CN1370068A - 包含苯甲酰胺衍生物作为活性成分的药物制剂 - Google Patents
包含苯甲酰胺衍生物作为活性成分的药物制剂 Download PDFInfo
- Publication number
- CN1370068A CN1370068A CN00811718A CN00811718A CN1370068A CN 1370068 A CN1370068 A CN 1370068A CN 00811718 A CN00811718 A CN 00811718A CN 00811718 A CN00811718 A CN 00811718A CN 1370068 A CN1370068 A CN 1370068A
- Authority
- CN
- China
- Prior art keywords
- pharmaceutical preparation
- sodium
- preparation
- pharmaceutical
- carbonate
- 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
- 150000003936 benzamides Chemical class 0.000 title abstract 2
- 239000004480 active ingredient Substances 0.000 title 1
- 239000008177 pharmaceutical agent Substances 0.000 title 1
- -1 organic acid salt Chemical class 0.000 claims abstract description 24
- 239000000654 additive Substances 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 239000000126 substance Substances 0.000 claims abstract description 11
- 239000007787 solid Substances 0.000 claims abstract description 9
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 45
- 238000002360 preparation method Methods 0.000 claims description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 19
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 18
- 239000007788 liquid Substances 0.000 claims description 17
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 16
- 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 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- LVTYICIALWPMFW-UHFFFAOYSA-N diisopropanolamine Chemical compound CC(O)CNCC(C)O LVTYICIALWPMFW-UHFFFAOYSA-N 0.000 claims description 14
- 229940043276 diisopropanolamine Drugs 0.000 claims description 14
- 230000000996 additive effect Effects 0.000 claims description 13
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 12
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 claims description 12
- 150000007529 inorganic bases Chemical class 0.000 claims description 12
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 claims description 11
- 239000011734 sodium Substances 0.000 claims description 11
- 229910052708 sodium Inorganic materials 0.000 claims description 11
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 10
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 10
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 10
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 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 9
