CN1184429A - 治疗酒精成瘾的药物组合物 - Google Patents

治疗酒精成瘾的药物组合物 Download PDF

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CN1184429A
CN1184429A CN96193877A CN96193877A CN1184429A CN 1184429 A CN1184429 A CN 1184429A CN 96193877 A CN96193877 A CN 96193877A CN 96193877 A CN96193877 A CN 96193877A CN 1184429 A CN1184429 A CN 1184429A
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P·莫拉佐尼
E·鲍姆巴德利
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Abstract

本发明涉及治疗酒精成瘾的药物组合物,其特征在于它们含有作为有效成分的一种丹参的精制亲脂提取物。

Description

治疗酒精成瘾的药物组合物
本发明涉及治疗酒精成瘾的药物组合物，其特征在于它们含有作为有效成分的一种丹参的精制亲脂提取物。本发明还涉及制备丹参的精制亲脂提取物的方法，以及由此而获得的提取物。此外，本发明还涉及此提取物中所含的纯有效成分(丹参酮IIA和Miltirone)在酒精成瘾中的应用，以及用于所说治疗的药物组合物，此组合物的有效成分为丹参酮IIA和/或Miltirone。
酒精滥用和酒精成瘾是可以统称为酒精中毒症的现象，它代表整个现代社会一种严重的难题(Gessa G.L.，Bisogno compulsivo di bere e“principio del piacere”[对饮酒的强迫需要和快乐原则]，Medicina delletossicodipendenze[药物成瘾医学] II，5(1994))。例如，在意大利重度酗酒者超过人口的9％(大约为5百万人)，并且酒精成瘾者超过1百万(Calamo-Specchia F.P.，Epidemiologia dell’alcolismo in Italia[意大利酒精中毒症的流行病学]，Atti del VII Congresso Nazionale dellaS.I.A.[第7届S.I.A.全国大会记录]Mediserve，罗马，295-301，(1991))。如果考虑到诸如美国等国家，这些数字更高，在美国酒精成瘾者超过1千3百万。滥用酒精和酒精成瘾可导致社会资金的巨大浪费(最近报道，自1991年以来在美国每年花费大约200,000,000,000美元)，并且还可引起所卷入的个体巨大的社会和心理损害。
除了那些心理本性疗法(群体疗法等)，现存治疗酒精中毒症的方法在于使用诸如戒酒硫和氨基甲酸钙的药物，它们在每次饮酒出现各种不需要的现象的时候对酒精的代谢起作用，抑制肝脏醛脱氢酶，由此升高血的乙醛水平。
按照本领域目前的状况，衍生物已经用于治疗酒精中毒症的唯一植物是葛根(葛根)，它在中医中广泛应用，并构成专利申请WO93/00896的主题。
现在已经惊喜的发现丹参根的精制亲脂提取物可成功地用于减少酒精和其他可引起成瘾的药物的自主消耗。另外，已经证明从提取物中分离的单个纯产物，例如丹参酮IIA和Miltirone，也是可用的。在中国药典中正式列有丹参的干燥根(丹参，丹参根)；它们广泛用于治疗月经紊乱、诸如心绞痛和血小板功能异常的心血管疾病以及失眠症(Tang，W.Eisenbrand，G.，丹参，来源植物的中药；传统中医中的化学、药理学和应用，pp.891-902-springer-verlag，柏林(1992)；Kee ChangHuang，中草药药理学中的抗心绞痛草药，pp.81-84-CRC出版社，Boca Raton(1993))。
丹参的水-乙醇提取物用于脂肪过度沉积的局部治疗也是已知的(意大利专利1,239,281)。
本发明的提取物与已知的提取物不同，它是亲脂型的，并通过在大约20至50℃之间，用丙酮提取丹参的根而获得，其中药物/溶剂比例(w/v)在1∶2和1∶10之间，优选1∶5左右。在浓度降低至起始量的1/20至1/50左右后，加入水和水不溶混溶剂。用95°酒精(如需要)稀释后，通过反复用水冲洗除去丙酮，同时浓缩含有有效成分的有机相。
本发明的亲脂提取物的特征是丹参酮IIA的含量为5至30％w/w，优选15至25％，并且Miltirone的含量为0.5至3％w/w，优选0.8至2％。
应用称为“撒丁岛酒精偏爱”(Sp)系的消耗酒精鼠对酒精消耗的抑制作用进行测定(Fadda F.，Mosca E.，Colombo G.，Gessa G.L.，酒精偏爱鼠：乙醇诱导的多巴胺代谢的刺激作用的遗传敏感性，Physiol.Behav.47，727(1990))。
在最近这些年中，已经成功地应用这些动物对不同物质对酒精自主消耗的作用进行了测定，使它们在酒精和水消耗之间进行自由选择，每天每公斤体重给6至7g酒精(水对酒精的比例大于2∶1)；例如，见：BalakleevskyA.，Colombo G.，Fadda F.，Gessa G.L.，Ro19-4603，一种苯并二氮杂卓受体反兴奋剂可减小选择性喂养的对高酒精偏爱的鼠自主酒精消耗，Alcohol Alcohol.25，449-452(1990)；Fadda F.，Garau B.，ColomboG.，Gessa G.L.，伊拉地平和其他钙通道拮抗剂减小酒精偏爱鼠的酒精消耗，酒精中毒症：临床和实验研究16(3)，449-452(1992)。
将这些动物保持在正常的喂养条件下，在水(总是存在的)和酒精(一种10％v/v的溶液)之间对它们进行自由选择，其中酒精一天供给4小时(即：在白天/夜晚循环中，黑暗的头4小时)。在每天的同一时间记录所消耗的水和酒精的量。任意供给食物。一旦酒精和水的消耗稳定下来，则口服给予溶解在二甲亚砜中的不同剂量的丹参精制亲脂提取物(按照上面所述制备)，其量为2ml/kg，一天一次，连续5天。相同量的载体作为对照。在治疗末记录酒精和水的消耗，直到在治疗前记录的值重建。通过用于多重比较的Dunnet试验评价载体单独治疗组中所获得值的平均数的统计学显著差异(*p＜0.05，**p＜0.01)。
附图1显示增大剂量的提取物反复口服给药对酒精消耗的影响；附图2显示增大的剂量对水消耗的影响。另一方面，附图3显示重复剂量的提取物和在此所含的有效成分(丹参酮IIA和Miltirone)对酒精消耗的影响；最后，附图4显示给予重复剂量的提取物和所说的有效成分对水消耗的影响。
从附图1和2的实验中可以得到这样的结论，此提取物可明显地减小酒精消耗，并且以一种剂量相关的方式减小酒精消耗，这种结果可在首日给药后的某些情况下(即用最高剂量)获得。此酒精消耗的减小保持不变，这样直到第5天，然后随着治疗的中止，此减小出现倒退。而且惊奇地注意到，这种趋势伴随着水消耗逐渐升高的趋势，好象此动物用水代替了酒精。此后者的观察特别重要，这是因为它表明用所实验的产物进行的治疗被极好的耐受，并且动物在没有任何困难的情况下，通过用水代替酒精返回到一种更加生理化的生活周期。
用不变剂量的提取物与丹参酮IIA和Miltirone给药，重复5天(附图3和4)，这样进一步证实上面所示的结果，并且说明此纯成分(考虑到剂量)是提取物收效的主要因素。
因此本发明所提供的药物组合物可进行口服给药，并且或者含有丹参的亲脂提取物，或者含有精制有效成分丹参酮IIA和/或Miltirone作为有效成分，其后者可从市场中获得，或通过常用方法纯化此亲脂提取物而获得。除了常用的赋形剂或载体，本发明的组合物可含有大约10至500mg的提取物或相等剂量的丹参酮IIA和Miltirone(考虑到它们提取物的含量)。
                    实施例1亲脂提取物的制备
在50℃，用5升丙酮将1kg上好的丹参根提取4遍。在真空下将此重组的提取物浓缩至500ml；用1升二氯甲烷和500ml H2O稀释此浓缩液。分离相，并用水冲洗含有有效成分的有机相，直到将丙酮和不需要的极性物质除去。
将氯亚甲基相浓缩为小量；用300ml 95°酒精稀释残余物。在60℃，于真空下将此溶液浓缩至干燥。干燥一整夜后，获得11.3g提取物，它含有15.2％丹参酮IIA和1.1％Miltirone。
                实施例2胶囊形式的制剂每130mg胶囊含有：实施例1的提取物          25mg预凝胶淀粉               25mg微晶纤维素               49mg乳糖                     15mg胶体硅                    6mg交联羧基甲基纤维素钠    6.5mg聚乙烯吡咯烷酮          2.5mg硬脂酸镁                  1mg
                实施例3片剂形式的制剂：每400mg片剂含有：实施例1的提取物         100mg预凝胶淀粉              100mg微晶纤维素               96mg乳糖                     45mg胶体硅                   25mg交联羧基甲基纤维素钠     20mg聚乙烯吡咯烷酮           10mg硬脂酸镁                  4mg

