧甲淀粉钠混合均匀,加入适量纯化水,捏合制软材,过24目筛制湿颗粒,60℃常压干燥至水分1.5~2.0%和≤1%。
表6
用量(每片份) | 处方14 | 处方15 | 处方16 |
托吡酯 | 100mg | 100mg | 100mg |
微晶纤维素 | 68.8mg | 67.5mg | 66.3mg |
乳糖 | 123.4mg | 123.4mg | 123.4mg |
碳酸氢钠 | 1.2mg(5%当量) | 2.5mg(10%当量) | 3.7mg(15%当量) |
预胶化淀粉 | 15mg | 15mg | 15mg |
羧甲淀粉钠 | 9.6mg | 9.6mg | 9.6mg |
制备方法:称取处方量的托吡酯、微晶纤维素、乳糖、碳酸氢钠、预胶化淀粉、羧甲淀粉钠混合均匀,加入适量纯化水,捏合制软材,过24目筛制湿颗粒,60℃常压干燥至水分1.5~2.0%和≤1%。
表7
用量(每片份) | 处方17 | 处方18 | 处方19 | 用量(每片份) |
托吡酯 | 100mg | 100mg | 100mg | 托吡酯 |
微晶纤维素 | 68.5mg | 67mg | 64mg | 微晶纤维素 |
乳糖 | 123.4mg | 123.4mg | 123.4mg | 乳糖 |
碳酸钙 | 1.5mg(5%当量) | 3mg(10%当量) | 6mg(20%当量) | 碳酸钙 |
预胶化淀粉 | 15mg | 15mg | 15mg | 预胶化淀粉 |
羧甲淀粉钠 | 9.6mg | 9.6mg | 9.6mg | 羧甲淀粉钠 |
制备方法:称取处方量的托吡酯、微晶纤维素、乳糖、碳酸钙、预胶化淀粉、羧甲淀粉钠混合均匀,加入适量纯化水,捏合制软材,过24目筛制湿颗粒,60℃常压干燥至水分1.5~2.0%和≤1%。
稳定性放置方法
取本实施例中处方1~19制备的不同水分样品颗粒各约1.5g,分别置20ml西林瓶中密封,于不同温湿度条件下放置(90℃下24h、60℃下28天,40℃* RH 75%下6个月),考察稳定性。检查硫酸盐、氨基磺酸盐及其降解杂质总量(硫酸盐与氨基磺酸盐之和)等。
稳定剂优化结果
表8 稳定剂优化结果-90℃ 24h-1
初始水分 % | 碱性稳定剂种类及用量 | 硫酸盐 % | 氨基磺酸 % | 降解杂质总量% |
1.66 | 不含碱性稳定剂 | 18.12 | 0.49 | 18.61 |
2.04 | 5%当量磷酸氢二钠 | 5.27 | 0.54 | 5.81 |
1.87 | 10%当量磷酸氢二钠 | 5.25 | 0.98 | 6.23 |
1.50 | 15%当量磷酸氢二钠 | 5.11 | 1.30 | 6.41 |
1.78 | 5%当量枸橼酸三钠 | 5.03 | 0.51 | 5.64 |
1.97 | 10%当量枸橼酸三钠 | 4.94 | 0.47 | 5.51 |
1.82 | 15%当量枸橼酸三钠 | 4.97 | 0.45 | 5.72 |
1.98 | 5%当量轻质氧化镁 | 6.41 | 0.64 | 7.05 |
1.88 | 10%当量轻质氧化镁 | 5.46 | 0.73 | 6.19 |
1.74 | 15%当量轻质氧化镁 | 5.31 | 0.94 | 6.25 |
1.89 | 5%当量苯甲酸钠 | 5.38 | 0.41 | 5.79 |