- 229920002472 Starch Polymers 0.000 claims description 9
- 235000019359 magnesium stearate Nutrition 0.000 claims description 9
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 9
- 235000019698 starch Nutrition 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 235000010355 mannitol Nutrition 0.000 claims description 8
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 7
- SLINHMUFWFWBMU-UHFFFAOYSA-N Triisopropanolamine Chemical compound CC(O)CN(CC(C)O)CC(C)O SLINHMUFWFWBMU-UHFFFAOYSA-N 0.000 claims description 7
- 229910021529 ammonia Inorganic materials 0.000 claims description 7
- 239000011230 binding agent Substances 0.000 claims description 7
- 239000011248 coating agent Substances 0.000 claims description 7
- 238000000576 coating method Methods 0.000 claims description 7
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 7
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 claims description 7
- 239000000314 lubricant Substances 0.000 claims description 7
- 239000000463 material Substances 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 239000011736 potassium bicarbonate Substances 0.000 claims description 7
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 7
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 7
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- 235000017550 sodium carbonate Nutrition 0.000 claims description 7
- 239000008107 starch Substances 0.000 claims description 7
- 235000012222 talc Nutrition 0.000 claims description 7
- 239000000454 talc Substances 0.000 claims description 7
- 229910052623 talc Inorganic materials 0.000 claims description 7
- 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 6
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 6
- 239000004475 Arginine Substances 0.000 claims description 6
- RVEWUBJVAHOGKA-WOYAITHZSA-N Arginine glutamate Chemical compound OC(=O)[C@@H](N)CCC(O)=O.OC(=O)[C@@H](N)CCCNC(N)=N RVEWUBJVAHOGKA-WOYAITHZSA-N 0.000 claims description 6
- 239000004471 Glycine Substances 0.000 claims description 6
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 6
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 6
- HTAWSOSQCJAPJB-UHFFFAOYSA-H [Al+3].NCC(=O)[O-].O[Al+]O.NCC(=O)[O-].NCC(=O)[O-].NCC(=O)[O-] Chemical compound [Al+3].NCC(=O)[O-].O[Al+]O.NCC(=O)[O-].NCC(=O)[O-].NCC(=O)[O-] HTAWSOSQCJAPJB-UHFFFAOYSA-H 0.000 claims description 6
- 239000001099 ammonium carbonate Substances 0.000 claims description 6
