CN100390161C - 羟基丹参酮ⅱa磺酸钠及其用途 - Google Patents
羟基丹参酮ⅱa磺酸钠及其用途 Download PDFInfo
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- 239000011734 sodium Substances 0.000 title claims description 66
- 229910052708 sodium Inorganic materials 0.000 title claims description 66
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- AIGAZQPHXLWMOJ-UHFFFAOYSA-N tanshinone IIA Natural products C1=CC2=C(C)C=CC=C2C(C(=O)C2=O)=C1C1=C2C(C)=CO1 AIGAZQPHXLWMOJ-UHFFFAOYSA-N 0.000 claims abstract description 102
- HYXITZLLTYIPOF-UHFFFAOYSA-N Tanshinone II Natural products O=C1C(=O)C2=C3CCCC(C)(C)C3=CC=C2C2=C1C(C)=CO2 HYXITZLLTYIPOF-UHFFFAOYSA-N 0.000 claims abstract description 101
- AZEZEAABTDXEHR-UHFFFAOYSA-M sodium;1,6,6-trimethyl-10,11-dioxo-8,9-dihydro-7h-naphtho[1,2-g][1]benzofuran-2-sulfonate Chemical compound [Na+].C12=CC=C(C(CCC3)(C)C)C3=C2C(=O)C(=O)C2=C1OC(S([O-])(=O)=O)=C2C AZEZEAABTDXEHR-UHFFFAOYSA-M 0.000 claims abstract description 84
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 23
- 238000002360 preparation method Methods 0.000 claims abstract description 23
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- 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 65
- 239000000243 solution Substances 0.000 claims description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- 239000013558 reference substance Substances 0.000 claims description 13
- 238000012360 testing method Methods 0.000 claims description 12
- 239000000470 constituent Substances 0.000 claims description 7
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- 238000001514 detection method Methods 0.000 claims description 6
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 claims description 5
- -1 hydroxyl Tanshinone I Chemical compound 0.000 claims description 5
- 239000000843 powder Substances 0.000 claims description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
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- 230000014759 maintenance of location Effects 0.000 claims description 3