Claims (11)

1.丹参根的亲脂提取物，其特征在于：它含有5至30％w/w的丹参酮IIA和0.5至3％w/w的Miltirone。
2.一种根据权利要求1的提取物，它含有15至25％w/w的丹参酮IIA。
3.一种根据权利要求1或2的提取物，它含有0.8至2％的Miltirone。
4.一种制备权利要求1-3的提取物的方法，它包括用丙酮提取丹参根，随后浓缩，用水和一种水不溶混溶剂处理浓缩液，通过用水冲洗和有机相的浓缩除去丙酮。
5.丹参亲脂提取物，它可通过用丙酮提取丹参根，随后浓缩，用水和一种水不溶混溶剂处理浓缩液，通过用水冲洗和有机相的浓缩除去丙酮而获得。
6.口服药物组合物，它含有与适宜的载体混合的权利要求1-3或5的提取物。
7.根据权利要求6的组合物，其形式为胶囊或片剂。
8.根据权利要求1-3或5的提取物在制备治疗酒精成瘾的药物中的应用。
9.丹参酮IIA在制备治疗酒精成瘾的药物中的应用。
10.Miltirone在制备治疗酒精成瘾的药物中的应用。
11.口服药物组合物，它含有与适宜的载体混合并作为有效成分的丹参酮IIA和/或Miltirone。
CN96193877A 1995-05-12 1996-05-08 治疗酒精成瘾的药物组合物 Expired - Fee Related CN1066336C (zh)

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