- 235000012501 ammonium carbonate Nutrition 0.000 claims description 6
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 6
- 235000009697 arginine Nutrition 0.000 claims description 6
- AIXAANGOTKPUOY-UHFFFAOYSA-N carbachol Chemical compound [Cl-].C[N+](C)(C)CCOC(N)=O AIXAANGOTKPUOY-UHFFFAOYSA-N 0.000 claims description 6
- 229960004484 carbachol Drugs 0.000 claims description 6
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 claims description 6
- PXEDJBXQKAGXNJ-QTNFYWBSSA-L disodium L-glutamate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](N)CCC([O-])=O PXEDJBXQKAGXNJ-QTNFYWBSSA-L 0.000 claims description 6
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 6
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 6
- 235000019800 disodium phosphate Nutrition 0.000 claims description 6
- 235000013923 monosodium glutamate Nutrition 0.000 claims description 6
- 238000005453 pelletization Methods 0.000 claims description 6
- 239000002002 slurry Substances 0.000 claims description 6
- 239000001632 sodium acetate Substances 0.000 claims description 6
- 235000017281 sodium acetate Nutrition 0.000 claims description 6
- 235000010413 sodium alginate Nutrition 0.000 claims description 6
- 239000000661 sodium alginate Substances 0.000 claims description 6
- 229940005550 sodium alginate Drugs 0.000 claims description 6
- 239000001509 sodium citrate Substances 0.000 claims description 6
- 239000004320 sodium erythorbate Substances 0.000 claims description 6
- 235000010352 sodium erythorbate Nutrition 0.000 claims description 6
- 229940073490 sodium glutamate Drugs 0.000 claims description 6
- RBWSWDPRDBEWCR-RKJRWTFHSA-N sodium;(2r)-2-[(2r)-3,4-dihydroxy-5-oxo-2h-furan-2-yl]-2-hydroxyethanolate Chemical compound [Na+].[O-]C[C@@H](O)[C@H]1OC(=O)C(O)=C1O RBWSWDPRDBEWCR-RKJRWTFHSA-N 0.000 claims description 6
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 claims description 6
- 229940038773 trisodium citrate Drugs 0.000 claims description 6
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 5
- 229920000881 Modified starch Polymers 0.000 claims description 5
- 239000002202 Polyethylene glycol Substances 0.000 claims description 5
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 5
- 239000001530 fumaric acid Substances 0.000 claims description 5
- 229920001223 polyethylene glycol Polymers 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 235000011181 potassium carbonates Nutrition 0.000 claims description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 5