1.95 | 10%当量苯甲酸钠 | 5.18 | 0.40 | 5.58 |
1.59 | 15%当量苯甲酸钠 | 4.26 | 0.47 | 4.97 |
1.58 | 5%当量碳酸氢钠 | 6.04 | 0.64 | 6.68 |
1.97 | 10%当量碳酸氢钠 | 5.04 | 1.27 | 6.31 |
1.85 | 15%当量碳酸氢钠 | 3.91 | 2.09 | 6.00 |
1.86 | 5%当量碳酸钙 | 12.17 | 0.52 | 12.69 |
1.64 | 10%当量碳酸钙 | 11.65. | 0.55 | 12.20 |
1.72 | 20%当量碳酸钙 | 12.22 | 0.46 | 12.68 |
表9 稳定剂优化结果-90℃ 24h-2
初始水分 % | 碱性稳定剂种类及用量 | 硫酸盐 % | 氨基磺酸 % | 降解杂质总量% |
≤1 | 不含碱性稳定剂 | 7.10 | 0.24 | 7.34 |
≤1 | 5%当量磷酸氢二钠 | 6.88 | 0.42 | 7.30 |
≤1 | 10%当量磷酸氢二钠 | 7.75 | 0.86 | 8.61 |
≤1 | 15%当量磷酸氢二钠 | 7.56 | 1.27 | 8.83 |
≤1 | 5%当量枸橼酸三钠 | 6.85 | 0.34 | 7.19 |
≤1 | 10%当量枸橼酸三钠 | 7.08 | 0.36 | 7.44 |
≤1 | 15%当量枸橼酸三钠 | 6.79 | 0.21 | 7.00 |
≤1 | 5%当量轻质氧化镁 | 6.32 | 0.19 | 6.51 |
≤1 | 10%当量轻质氧化镁 | 6.49 | 0.23 | 6.72 |
≤1 | 15%当量轻质氧化镁 | 5.73 | 0.29 | 6.02 |
≤1 | 5%当量苯甲酸钠 | 5.96 | 0.17 | 6.13 |
≤1 | 10%当量苯甲酸钠 | 5.79 | 0.16 | 5.95 |
≤1 | 15%当量苯甲酸钠 | 4.39 | 0.16 | 4.55 |
≤1 | 5%当量碳酸氢钠 | 6.06 | 0.32 | 6.38 |
≤1 | 10%当量碳酸氢钠 | 7.06 | 0.90 | 7.96 |
≤1 | 15%当量碳酸氢钠 | 6.59 | 0.39 | 6.98 |
≤1 | 5%当量碳酸钙 | 6.97 | 0.32 | 7.29 |
≤1 | 10%当量碳酸钙 | 6.74. | 0.25 | 6.99 |
≤1 | 20%当量碳酸钙 | 6.28 | 0.26 | 6.54 |
表10 稳定剂优化结果-60℃ 28天
水分 | 处方 | 60℃ | 14天 | 60℃ | 28天 | ||
% | 碱性稳定剂种类及用量 | 硫酸盐 % | 氨基磺酸 % | 降解杂质总量% | 硫酸盐 % | 氨基磺酸 % | 降解杂质总量% |
1.66 | 不含碱性稳定剂 | 3.58 | 0.30 | 3.88 | 18.31 | 0.53 | 18.84 |
2.04 | 5%当量磷酸氢二钠 | 1.30 | 0.55 | 1.85 | 7.05 | 0.32 | 7.37 |
1.87 | 10%当量磷酸氢二钠 | 0.39 | 0.86 | 1.25 | 6.29 | 0.76 | 7.05 |