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- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 3
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 3
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 3
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- 239000000377 silicon dioxide Substances 0.000 claims description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 3
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- 239000003814 drug Substances 0.000 description 9
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
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- 208000024172 Cardiovascular disease Diseases 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种化合物羟基丹参酮IIA磺酸钠，其分子结构式为：见右下式，并且公开了这种化合物在丹参酮IIA磺酸钠原料及丹参酮IIA磺酸钠制剂有关物质检查时作为杂质对照品的一种应用。丹参酮IIA磺酸钠制剂为丹参酮IIA磺酸钠水针剂、丹参酮IIA磺酸钠冻干粉针剂、丹参酮IIA磺酸钠大容量注射剂、丹参酮IIA磺酸钠口服固体制剂。本发明的应用有效控制了丹参酮IIA磺酸钠原料及丹参酮IIA磺酸钠制剂的有关物质，从而保证了丹参酮IIA磺酸钠制剂临床使用的安全性和有效性。
Description
技术领域
本发明涉及一种化合物羟基丹参酮IIA磺酸钠及其用途，尤其是化合物羟基丹参酮IIA磺酸钠在丹参酮IIA磺酸钠原料及丹参酮IIA磺酸钠制剂有关物质检查时作为杂质对照品的应用，属于医药技术领域。
背景技术
丹参为唇型科植物丹参的干燥根及根茎，具有祛瘀止血、活血调经、清心除烦的功效，活血化瘀的常用中药，其有效成分为脂溶性的二萜化合物和水溶性的酚酸类化合物。中医有“一味丹参饮，功同四物汤”之说，其功效可见一斑。丹参是广泛应用于心血管等中药复方中，以丹参为主要的中药制剂开发也相当活跃。
丹参酮IIA是丹参中有效脂溶性成分，上世纪60年代，Kakisawa确定了丹参酮IIA的结构式；随后，Baidlre等人合成了丹参酮IIA。由于丹参酮IIA肠道吸收差，临床起效慢，故植物化学家钱名坤等人半合成了丹参酮IIA磺酸钠，并由上海制药一厂、中药三厂等制备成注射液制剂，用于心脑血管疾病的治疗和预防。注射液推向市场后，其确切的疗效得到广大医患者的欢迎。
丹参酮IIA磺酸钠原料及丹参酮IIA磺酸钠注射液上市后，发现无论是原料还是水针剂在生产和销售过程中都会在储存过程中出现酸性增强，含量降低的现象，但这种降低趋势并不与存放时间成正比。由于原按中药管理，原有质量标准没有对丹参酮IIA磺酸钠原料及丹参酮IIA磺酸钠制剂的有关物质进行有效监控。经长期研究发现丹参酮IIA磺酸钠注射液(市售)的室温长期留样中含一种未知杂质高达7-15％，目前该药品按化学药品管理，确证该杂质结构以及控制其含量是提高丹参酮IIA磺酸钠制剂质量的重要任务。
发明内容
技术问题：本发明提供了一种化合物羟基丹参酮IIA磺酸钠及其在丹参酮IIA磺酸钠原料及丹参酮IIA磺酸钠制剂有关物质检查时作为杂质对照品的应用。
技术方案：通过发明人大量的研究发现，丹参酮IIA磺酸钠原料及丹参酮IIA磺酸钠制剂在存储的过程，会产生一种杂质化合物，这种杂质化合物会随本品受环境的破坏程度增加而增长，其他杂质量增长甚微，通过化学方法分离出这种化合物，进行结构确证，其结构式为：
化合物羟基丹参酮IIA磺酸钠的用途，在于丹参酮IIA磺酸钠原料及丹参酮IIA磺酸钠制剂有关物质检查时作为杂质对照品。
丹参酮IIA磺酸钠制剂可以为丹参酮IIA磺酸钠水针剂、丹参酮IIA磺酸钠冻干粉针剂、丹参酮IIA磺酸钠大容量注射剂、丹参酮IIA磺酸钠口服固体制剂。
丹参酮IIA磺酸钠注射剂有关物质检查质量标准为：