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 4
- 239000000203 mixture Substances 0.000 abstract description 22
- 239000003814 drug Substances 0.000 abstract description 9
- 238000000034 method Methods 0.000 abstract description 8
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- 239000008194 pharmaceutical composition Substances 0.000 abstract description 3
- 239000007857 degradation product Substances 0.000 abstract 2
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- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 6
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Abstract
将药学上有用的苯甲酰胺衍生物或其药学上可接受的盐与不易产生降解产物的添加剂混合,掺入有机酸盐、胺化合物和无机碱性物质,通过干法造粒制成固体制剂,进一步调节液体制剂的pH为4－12,可以得到稳定的药物制剂。可以得到产生极少降解产物并且足够稳定以用作药物的药物制剂。
Description
发明领域
本发明涉及药物组合物，尤其涉及包含苯甲酰胺衍生物或其药学上可接受的盐作为活性成分的药物制剂，它可用作药物，尤其是抗癌药。
背景技术
根据本发明的苯甲酰胺衍生物或其药学上可接受的盐具有抑制组蛋白脱乙酰酶和诱导分化的能力，可用作与细胞生长有关的疾病的治疗或改善剂，这些疾病如恶性肿瘤、自体免疫疾病、皮肤疾病、感染、血管疾病、变应性疾病、胃肠紊乱、激素疾病、糖尿病等，还可用作基因疗法效果的增强剂，或免疫抑制剂。确切地说，它们是有效的抗肿瘤药，有效对抗造血器官肿瘤和实体瘤(日本未审专利公报(公开)No.10-152462)。
不过，尽管本发明的苯甲酰胺衍生物及其药学上可接受的盐本身是稳定的，但当与添加剂混合时会变得不稳定，随着时间的推移显著分解，这些添加剂例如轻质硅酸酐、乳糖、玉米淀粉、羧甲基纤维素、硅酸铝镁、二氧化钛、聚乙二醇和聚山梨酸酯，它们常用于制备适合于口服、经皮或组织给药的剂型。
此外，湿法造粒是制备固体制剂最常用的造粒方法，当用该方法配制片剂时，它们变得更不稳定，产生大量不同于简单水解产物的分解产物，导致在药物制剂中活性成分的比例因其显著分解而低达约0.001至25％，因此作为固体药物制剂不适合用作药物。而且，采用液体制剂常用成分如聚山梨酸酯、聚乙二醇和甘油的药物制剂是不稳定的。因而，作为药物难以使用含有约0.001至25％苯甲酰胺衍生物或其药学上可接受的盐作为活性成分的药物制剂。
发明公开
本发明意欲提高含有药学上有用的苯甲酰胺衍生物或其药学上可接受的盐作为活性成分的组合物的稳定性，以及有效使用它们作为药物制剂。
为了解决上述问题，针对温度、湿度和物理化学性质对溶液、粉剂和固体形状产品的影响而进行了广泛研究，在这些产品中已经加入了苯甲酰胺衍生物或其药学上可接受的盐。其结果是，本发明人已经发现，通过在药物制剂常用添加剂中选择性使用那些不易诱导苯甲酰胺衍生物分解的添加剂，加入有机酸盐、氨基化合物和无机碱性物质等作为稳定剂，利用干法造粒或者调节pH在4-12的范围内，优选在7-11的范围内，可以解决活性成分不稳定的问题，并且可以生产稳定、优异的药物制剂，从而完成了本发明。
因而，本发明涉及
[1]一种药物制剂，包含式(1)所示的苯甲酰胺衍生物：
其中A代表由式(2)中任意一种所示结构：
或其药学上可接受的盐，和一种或多种选自赋形剂、崩解剂、粘合剂、润滑剂、包衣剂和溶剂的添加剂；
[2]作为优选实施方案的上述[1]的药物制剂，其中所述苯甲酰胺衍生物由式(3)所示：
[3]作为优选实施方案的上述[1]或[2]的药物制剂，其中所述赋形剂是D-甘露糖醇；
[4]作为另一优选实施方案的上述[1]至[3]中任意一项的药物制剂，其中所述崩解剂选自部分预胶凝淀粉、羧甲基纤维素(carmellose)钙和羧甲基淀粉钠中的一种或多种；
[5]作为优选实施方案的上述[1]至[4]中任意一项的药物制剂，其中所述粘合剂是羟丙基纤维素；
[6]作为优选实施方案的上述[1]至[5]中任意一项的药物制剂，其中所述润滑剂是选自硬脂酸镁和滑石中的一种或一种以上；
[7]作为优选实施方案的上述[1]至[6]中任意一项的药物制剂，其中所述包衣剂是羟丙基甲基纤维素；
[8]作为优选实施方案的上述[1]至[7]中任意一项的药物制剂，其中所述溶剂选自丙二醇、二甲基乙酰胺和聚乙二醇中的一种或多种；
[9]作为优选实施方案的上述[1]至[8]中任意一项的药物制剂，其中所述制剂进一步包含选自有机酸盐、氨基化合物和无机碱性物质中的一种或多种；
[10]作为优选实施方案的上述[1]至[9]中任意一项的药物制剂，其中所述有机酸盐选自富马酸一钠、藻酸钠、脱氢乙酸钠、异抗坏血酸钠和柠檬酸三钠中的一种或多种；