1.50 | 15%当量磷酸氢二钠 | 0.09 | 0.96 | 1.05 | 4.85 | 1.17 | 6.02 |
1.78 | 5%当量枸橼酸三钠 | 0.31 | 0.13 | 0.44 | 5.48 | 0.36 | 5.84 |
1.97 | 10%当量枸橼酸三钠 | 0.18 | 0.09 | 0.27 | 5.99 | 0.35 | 6.34 |
1.82 | 15%当量枸橼酸三钠 | 0.05 | 0.05 | 0.10 | 4.23 | 0.25 | 4.48 |
1.98 | 5%当量轻质氧化镁 | 0.92 | 0.36 | 1.28 | 7.04 | 0.34 | 7.38 |
1.88 | 10%当量轻质氧化镁 | 0.07 | 0.19 | 0.26 | 5.58 | 0.41 | 5.99 |
1.74 | 15%当量轻质氧化镁 | 0.06 | 0.21 | 0.27 | 6.10 | 0.52 | 6.62 |
1.89 | 5%当量苯甲酸钠 | 0.37 | 0.11 | 0.48 | 7.24 | 0.25 | 7.49 |
1.95 | 10%当量苯甲酸钠 | 0.23 | 0.10 | 0.33 | 6.84 | 0.28 | 7.12 |
1.59 | 15%当量苯甲酸钠 | 0.00 | 0.04 | 0.04 | 5.07 | 0.27 | 5.34 |
1.58 | 5%当量碳酸氢钠 | 0.50 | 0.68 | 1.18 | 6.23 | 0.41 | 6.64 |
1.97 | 10%当量碳酸氢钠 | 0.70 | 1.20 | 1.90 | 8.75 | 0.82 | 9.57 |
1.85 | 15%当量碳酸氢钠 | 0.33 | 1.89 | 2.22 | 6.25 | 1.72 | 7.97 |
1.86 | 5%当量碳酸钙 | 3.04 | 0.33 | 3.37 | 15.13 | 0.55 | 15.68 |
1.64 | 10%当量碳酸钙 | 2.88 | 0.30 | 3.18 | 14.44 | 0.45 | 14.89 |
1.72 | 20%当量碳酸钙 | 2.75 | 0.29 | 3.04 | 13.28 | 0.47 | 13.75 |
表11稳定剂优化结果-加速(40℃* RH 75%)6月
水分% | 碱性稳定剂种类及用量 | 硫酸盐 % | 氨基磺酸 % | 降解杂质总量% |
1.66 | 不含碱性稳定剂 | 4.87 | 0.17 | 5.04 |
2.04 | 5%当量磷酸氢二钠 | 0.43 | 0.35 | 0.78 |
1.87 | 10%当量磷酸氢二钠 | 0.07 | 0.50 | 0.57 |
1.5 | 15%当量磷酸氢二钠 | 0.00 | 0.31 | 0.31 |
1.78 | 5%当量枸橼酸三钠 | 0.09 | 0.05 | 0.14 |
1.97 | 10%当量枸橼酸三钠 | 0.04 | 0.06 | 0.10 |
1.82 | 15%当量枸橼酸三钠 | 0.00 | 0.04 | 0.04 |
1.98 | 5%当量轻质氧化镁 | 0.12 | 0.20 | 0.32 |
1.88 | 10%当量轻质氧化镁 | 0.00 | 0.14 | 0.14 |
1.74 | 15%当量轻质氧化镁 | 0.03 | 0.16 | 0.19 |