用十八烷基硅烷键合硅胶为填充剂，以甲醇：0.02mol/L磷酸二氢钠溶液为65∶30至65∶40，稀磷酸调pH值至2.5-3.7的溶液为流动相；检测波长为271nm，流速1.0ml/min；进样量20ul，取丹参酮IIA对照品、羟基丹参酮IIA磺酸钠对照品适量，加甲醇溶解制成各含10ug/ml的溶液，为系统预试验溶液；丹参酮IIA磺酸钠、丹参酮IIA与羟基丹参酮IIA磺酸钠及其他杂质峰的分离度应符合规定，理论塔板数按丹参酮IIA磺酸钠计算应不低于2000；取本品相当于丹参酮IIA磺酸钠2mg，精密量或称定，置10ml量瓶中，加流动相溶解并稀释至刻度，摇匀，作为供试品溶液；精密量取供试品溶液1ml置100ml量瓶中，加流动相稀释至刻度，摇匀，作为对照溶液，照色谱条件，取对照液20μl注入色谱仪，调节检测灵敏度，使主成分峰高为满量程的10～25％，再分别取对照溶液、供试品溶液各20μl注入色谱仪，记录色谱图至供试液主成分峰保留时间的3倍；供试品色谱图上如显杂质峰，单个最大杂质峰面积不得大于对照溶液峰面积3倍(2.0％)，总杂质峰面积之和不得大于对照溶液的峰面积8倍(5.0％)。
有益效果：羟基丹参酮IIA磺酸钠是丹参酮IIA磺酸钠原料及丹参酮IIA磺酸钠制剂在储存和运输过程产生的一种主要有关物质，是丹参酮IIA磺酸钠氧化产物，这种物质的含量多少直接影响了丹参酮IIA磺酸钠原料及丹参酮IIA磺酸钠制剂的品质质量。文献报道有提到羟基丹参酮IIA，而且对这种化合物的具体来源方法、光谱分析没有公开，本发明针对丹参酮IIA磺酸钠原料及丹参酮IIA磺酸钠制剂出现的杂质深入研究，经过大量的分离、提纯、合成实验得到这种化合物质，并光谱分析确证为羟基丹参酮IIA磺酸钠，并证明其为丹参酮IIA磺酸钠原料及丹参酮IIA磺酸钠制剂中的最主要杂质。把羟基丹参酮IIA磺酸钠作为丹参酮IIA磺酸钠原料及丹参酮IIA磺酸钠制剂有关物质检测时的杂质对照品，能有效的、直接的监控丹参酮IIA磺酸钠原料及丹参酮IIA磺酸钠制剂的有关物质。本发明的应用有效控制了丹参酮IIA磺酸钠原料及丹参酮IIA磺酸钠制剂的有关物质，从而保证了丹参酮IIA磺酸钠制剂临床使用的安全性和有效性。
附图说明
图1A是羟基丹参酮IIA磺酸钠的氢谱图。
图1B是羟基丹参酮IIA磺酸钠的氢谱图。
具体实施方式
实施例1：羟基丹参酮IIA磺酸钠分离纯化
取批号030340丹参酮IIA磺酸钠水针10支光照挥干水分，加甲醇溶清观察板层情况，氯仿/甲醇(7∶1)反复展开，可见Rf值略低于丹参酮IIA磺酸钠有一微量杂质点。制备板分离，分得约10mg橙红色固体，该化合物进一步纯化HPLC半制备柱纯化橙红色固体，分得一种物质(A)。
实施例2：羟基丹参酮IIA磺酸钠的合成
将396mg(0.001mol)的丹参酮IIA磺酸钠溶于10ml水中，冰水浴，滴加适量醋酸，然后分批加入118mg(0.001mol)的铬酸，搅拌，保持温度在5～10℃，30分钟后停止搅拌，将反应液立刻加入1立升饱和氯化钠水溶液中，即有红色固体析出，离心，沉淀物用饱和氯化钠溶液洗二次，再用适量水洗一次，使固体物ph＝5-6，将滤取固体物经硅胶柱层析(洗脱液：CHCl3∶CH3OH＝8∶1)，收集所需洗脱液，减压蒸发，干燥，得红色晶体约200mg。
实施例3：羟基丹参酮IIA磺酸钠的结构确证
经确认实施例1分得的物质(A)与实施例2中合成的物质结构相同，其氢谱图为图1A，图1B。
(Ms：390(M+1))。
NMR(CDCl3，δ)：1.36(s，6H，2×CH3)，2.1~2.4(m，4H，CH2，CH2)，2.7(s，3H，CH3)，3.7(s，H，CH-OH)，7.50(s，H，CH)，7.7(s，H，CH)。
实施例4：羟基丹参酮IIA磺酸钠作为有关物质的对照品测定丹参酮IIA磺酸钠水针的有关物质
丹参酮IIA磺酸钠冻干粉针剂有关物质质量标准：
用十八烷基硅烷键合硅胶为填充剂，以甲醇-0.02mol/L磷酸二氢钠溶液(稀磷酸调pH值3.5)(65∶35)为流动相。检测波长为271nm，流速1.0ml/min。进样量20ul，取丹参酮IIA对照品、羟基丹参酮IIA磺酸钠对照品和丹参酮I磺酸钠对照品适量，加甲醇溶解制成各含10ug/ml的溶液，为系统预试验溶液。丹参酮IIA磺酸钠、丹参酮IIA与丹参酮I磺酸钠、羟基丹参酮IIA磺酸钠及其他杂质峰的分离度应符合规定，理论塔板数按丹参酮IIA磺酸钠计算应不低于2000。
取本品5mg，精密称定，置10ml量瓶中，加流动相溶解并稀释至刻度，摇匀，作为供试品溶液；精密量取供试品溶液1ml置100ml量瓶中，加流动相稀释至刻度，摇匀，作为对照溶液，照色谱条件，取对照液20μl注入色谱仪，调节检测灵敏度，使主成分峰高为满量程的10～25％，再分别取对照溶液、供试品溶液各20μl注入色谱仪，记录色谱图至供试液主成分峰保留时间的3倍。供试品色谱图上如显杂质峰，单个最大杂质峰面积不得大于对照溶液峰面积3倍(2.0％)，总杂质峰面积之和不得大于对照溶液的峰面积8倍(5.0％)。
