CN1275989A - 具有生理作用的胆汁酸金属盐及其在治疗中的应用 - Google Patents
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Abstract
本发明涉及具有治疗活性的胆汁酸金属盐,以及含有所述胆汁酸金属盐的医药组合物和兽药组合物。
Description
本发明涉及具有治疗活性的胆汁酸金属盐。
本发明还涉及含有所述胆汁酸金属盐的医药组合物和兽药组合物。
有多种金属阳离子在体内起生理作用：除了作为血红蛋白组分的铁以外，不同含量的锌、铜、硒、钼、钴、锰等微量元素是酶和生理系统行使正常功能所必须的。这些元素通常是通过饮食吸收的，但是对于由于病理或饮食导致的这些元素的缺乏，就需要通过将适当的盐或复合物给药来进行药物补充或饮食补充。
对于铁，该问题尤其突出，经常需要将铁给药来治疗缺铁性贫血。为了治疗铁缺乏，目前正在使用盐例如葡萄糖酸亚铁或硫酸亚铁或铁与丁二酰化蛋白的复合物。
现在已经发现，上述胆汁酸金属盐能使金属阳离子选择性地在肠肝循环内高度、逐步地吸收。
使用胆汁酸作为铁或微量元素的载体被证明特别有效，并且能克服影响现有技术化合物的一些缺陷。
实际上作为肠粘膜屏障渗透因子的胆汁酸能提供较高的生物利用度，这是因为它们经过肠肝循环的再循环作用，以及因此所具有的逐步吸收动力学。此外，尤其是对于铁盐，使用胆汁酸作为载体能避免产生将这些化合物口服给药所带来的通常副作用，例如便秘、胃肠道反应、腹涨、上腹部痛。
依据常规方法，用天然胆汁酸或其衍生物与金属氢氧化物反应，或者用合适的金属盐与胆汁酸的碱金属盐或碱土金属盐进行交换反应，可制得本发明胆汁酸金属盐。
天然胆汁酸的实例包括胆酸、脱氧胆酸、鹅脱氧胆酸、鹅胆酸、乌索脱氧胆酸、乌索胆酸、猪脱氧胆酸、以及相应的牛磺(tauro-)和甘氨共轭物(glyco-conjugates)。
可任选地将天然胆汁酸衍生化，例如通过与二元羧酸或多元羧酸如琥珀酸酸、戊二酸酸、环己烷二甲酸的酸酐反应，来引入其它可成盐的酸性基团。
所述衍生物有一些是已知的，并且可依据常规方法制得，例如在意大利专利第1.163.090号中公开的方法。
一种不同方法是，用酒石酸将胆汁酸分子上的酮基缩酮化，用酮基丙二酸(ketomalonic acid)将猪胆酸缩酮化。
当出于治疗和应用目的而需要增加金属阳离子/胆汁酸的摩尔比时，在每个胆汁酸分子上存在更易于成盐的基团可实现这一点。
依据本发明，用选自下述的金属可将天然或半合成胆汁酸成盐化：铁(II)、铁(III)、铜(I)、铜(II)、锌、钴、钼、铂、金、锰、钒、硒、锡、镍。
特别优选可用于在人和动物中治疗铁缺乏的亚铁盐或三价铁盐，尤其是三价铁盐。
对于治疗应用或其它应用，可依据常规技术，用赋形剂[例如在《Remington’s药物科学手册》(Remington’s PharmaceuticalSciences Handbook)，Mack.Pub.，N.Y.，U.S.A.中描述的赋形剂]将本发明胆汁酸金属盐配制成药物组合物。
所述组合物的实例包括胶囊、片剂、糖浆剂或可饮用溶液剂、胃释和/或缓释剂型等。当然，日剂量取决于阳离子的类型：对于铁，本发明胆汁酸金属盐的日给药剂量可以为100mg-3g，每日给药1-4次。
此外，本发明胆汁酸金属盐也可以包含在饮食配方或人用或兽用营养制剂中，其可任选性地与具有补充或任何具有有用活性的其它组分一起使用。
利用下述实施例来进一步举例说明本发明。
实施例1
制备胆汁酸铁(II)盐
将10g酸溶于含有少量氢氧化钠(＝10％，对于能释放琥珀酸盐的胆汁酸为20％)、PH为8的7.5体积水中。
溶解完全后，在35℃及搅拌下，将FeCl36H2O水溶液加到该混合物中，其中所述FeCl36H2O水溶液是通过将2.42g(对于胆酸或脱氢胆酸，为化学计量+10％过量)、2.53g(对于鹅脱氧胆酸或乌索脱氧胆酸，为化学计量+10％过量)、或5.02g(对于能释放琥珀酸盐的胆汁酸，为化学计量+10％过量)三价铁盐缓慢地溶于25ml而预先制得的。
将所得混合物搅拌至沉淀完全，然后洗涤沉淀直至不含有氯化物。产率：95％以上。