1.89 | 5%当量苯甲酸钠 | 0.43 | 0.11 | 0.54 |
1.95 | 10%当量苯甲酸钠 | 0.20 | 0.07 | 0.27 |
1.59 | 15%当量苯甲酸钠 | 0.01 | 0.02 | 0.03 |
1.58 | 5%当量碳酸氢钠 | 0.13 | 0.87 | 1.00 |
1.97 | 10%当量碳酸氢钠 | 0.65 | 1.54 | 2.19 |
1.85 | 15%当量碳酸氢钠 | 0.07 | 2.47 | 2.54 |
结果表明
所有含碱性稳定剂的处方,降解杂质总量小于未加稳定剂处方,尤其降低硫酸盐。即使水分更高,其稳定性更高,表明加入稳定剂可以提高组合物耐水性和稳定性。另外不同稳定剂,有些稳定剂加入比例越多,降解杂质越少,如磷酸氢二钠、枸橼酸钠、氧化镁、苯甲酸钠等,而碳酸氢钠的则出现异常,用量增多,硫酸盐降低,但是氨基磺酸盐则是持续增加,且增加更快,导致降解杂质总量持续增加。
90℃24小时下,含适宜稳定剂的相同处方组合物含水量较低(≤1%)与含水量较高(1.5%~2.0%)相比,降解杂质并不更优,与不加稳定剂处方基本一致,根据本发明的主要技术手段的原理可以解释如下:碱性稳定剂的碱性需要一定量的水分,用以溶解稳定剂,产生碱性液体环境,而干燥状态下不会明显发生这个过程,其稳定作用并不明显;因此碱性稳定剂的水溶性引入有利于碱性稳定作用的发生,也预示加入碱性稳定剂,含水量越高,对比不含稳定的组合物,其稳定作用越明显。因此后续稳定性只60℃及加速试验只考察了较高水分(1.5%~2.0%)组合物,结果证实了本发明的构思。
值得一提的是,碳酸钙的加入,对托吡酯的稳定性几无影响,这可能与碳酸钙的性质相关。碳酸钙本身难溶于水,不能提供有利于托吡酯稳定的容量的弱碱性微环境;碳酸钙与硫酸开始反应后生成难溶硫酸钙阻止进一步反应,降解杂质硫酸和氨基磺酸无法被消耗,导致累积,使得微环境偏酸,加速托吡酯降解,无法起到稳定剂作用;也会使物料在硫酸的脱水作用下碳化,使物料性状变灰、变黑,出现黑点或深色斑点,这也是性状变化可以直观观测托吡酯稳定性的变化。而本实施例其他稳定剂如磷酸氢二钠、枸橼酸钠、苯甲酸钠、碳酸氢钠均溶于水,有足够容量的弱碱性环境;而氧化镁虽然难溶与水,但是可与降解产物的硫酸、氨基磺酸反应,因为反应产物硫酸镁溶于水,因此也可以消耗降解产物,维持一个足够容量的弱碱性微环境,使托吡酯稳定。
因此,优选的稳定剂为溶于水的稳定剂或可与硫酸持续反应的稳定剂,比如磷酸氢二钠、枸橼酸钠、氧化镁、苯甲酸钠。而枸橼酸钠、氧化镁、苯甲酸钠、苯甲酸钠加入量为10%当量时,硫酸盐、氨基磺酸盐均未超过0.25%,更优选的稳定剂为枸橼酸钠、氧化镁、苯甲酸钠;而枸橼酸钠、苯甲酸钠加入量为5%当量时,降解杂质总量均未超过0.5%,最优选的稳定剂为枸橼酸钠、苯甲酸钠。
实施例2——优选处方与参比制剂稳定性对比
检测方法
托吡酯片在高温高湿条件下易降解产生硫酸盐和氨基磺酸盐并伴随有性状的明显变化。本实例中以性状作为指标对比优选处方样品与参比制剂样品稳定性。
如下处方均为每片份的量。
优选处方样品制备方法
(1)
托吡酯 100mg
微晶纤维素 65.7mg
乳糖 123.4mg
枸橼酸钠 4.3mg
预胶化淀粉 15mg
羧甲淀粉钠 9.6mg
制备方法:称取处方量的托吡酯、微晶纤维素、乳糖、预胶化淀粉、羧甲淀粉钠混合均匀,枸橼酸钠用适量纯化水溶解后加入混粉中,捏合制软材,过24目筛制湿颗粒,60℃常压干燥至水分≤2%。