[11]作为优选实施方案的上述[1]至[9]中任意一项的药物制剂，其中所述氨基化合物选自三(羟甲基)氨基甲烷、单乙醇胺、二乙醇胺、三乙醇胺、二异丙醇胺、三异丙醇胺、氨基乙酸二羟基铝、精氨酸、肌酸酐、谷氨酸钠、甘氨酸、L-精氨酸L-谷氨酸盐和碳酰胆碱中的一种或多种；
[12]作为优选实施方案的上述[1]至[9]中任意一项的药物制剂，其中所述无机碱性物质选自碳酸钠、碳酸钾、碳酸铵、碳酸氢钠、碳酸氢钾、氢氧化钠、磷酸氢二钠和氨中的一种或多种；
[13]作为优选实施方案的上述[1]至[12]中任意一项的药物制剂，其中该制剂是包含通过干法造粒制备的颗粒的固体制剂；和
[14]作为优选实施方案的上述[1]至[13]中任意一项的药物制剂，其中该制剂是液体制剂且pH被调节在4-12的范围内。实施本发明的方式
下面将更加详细地解释本发明。
本文所用的药物制剂一般是指这样的制剂，其通过将一种或多种添加剂与一种活性成分或几种活性成分配制而成，并且已被配制成适用于各种药物剂型的形状。
按照本发明，固体制剂，尤其是粉剂可以这样制备，利用本领域技术人员常用的方法，向活性成分中加入一种或多种不易诱导分解的添加剂。不易诱导分解的添加剂实例包括：作为赋形剂的D-甘露糖醇；作为崩解剂的部分预胶凝淀粉、羧甲基淀粉钠和羧甲基纤维素钙；作为粘合剂的羟丙基纤维素；作为润滑剂的硬脂酸镁和滑石；和作为包衣剂的羟丙基甲基纤维素。可以使用它们中的一种或多种。
按照本发明，固体制剂，尤其是颗粒剂、片剂和胶囊剂可以通过干法造粒制备，其中向活性成分中加入不易诱导分解的添加剂，在摇动器如造粒机和V-型混合机内混合，这之后用辊压机压塑混合物，进一步用电动磨压碎，从而形成颗粒。
此外，更稳定的颗粒剂、片剂和胶囊剂可以这样获得，向活性成分中加入一种或多种选自下组的成分：有机酸盐，例如富马酸一钠、藻酸钠、脱氢乙酸钠、异抗坏血酸钠和柠檬酸三钠；氨基化合物，例如三(羟甲基)氨基甲烷、单乙醇胺、二乙醇胺、三乙醇胺、二异丙醇胺、三异丙醇胺、氨基乙酸二羟基铝、精氨酸、肌酸酐、谷氨酸钠、甘氨酸、L-精氨酸L-谷氨酸盐和碳酰胆碱；无机碱性物质，例如碳酸钠、碳酸钾、碳酸锂、碳酸锶、碳酸铵、碳酸氢钠、碳酸氢钾、碳酸氢锂、碳酸氢锶、氢氧化钠、磷酸氢二钠和氨，再按干法造粒进行造粒。
当加入有机酸盐、氨基化合物或无机碱性物质时，可以没有限制地使用添加剂，例如赋形剂、崩解剂、粘合剂、润滑剂和包衣剂。实例包括作为赋形剂的乳糖、乳糖酐、D-甘露糖醇、玉米淀粉和结晶性纤维素；作为粘合剂的羟丙基纤维素、聚乙烯吡咯烷酮、甲基纤维素、甘油和水；作为崩解剂的羧甲基纤维素、羧甲基纤维素钙、低取代的羟丙基纤维素和部分预胶凝淀粉；作为润滑剂的硬脂酸镁、硬脂酸钙、硬脂酸和滑石；和作为包衣剂的羟丙基甲基纤维素、甲基丙烯酸共聚物和羟丙基甲基纤维素邻苯二甲酸酯。
按照本发明，稳定的液体制剂、糖浆剂、注射剂、乳剂、悬浮剂、栓剂、其内容物为液体的软胶囊剂或其内容物为液体的硬胶囊剂等可以这样制备，利用本领域技术人员常用的方法，将活性成分溶于不易诱导该活性成分分解的溶剂，例如丙二醇和二甲基乙酰胺。
更稳定的液体制剂、糖浆剂、注射剂、乳剂、悬浮剂、栓剂、其内容物为液体的软胶囊剂或其内容物为液体的硬胶囊剂等可以这样制备，在溶剂中溶解一种或多种选自下组的成分：有机酸盐，例如富马酸一钠、藻酸钠、脱氢乙酸钠、异抗坏血酸钠和柠檬酸三钠；氨基化合物，例如三(羟甲基)氨基甲烷、单乙醇胺、二乙醇胺、三乙醇胺、二异丙醇胺、三异丙醇胺、氨基乙酸二羟基铝、精氨酸、肌酸酐、谷氨酸钠、甘氨酸、L-精氨酸L-谷氨酸盐和碳酰胆碱；无机碱性物质，例如碳酸钠、碳酸钾、碳酸锂、碳酸锶、碳酸铵、碳酸氢钠、碳酸氢钾、碳酸氢锂、碳酸氢锶、氢氧化钠、磷酸氢二钠和氨，再用酸或碱调节pH在4-12的范围内。
本文所用的酸或碱是指能够用作药物的有机碱、无机碱、有机酸或无机酸。有机碱是指三(羟甲基)氨基甲烷、单乙醇胺、二乙醇胺、三乙醇胺、二异丙醇胺、三异丙醇胺、精氨酸等。无机碱是指氢氧化钠、氨水、碳酸氢钾、碳酸钾、碳酸氢钠、碳酸钠等。有机酸是指柠檬酸、琥珀酸、乙酸、酒石酸、乳酸等。无机酸是指盐酸、硫酸、磷酸等。
按照本发明，为了生产冻干制剂，将活性成分与公知的溶剂混合，例如一种或多种选自纯净水、聚乙二醇、丙二醇、聚山梨酸酯和二甲基乙酰胺的溶剂；向所得组合物中进一步加入一种或多种选自下组的添加剂：糖；明胶；糊精；有机酸盐，例如富马酸一钠、藻酸钠、谷氨酸钠、脱氢乙酸钠、异抗坏血酸钠、柠檬酸三钠和精氨酸-谷氨酸盐；胺化合物，例如三(羟甲基)氨基甲烷、氨水、单乙醇胺、二乙醇胺、三乙醇胺、二异丙醇胺、三异丙醇胺、氨基乙酸二羟基铝、精氨酸、肌酸酐、甘氨酸和碳酰胆碱；无机碱性物质，例如碳酸铵、磷酸氢二钠、碳酸钠、碳酸氢钠和碳酸氢钾；然后根据需要用酸或碱调节所得组合物的pH为4-12，再在减压下冷冻干燥该组合物。
本发明的药物制剂可以通过任何方法给药，这取决于不同的剂型、患者的年龄与性别、疾病的严重性和其他条件。例如，片剂、丸剂、液体制剂、糖浆剂、悬浮剂、乳剂、颗粒剂和胶囊剂可以口服给药，注射剂可以静脉内给药，单独或者与常规补充物如葡萄糖和氨基酸混合，根据需要还可以通过肌内、皮下或腹膜内方式单独给药。用溶剂如盐水和纯净水再生的冻干制剂可以静脉内给药，单独或者与常规补充物如葡萄糖和氨基酸等混合，根据需要还可以通过肌内、皮下或腹膜内方式单独给药。栓剂可以直接通过直肠内方式给药。
酌情选择本发明药物制剂的剂量，这取决于给药的方法、患者的年龄与性别、疾病的严重性等。一般来说，活性成分化合物的每日剂量优选地在约0.0001至100mg/kg的范围内，对单位剂型的药物制剂来说，活性成分化合物优选为约0.001至1,000mg。
作为本发明活性成分的苯甲酰胺或其药学上可接受的盐例如可以通过日本未审专利公报(公开)No.10-152462所述方法加以制备。