所得盐的特征如下所述：盐 熔点 铁含量胆酸铁 237-239℃ 4.07-4.67(3α，7α，12α-三羟基-5β-胆烷酸铁)脱氧胆酸铁 218-219℃ 4.24-4.84(3α，12α-二羟基-5β-胆烷酸铁)脱氢胆酸铁 216-218℃ 4.13-4.73(3，7，12，5β-三酮胆烷酸铁)鹅脱氧胆酸铁 214-218℃ 4.24-4.84(3α，7α-二羟基-5β-胆烷酸铁)乌索脱氧胆酸铁 200℃ 4.24-4.84(3α，7α，-二羟基-5β-胆烷酸铁)猪脱氧胆酸 193℃ 4.24-4.84(3α，6α-二羟基-5β-胆烷酸铁)二琥珀酰乌索脱氧胆酸铁 268-270℃ 8.05-9.25(能生物释放琥珀酸盐的3α，7α-二羟基-5β-胆烷酸铁)
实施例2
附图1和2表示，将19.2mg铁/天以乌索脱氧胆酸铁的形式对两名铁缺乏病人给药后，所获得的血清铁含量结果。
Claims (10)
1.具有生理作用的胆汁酸金属盐。
2.权利要求1的盐，其中所述金属选自铁(II)、铁(III)、铜(I)、铜(II)、锌、钴、钼、铂、金、锰、钒、硒、锡、镍。
3.权利要求1的盐，其中所述金属是铁。
4.权利要求1-3任一项的盐，其中所述胆汁酸选自胆酸、脱氧胆酸、鹅脱氧胆酸、鹅胆酸、乌索胆酸、乌索脱氧胆酸、猪脱氧胆酸、以及相应的牛磺和甘氨共轭物。
5.权利要求1-4的盐，其中胆酸上引入了其它可成盐基团。
6.权利要求5的盐，其中所述可成盐基团选自二元羧酸或多元羧酸，优选琥珀酸、戊二酸、环己烷二甲酸。
7.权利要求1-4任一项的盐，其中用酒石酸将任一酮基缩酮化。
8.权利要求1-7任一项的盐在制备用于治疗微量元素缺乏的药物中的应用。
9.权利要求1-7任一项的铁(II)盐在制备用于铁治疗的药物中的应用。
10.含有至少一种权利要求1-7任一项所述的盐作为活性组分，以及常规载体和赋形剂的药物组合物。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB971823979A CN1153778C (zh) | 1997-10-09 | 1997-10-09 | 具有生理作用的胆汁酸金属盐及其在治疗中的应用 |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB971823979A CN1153778C (zh) | 1997-10-09 | 1997-10-09 | 具有生理作用的胆汁酸金属盐及其在治疗中的应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1275989A true CN1275989A (zh) | 2000-12-06 |
| CN1153778C CN1153778C (zh) | 2004-06-16 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB971823979A Expired - Fee Related CN1153778C (zh) | 1997-10-09 | 1997-10-09 | 具有生理作用的胆汁酸金属盐及其在治疗中的应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1153778C (zh) |
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1997
- 1997-10-09 CN CNB971823979A patent/CN1153778C/zh not_active Expired - Fee Related
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| Publication number | Publication date |
|---|---|
| CN1153778C (zh) | 2004-06-16 |
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