(2)
托吡酯 100mg
微晶纤维素 61.3mg
乳糖 123.4mg
枸橼酸钠 8.7mg
预胶化淀粉 15mg
羧甲淀粉钠 9.6mg
制备方法:称取处方量的托吡酯、微晶纤维素、乳糖、预胶化淀粉、羧甲淀粉钠混合均匀,枸橼酸钠用适量纯化水溶解后加入混粉中,捏合制软材,过24目筛制湿颗粒,60℃常压干燥至水分≤2%。
(3)
托吡酯 100mg
微晶纤维素 57mg
乳糖 123.4mg
枸橼酸钠 13.0mg
预胶化淀粉 15mg
羧甲淀粉钠 9.6mg
制备方法:称取处方量的托吡酯、微晶纤维素、乳糖、预胶化淀粉、羧甲淀粉钠混合均匀,枸橼酸钠用适量纯化水溶解后加入混粉中,捏合制软材,过24目筛制湿颗粒,60℃常压干燥至水分≤2%。
(4)
托吡酯 100mg
微晶纤维素 67.9mg
乳糖 123.4mg
苯甲酸钠 2.1mg
预胶化淀粉 15mg
羧甲淀粉钠 9.6mg
制备方法:称取处方量的托吡酯、微晶纤维素、乳糖、预胶化淀粉、羧甲淀粉钠混合均匀,苯甲酸钠用适量纯化水溶解后加入混粉中,捏合制软材,过24目筛制湿颗粒,60℃常压干燥至水分≤2%。
(5)
托吡酯 100mg
微晶纤维素 65.8mg
乳糖 123.4mg
苯甲酸钠 4.2mg
预胶化淀粉 15mg
羧甲淀粉钠 9.6mg
制备方法:称取处方量的托吡酯、微晶纤维素、乳糖、预胶化淀粉、羧甲淀粉钠混合均匀,苯甲酸钠用适量纯化水溶解后加入混粉中,捏合制软材,过24目筛制湿颗粒,60℃常压干燥至水分≤2%。
(6)
托吡酯 100mg
微晶纤维素 63.6mg
乳糖 123.4mg
苯甲酸钠 6.4mg
预胶化淀粉 15mg
羧甲淀粉钠 9.6mg
制备方法:称取处方量的托吡酯、微晶纤维素、乳糖、预胶化淀粉、羧甲淀粉钠混合均匀,苯甲酸钠用适量纯化水溶解后加入混粉中,捏合制软材,过24目筛制湿颗粒,60℃常压干燥至水分≤2%。
(7)
托吡酯 100mg
微晶纤维素 66.0mg
乳糖 123.4mg
醋酸钠 4mg(10%当量)
预胶化淀粉 15mg
羧甲淀粉钠 9.6mg
制备方法:称取处方量的托吡酯、微晶纤维素、乳糖、预胶化淀粉、羧甲淀粉钠混合均匀,醋酸钠用适量纯化水溶解后加入混粉中,捏合制软材,过24目筛制湿颗粒,60℃常压干燥至水分≤2%。
(8)
托吡酯 100mg
微晶纤维素 67.6mg
乳糖 123.4mg
氧化锌 2.4mg(10%当量)
预胶化淀粉 15mg
羧甲淀粉钠 9.6mg
制备方法:称取处方量的托吡酯、微晶纤维素、乳糖、预胶化淀粉、羧甲淀粉钠、氧化锌混合均匀,将纯化水加入混粉中,捏合制软材,过24目筛制湿颗粒,60℃常压干燥至水分≤2%。
(9)
托吡酯 100mg
微晶纤维素 64.3mg
乳糖 123.4mg
酒石酸钠 5.7mg(10%当量)
预胶化淀粉 15mg
羧甲淀粉钠 9.6mg
制备方法:称取处方量的托吡酯、微晶纤维素、乳糖、预胶化淀粉、羧甲淀粉钠、酒石酸钠混合均匀,将纯化水加入混粉中,捏合制软材,过24目筛制湿颗粒,60℃常压干燥至水分≤2%。
取本实施例中(1)~(9)制备的样品颗粒各约1 g,分别置10ml西林瓶中密封,于40℃,相对湿度75%条件(加速)下考察稳定性。参比制剂(托吡酯片,100mg,西安杨森)去除外包装后相同条件下放置。
稳定性对比结果
表12稳定性对比结果