本文所用的药物除了抗癌药以外还指用于治疗和/或改善自体免疫疾病、皮肤疾病、感染、血管疾病、变应性疾病、胃肠紊乱、激素疾病、糖尿病等的药剂和基因疗法效果增强剂或免疫抑制剂。
下面将参照实施例和参照例中的下列化合物N-(2-氨基苯基)-4-[N-(吡啶-3-基)甲氧羰基]氨基甲基苯甲酰胺(化合物1)以更加详细地解释本发明。不过请注意，本发明无论如何也不局限于这些实例。化合物1
实施例1
将化合物1(1g)与各为1g的D-甘露糖醇、部分预胶凝淀粉、羧甲基纤维素钙、羟丙基纤维素、羟丙基甲基纤维素、硬脂酸镁和滑石混合，制得粉末制剂。类似地，将乳糖、玉米淀粉、结晶性纤维素、羧甲基纤维素、轻质硅酸酐、硅酸铝镁和二氧化钛混合，制得供比较的对照样本。将这些制剂在60℃气密条件下贮存4周并且在40℃和相对湿度75％的开放条件下贮存3个月后，进行HPLC分析。相对于活性成分而言的降解产物百分比(％)如表1所示。按1∶1与D-甘露糖醇、部分胶凝淀粉、羧甲基纤维素钙、羟丙基纤维素、羟丙基甲基纤维素、硬脂酸镁或滑石混合制得的粉末制剂是稳定的。
表(1)：各种粉剂的稳定性
贮存条件添加剂 60℃气密4周 40℃75％ RH开放3个月供比较的对照样本无 0.18 0.19乳糖 0.55 0.44玉米淀粉 0.39 0.34结晶性纤维素 0.25 0.61羧甲基纤维素 0.43 0.41轻质硅酸酐 5.87 0.01硅酸铝镁 17.94 5.45二氧化钛 1.75 0.82实施例D-甘露糖醇 0.21 0.21部分胶凝淀粉 0.21 0.34羧甲基纤维素钙 0.30 0.21羟丙基纤维素 0.20 0.20硬脂酸镁 0.22 0.20羟丙基甲基纤维素 0.27 0.21滑石 0.36 0.23
表中数据代表由化合物1分解产生的降解产物的总量(％)。
实施例2
按下列操作制备表(2)所示药物制剂a、b、c、d、e和f。因而，依次加入分成预定量的1/8、2/8和5/8的化合物1和D-甘露糖醇，用造粒机混合，制得均匀粉末。此外，向其中加入1/2预定量的硬脂酸镁，在V-型混合机内混合20分钟，用辊压机压塑，进一步用电动磨压碎，制得颗粒。随后，加入预定量的羧甲基淀粉钠和1/2预定量的硬脂酸镁，在V-型混合机内混合，用压片机制成片剂，得到样本a、b、c、d、e和f。
表(2)：片剂的配方(单位：mg)成分/数量 本发明的样本
a b c d e f活性成分 5.0 1.0 1.0 1.0 1.0 1.0D-甘露糖醇 56.0 60.0 60.0 60.0 60.0 60.0羧甲基淀粉钠 3.3 3.3 3.3 3.3 3.3 3.3硬脂酸镁 0.7 0.7 0.7 0.7 0.7 0.7三(羟甲基)氨基甲烷 - - 0.5 - - -碳酸氢钾 - - - 0.5 - -碳酸钠 - - - - 0.5 -碳酸钾 - - - - - 0.5总计 65.0 65.0 65.5 65.5 65.5 65.5参照例1
通过湿法造粒按照表(3)所示配方造粒D-甘露糖醇、部分胶凝淀粉、羧甲基纤维素钙、硬脂酸镁、羟丙基纤维素、在与化合物1混合物时比较稳定的聚乙烯吡咯烷酮K30等，用压片机制成片剂，得到样本g-i。
表(3)：片剂的配方(单位：mg)成分/数量 样本
g h i活性成分 1.0 1.0 1.0D-甘露糖醇 40.6 40.6 40.6部分胶凝淀粉 17.4 17.4 17.4羟丙基纤维素 2.0 2.0 -聚乙烯吡略烷酮 - - 2.0羧甲基纤维素钙 3.3 - 3.3硬脂酸镁 0.7 0.7 0.7总计 65.0 65.0 65.0
将实施例2和参照例1所得样本在60℃气密条件下贮存4周，和在80℃气密条件下贮存3天，然后进行HPLC分析，得到化合物1的降解产物百分比(％)如表4所示。通过参照例1所示湿法造粒所得含有1mg活性成分的药物制剂是不稳定的，因为它们产生不同于水解产物的降解产物，而实施例2所示含有5.0mg和1.0mg的本发明样本都是稳定的，因为降解产物的产生维持在较低水平。
表(4)：含有化合物1的片剂的稳定性样本 贮存条件
含量(mg) 60℃气密4周(％) 80℃气密3天(％)本发明样本a 5.0 0.4 0.4
b 1.0 1.0 1.3
c 1.0 0.7 0.5
d 1.0 - 0.4
e 1.0 - 0.4
f 1.0 - 0.4参照样本 g 1.0 4.1 3.0
h 1.0 4.5 2.1
i 1.0 5.8 5.3
表中数据代表由化合物1分解产生的降解产物的总量(％)。
实施例3
将化合物1以20mg/ml的浓度溶于丙二醇或二甲基乙酰胺，制得液体制剂。作为供比较的对照样本，将化合物1以20mg/ml的浓度溶于聚山梨酸酯80或聚乙二醇400。表(5)显示这些制剂在80℃气密条件下贮存3天后化合物1的降解产物百分比(％)。在溶于丙二醇或二甲基乙酰胺后，它们表现良好的稳定性。
表(5)：溶干不同溶剂中的稳定性添加剂 降解产物的量(％)聚山梨酸酯80 18.1聚乙二醇400 41.4二甲基乙酰胺 4.1丙二醇 3.6
表中数据代表由化合物1分解产生的降解产物的总量(％)。
实施例4
将化合物1以20mg/ml的浓度溶于聚乙二醇400，制得液体制剂，设为供比较的对照样本。向该供比较的对照样本中加入浓度各为0.05M的添加剂，制得本发明的液体制剂。表6显示这些制剂和供比较的对照样本在80℃气密条件下贮存3天后活性成分的降解产物百分比(％)。加入了本发明的有机酸盐、氨基化合物或无机碱性物质的样本的稳定性得以提高。
表6：在化合物1的20mg/ml聚乙二醇400溶液中掺入0.05M各添加剂的液体制剂的稳定性(贮存条件：80℃气密，贮存期：3天)
添加剂 降解产物的量(％) pH供比较的对照样本 无 41.4 5.3本发明样本 富马酸钠 21.6 7.0