三批丹参酮IIA磺酸钠冻干粉针剂有关物质的测定结果：
样品来源：上海第一生化药业申请丹参酮IIA磺酸钠冻干粉针剂样品
Claims (4)
1.一种化合物羟基丹参酮IIA磺酸钠，其分子结构式为：
2.一种如权利要求1所述的化合物羟基丹参酮IIA磺酸钠的用途，其特征在于化合物羟基丹参酮IIA磺酸钠在丹参酮IIA磺酸钠原料及丹参酮IIA磺酸钠制剂有关物质检查时作为杂质对照品。
3.根据权利要求2所述的化合物羟基丹参酮IIA磺酸钠的用途，其特征在于丹参酮IIA磺酸钠制剂为丹参酮IIA磺酸钠水针剂或丹参酮IIA磺酸钠冻干粉针剂或丹参酮IIA磺酸钠大容量注射剂或丹参酮IIA磺酸钠口服固体制剂。
4.根据权利要求2所述的化合物羟基丹参酮IIA磺酸钠的用途，其特征在于在丹参酮IIA磺酸钠注射剂有关物质检查质量标准为：
用十八烷基硅烷键合硅胶为填充剂，以甲醇：0.02mol/L磷酸二氢钠溶液为65∶30至65∶40，稀磷酸调pH值至2.5-3.7的溶液为流动相；检测波长为271nm，流速1.0ml/min；进样量20ul，取丹参酮II A对照品、羟基丹参酮II A磺酸钠对照品适量，加甲醇溶解制成各含10ug/ml的溶液，为系统预试验溶液；丹参酮II A磺酸钠、丹参酮II A与羟基丹参酮II A磺酸钠及其他杂质峰的分离度应符合规定，理论塔板数按丹参酮II A磺酸钠计算应不低于2000；取本品相当于丹参酮II A磺酸钠2mg，精密量或称定，置10ml量瓶中，加流动相溶解并稀释至刻度，摇匀，作为供试品溶液；精密量取供试品溶液1ml置100ml量瓶中，加流动相稀释至刻度，摇匀，作为对照溶液，照色谱条件，取对照液20μl注入色谱仪，调节检测灵敏度，使主成分峰高为满量程的10～25％，再分别取对照溶液、供试品溶液各20μl注入色谱仪，记录色谱图至供试液主成分峰保留时间的3倍；当供试品色谱图上显杂质峰时，单个最大杂质峰面积不得大于对照溶液峰面积3倍，总杂质峰面积之和不得大于对照溶液的峰面积8倍。
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| WO2005063232A1 (en) * | 2003-12-30 | 2005-07-14 | Md Bioalpha Co., Ltd. | Obesity and metabolic syndrome treatment with tanshinone derivatives which increase metabolic activity |
| CN1686104A (zh) * | 2005-04-12 | 2005-10-26 | 四川大学 | 丹参酮固体分散体和包合物及其用途 |
| US20050250751A1 (en) * | 2004-03-10 | 2005-11-10 | Kuo-Hsiung Lee | Neo-tanshinlactone and analogs as potent and selective anti-breast cancer agents |
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| WO2005063232A1 (en) * | 2003-12-30 | 2005-07-14 | Md Bioalpha Co., Ltd. | Obesity and metabolic syndrome treatment with tanshinone derivatives which increase metabolic activity |
| US20050250751A1 (en) * | 2004-03-10 | 2005-11-10 | Kuo-Hsiung Lee | Neo-tanshinlactone and analogs as potent and selective anti-breast cancer agents |
| CN1686104A (zh) * | 2005-04-12 | 2005-10-26 | 四川大学 | 丹参酮固体分散体和包合物及其用途 |
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| 药用鼠尾草二萜醌类及有关中药单体对羟自由基的清除效能. 薛明等.中国兽药杂志，第33卷第2期. 1999 |
| 药用鼠尾草二萜醌类及有关中药单体对羟自由基的清除效能. 薛明等.中国兽药杂志，第33卷第2期. 1999 * |
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