稳定剂种类及用量 | 初始水分 | 0月 | 加速4月 | 加速6月 |
性状 | 性状 | 性状 | ||
5%当量苯甲酸钠 | 1.54% | 白色,未见明显深色斑点。 | 白色,未见明显深色斑点。 | 白色,未见明显深色斑点及颗粒。 |
10%当量苯甲酸钠 | 1.56% | 白色,未见明显深色斑点。 | 白色,未见明显深色斑点。 | 类白色,未见明显深色斑点及颗粒。 |
15%当量苯甲酸钠 | 1.60% | 白色,未见明显深色斑点。 | 白色,未见明显深色斑点。 | 类白色,未见明显深色斑点及颗粒。 |
5%当量枸橼酸钠 | 1.58% | 白色,未见明显深色斑点。 | 白色,未见明显深色斑点。 | 白色,未见明显深色斑点及颗粒。 |
10%当量枸橼酸钠 | 1.76% | 白色,未见明显深色斑点。 | 白色,未见明显深色斑点。 | 类白色,未见明显深色斑点及颗粒。 |
15%当量枸橼酸钠 | 1.55% | 白色,未见明显深色斑点。 | 白色,未见明显深色斑点。 | 白色,未见明显深色斑点及颗粒。 |
10%当量醋酸钠 | 1.66% | 白色,未见明显深色斑点。 | 白色,未见明显深色斑点。 | 白色,未见明显深色斑点及颗粒。 |
10%当量氧化锌 | 1.53% | 白色,未见明显深色斑点。 | 白色,未见明显深色斑点。 | 白色,未见明显深色斑点及颗粒。 |
10%当量酒石酸钠 | 1.73% | 白色,未见明显深色斑点。 | 白色,未见明显深色斑点。 | 白色,未见明显深色斑点及颗粒。 |
参比制剂 | 1.64% | 去除衣膜显白色,未见明显深色斑点。 | 去除衣膜后片面及片子断面呈灰色,有黑色及橘黄色斑点。 | 去除衣膜后片面及片子断面呈灰色,有较多深色斑点。 |
实验结果表明优选后的处方样品加速稳定性优于参比制剂。
实施例3——片剂稳定性对比
表13
用量(每片份) | 处方31 | 处方32 |
托吡酯 | 100mg | 100mg |
微晶纤维素 | 61.3mg | 67mg |
乳糖 | 123.4mg | 123.4mg |
碱性稳定剂 | 枸橼酸钠8.7mg | 碳酸钙3mg |
预胶化淀粉 | 15mg | 15mg |
羧甲淀粉钠 | 9.6mg | 9.6mg |
胃溶型薄膜包衣预混剂 | 10mg | 10mg |
制备方法:处方31 称取处方量的托吡酯、微晶纤维素、乳糖、预胶化淀粉、羧甲淀粉钠混合均匀,枸橼酸钠用适量纯化水溶解后加入混粉中,捏合制软材,过24目筛制湿颗粒,60℃常压干燥至水分≤2%,24目筛整粒后加入处方量硬脂酸镁压制片芯,硬度约为90N。
处方32 称取处方量的托吡酯、微晶纤维素、乳糖、预胶化淀粉、羧甲淀粉钠、碳酸钙混合均匀,混粉加水捏合制软材,过24目筛制湿颗粒,60℃常压干燥至水分≤2%,24目筛整粒后加入处方量硬脂酸镁压制片芯,片剂直径9.5mm,硬度约为90N。
包衣 两处方相同
胃溶型薄膜包衣粉分散至适量纯化水后均匀喷雾覆盖片芯。包衣片干燥至水分1.5%~2.0%、1.0%~1.5%、≤1.0%后分别包装后置40℃、75%相对湿度条件下考察稳定性,同时对比市售参比制剂(托吡酯片,西安杨森)。结果见下表。
样品包装形式
单层低密度聚乙烯袋内包装,外加铝塑复合膜袋。
表14 片剂稳定性对比结果(40℃ 75%RH)
初始 | 加速3月 | 加速6月 | ||