藻酸钠 23.7 6.7
脱氢乙酸钠 13.0 8.6
异抗坏血酸钠 13.2 7.3
柠檬酸三钠 28.2 8.0
三(羟甲基)氨基甲烷 2.9 10.1
单乙醇胺 4.3 11.5
二乙醇胺 3.9 11.7
三乙醇胺 9.6 9.4
二异丙醇胺 4.7 9.9
三异丙醇胺 16.5 8.3
氨基乙酸二羟基铝 7.3 6.4
L-精氨酸 10.6 11.5
肌酸酐 18.6 7.0
谷氨酸钠 23.1 -
甘氨酸 26.7 -
L-精氨酸L-谷氨酸盐 29.4 6.5
碳酰胆碱 32.3 5.4
碳酸铵 3.6 10.7
磷酸氢二钠 10.8 7.6
碳酸钠 16.8 10.1
碳酸氢钠 25.0 6.5
碳酸氢钾 15.5 7.0
氨 4.6 11.7
表中数据代表由化合物1分解产生的降解产物的总量(％)。
实施例5
向化合物1的20mg/ml聚乙二醇400溶液中加入等体积的0.1M三(羟甲基)氨基甲烷缓冲液(其pH因所加入的盐酸或氢氧化钠而异)，制得化合物1的10mg/ml液体制剂。表7显示这些制剂在80℃气密条件下贮存3天后活性成分的降解产物百分比(％)。pH被调节在7-11范围内的本发明样本表现良好的稳定性。
表(7)：化合物1的10mg/ml聚乙二醇400溶液在不同pH下
的稳定性(贮存条件：80℃气密，贮存期：3天)
pH 降解产物的量(％)
3.8 98.6
13.2 48.8
7.3 11.9
7.7 8.2
8.5 5.8
9.5 5.6
10.1 4.4
表中数据代表由化合物1分解产生的降解产物的总量(％)。
实施例6
将化合物1以20mg/ml的浓度溶于聚乙二醇400，向其中加入氢氧化钠，以使最终浓度可以从0mM至10mM不等，制得液体制剂。表8显示这些制剂在各自的pH下和在80℃气密条件下贮存1天或7天后活性成分的降解产物百分比(％)。pH被调节在约7-11范围内的本发明样本表现良好的稳定性。
表(8)：将化合物1以20mg/ml溶于聚乙二醇400中，然后向其中加入氢氧化钠所得液体制剂的pH与稳定性之间的关系(贮存条件：80℃气密，贮存期：1天或7天)氢氧化钠的 pH 降解产物的量(％)浓度(mM) 80℃1天 80℃7天0 5.3 16.0 63.70.01 5.9 14.1 60.60.1 6.1 14.3 56.01.0 7.3 9.7 33.72.0 8.9 4.6 12.43.0 9.4 5.0 9.84.0 10.4 6.0 9.75.0 10.8 9.7 11.410.0 13.1 71.5 90.6
表中数据代表由化合物1分解产生的降解产物的总量(％)。
工业实用性
将药学上有用的苯甲酰胺衍生物或其药学上可接受的盐与不易产生降解产物的添加剂混合，掺入有机酸盐、胺化合物或无机碱性物质，通过干法造粒制成固体制剂，进一步调节液体制剂的pH为4-12，可以得到产生极少降解产物并且足够稳定以用作药物的药物制剂。
Claims (14)
1.一种药物制剂，包含式(1)所示的苯甲酰胺衍生物：
其中A代表由式(2)中任意一项所示结构：
或其药学上可接受的盐，和一种或多种选自赋形剂、崩解剂、粘合剂、润滑剂、包衣剂和溶剂的添加剂。
2.根据权利要求1的药物制剂，其中所述苯甲酰胺衍生物由式(3)所示：
3.根据权利要求1或2的药物制剂，其中所述赋形剂是D-甘露糖醇。
4.根据权利要求1至3中任意一项的药物制剂，其中所述崩解剂选自部分预胶凝淀粉、羧甲基纤维素钙和羧甲基淀粉钠中的一种或多种。
5.根据权利要求1至4中任意一项的药物制剂，其中所述粘合剂是羟丙基纤维素。
6.根据权利要求1至5中任意一项的药物制剂，其中所述润滑剂是选自硬脂酸镁和滑石中的一种或一种以上。
7.根据权利要求1至6中任意一项的药物制剂，其中所述包衣剂是羟丙基甲基纤维素。
8.根据权利要求1至7中任意一项的药物制剂，其中所述溶剂选自丙二醇、二甲基乙酰胺和聚乙二醇中的一种或多种。
9.根据权利要求1至8中任意一项的药物制剂，其中所述制剂进一步包含选自有机酸盐、氨基化合物和无机碱性物质中的一种或多种。
10.根据权利要求1至9中任意一项的药物制剂，其中所述有机酸盐选自富马酸一钠、藻酸钠、脱氢乙酸钠、异抗坏血酸钠和柠檬酸三钠中的一种或多种。
11.根据权利要求1至9中任意一项的药物制剂，其中所述氨基化合物选自三(羟甲基)氨基甲烷、单乙醇胺、二乙醇胺、三乙醇胺、二异丙醇胺、三异丙醇胺、氨基乙酸二羟基铝、精氨酸、肌酸酐、谷氨酸钠、甘氨酸、L-精氨酸L-谷氨酸盐和碳酰胆碱中的一种或多种。
12.根据权利要求1至9中任意一项的药物制剂，其中所述无机碱性物质选自碳酸钠、碳酸钾、碳酸铵、碳酸氢钠、碳酸氢钾、氢氧化钠、磷酸氢二钠和氨中的一种或多种。
13.根据权利要求1至12中任意一项的药物制剂，其中该制剂是包含通过干法造粒制备的颗粒的固体制剂。
14.根据权利要求1至13中任意一项的药物制剂，其中该制剂是液体制剂且pH被调节在4-12的范围内。
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| KR (1) | KR100683876B1 (zh) |
| CN (1) | CN1205931C (zh) |
| AR (1) | AR031074A1 (zh) |
| AU (1) | AU780151B2 (zh) |
| BG (1) | BG65662B1 (zh) |
| BR (1) | BR0013283A (zh) |
| CA (1) | CA2380757C (zh) |
| CY (1) | CY1116273T1 (zh) |
| CZ (1) | CZ302924B6 (zh) |