水分 | 性状 | 性状 | 性状 | |
处方31 | 1.76% | 白色,除去衣膜后片面及片子断面呈白色,无深色斑点。平均硬度115N | 白色,除去衣膜后片面及片子断面呈白色,无深色斑点。平均硬度110N | 白色,除去衣膜后片面及片子断面呈白色,无深色斑点。平均硬度105N |
处方31 | 1.20% | 白色,除去衣膜后片面及片子断面呈白色,无深色斑点。平均硬度112N | 白色,除去衣膜后片面及片子断面呈白色,无深色斑点。平均硬度106N | 白色,除去衣膜后片面及片子断面呈白色,无深色斑点。平均硬度102N |
处方31 | 0.94% | 白色,除去衣膜后片面及片子断面呈白色,无深色斑点。平均硬度110N | 白色,除去衣膜后片面及片子断面呈白色,无深色斑点。平均硬度105N | 白色,除去衣膜后片面及片子断面呈白色,无深色斑点。平均硬度100N |
处方32 | 1.55% | 白色,除去衣膜后片面及片子断面呈白色,无深色斑点。平均硬度108N | 整体呈灰色,有褐色斑点。平均硬度90N | 整体呈浅灰色,有较多褐色斑点。平均硬度73N |
参比制剂 | 1.64% | 白色,除去衣膜后片面及片子断面呈白色,无深色斑点。平均硬度110N | 整体呈灰色,有褐色斑点。平均硬度102N | 整体呈浅灰色,有较多褐色斑点。平均硬度100N |
实验结果表明:本发明优选片剂水分在1.76%以内均稳定,而且优于参比制剂,也优于碳酸钙的片剂。含碳酸钙的片剂在加速实验过程中颜色变深,硬度有明显下降趋势,6个月由108N下降至73N,下降幅度超过30%。
Claims (10)
1.托吡酯组合物,包括托吡酯和碱性稳定剂,碱性稳定剂的水溶液或混悬液的pH值为7.0~10,碱性稳定剂可溶于水或其与硫酸反应生成的硫酸盐可溶于水。
2.权利要求1所述的托吡酯组合物,碱性稳定剂的水溶液或混悬液的pH值为7.5~9.0。
3.权利要求1所述的托吡酯组合物,碱性稳定剂选自碱土金属氧化物、有机酸碱金属或碱土金属盐、无机酸碱金属盐,碱土金属氧化物选自氧化镁、氧化锌;有机酸碱金属或碱土金属盐选自三价枸橼酸盐、二价酒石酸盐、C1-C8一元羧酸盐、苯甲酸盐、对羟基羟苯甲酸酯盐;无机酸盐选自二价磷酸盐。
4.权利要求3所述的托吡酯组合物,三价枸橼酸盐选自枸橼酸钠、枸橼酸钾、枸橼酸镁和枸橼酸锌;二价酒石酸盐选自酒石酸钠、酒石酸钾、酒石酸镁和酒石酸锌;C1-C8一元羧酸盐选自醋酸钠、醋酸钾、醋酸钙、辛酸钠;苯甲酸盐为苯甲酸钠;对羟基羟苯甲酸酯盐选自对羟苯丙酯钠、羟苯甲酯钠;二价磷酸盐选自磷酸氢二钠、磷酸氢二钾、磷酸氢二铵。
5.权利要求4所述的托吡酯组合物,碱性稳定剂选自氧化镁、氧化锌、磷酸氢二钠、枸橼酸钠、苯甲酸钠、酒石酸钠、醋酸钠。
6.权利要求1所述的托吡酯组合物,碱性稳定剂与托吡酯的摩尔比为2%~20%。
7.权利要求6所述的托吡酯组合物,碱性稳定剂与托吡酯的摩尔比为5%~15%。
8.权利要求1所述的托吡酯组合物,其还包含一种或多种填充剂、粘合剂、崩解剂或润滑剂。
9.权利要求1所述的托吡酯组合物的方法,包括把碱性稳定剂粉碎成细粉加入到组合物中的步骤或溶于水后加入到组合物中后干燥的步骤。
10.权利要求1所述的托吡酯组合物的应用,用于制备胶囊剂、片剂、颗粒剂。
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