| DK (1) | DK1207881T3 (zh) |
| EE (1) | EE05331B1 (zh) |
| ES (1) | ES2536705T3 (zh) |
| HK (1) | HK1046501B (zh) |
| HR (1) | HRP20020181B1 (zh) |
| HU (1) | HU230386B1 (zh) |
| IL (1) | IL148169A0 (zh) |
| MX (1) | MXPA02001575A (zh) |
| NO (1) | NO328957B1 (zh) |
| NZ (1) | NZ517356A (zh) |
| PL (1) | PL201388B1 (zh) |
| PT (1) | PT1207881E (zh) |
| RU (1) | RU2257206C2 (zh) |
| SK (1) | SK287547B6 (zh) |
| TW (1) | TWI245630B (zh) |
| UA (1) | UA73316C2 (zh) |
| WO (1) | WO2001012193A1 (zh) |
| ZA (1) | ZA200201466B (zh) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001081031A (ja) * | 1999-08-30 | 2001-03-27 | Schering Ag | 溶解性および経口吸収性を改善したベンズアミド誘導体含有製剤 |
| US20040034039A1 (en) * | 2000-09-22 | 2004-02-19 | Yoshinori Nakano | Solid preparations |
| CA2478479A1 (en) | 2002-03-07 | 2003-09-18 | University Of Delaware | Methods, compositions, and kits for enhancing oligonucleotide-mediated nucleic acid sequence alteration using compositions comprising a histone deacetylase inhibitor, lambda phagebeta protein, or hydroxyurea |
| GB0316206D0 (en) * | 2003-07-10 | 2003-08-13 | Glaxo Group Ltd | Pharmaceutical formulation |
| CN101646460A (zh) | 2007-03-28 | 2010-02-10 | 参天制药株式会社 | 含有具有组蛋白脱乙酰化酶抑制作用的化合物作为有效成分的降眼压剂 |
| KR101405615B1 (ko) * | 2007-08-27 | 2014-06-12 | (주)아모레퍼시픽 | 조성물 내 ｐＨ 조절을 통해 안정화된 벤즈아미드 화합물을함유하는 피부 외용제 조성물, 및 그 벤즈아미드 화합물안정화 방법 |
| JP4921616B2 (ja) * | 2008-08-29 | 2012-04-25 | バイエル ファーマ アクチエンゲゼルシャフト | Ｎ‐（２‐アミノフェニル）‐４‐［ｎ‐（ピリジン‐３‐イル）‐メトキシカルボニル‐アミノメチル］‐ベンズアミド（ｍｓ‐２７５）結晶多形ｂ |
| GB2462893B (en) * | 2008-08-29 | 2010-10-13 | Bayer Schering Pharma Ag | N-(2-aminophenyl)-4-[N-(pyridine-3-yl)-methoxycarbonyl-aminomethyl]-benzamide (MS-275) polymorph B |
| JP5627062B1 (ja) * | 2013-04-04 | 2014-11-19 | 第一三共株式会社 | アミノカルボン酸の塩の固形組成物 |
| EP3437639A1 (en) | 2015-03-19 | 2019-02-06 | Daiichi Sankyo Company, Limited | Solid preparation containing colorant |
| US10561628B2 (en) | 2015-03-19 | 2020-02-18 | Daiichi Sankyo Company, Limited | Solid preparation including antioxidant |
| CN111867559A (zh) * | 2019-01-25 | 2020-10-30 | 株式会社爱茉莉太平洋 | 含有苯甲酰胺化合物以及增溶剂的组合物 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3354090B2 (ja) * | 1996-09-30 | 2002-12-09 | シエーリング アクチエンゲゼルシャフト | 分化誘導剤 |
| US6174905B1 (en) * | 1996-09-30 | 2001-01-16 | Mitsui Chemicals, Inc. | Cell differentiation inducer |
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1999
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