CN1501916A - 新型氨氯地平樟脑磺酸盐及其制备方法 - Google Patents
新型氨氯地平樟脑磺酸盐及其制备方法 Download PDFInfo
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- CN1501916A CN1501916A CNA028074432A CN02807443A CN1501916A CN 1501916 A CN1501916 A CN 1501916A CN A028074432 A CNA028074432 A CN A028074432A CN 02807443 A CN02807443 A CN 02807443A CN 1501916 A CN1501916 A CN 1501916A
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- amlodipine
- camphorsulfonic acid
- camsylate
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- C—CHEMISTRY; METALLURGY
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
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Abstract
本发明的氨氯地平樟脑磺酸盐是适用于药物组合物的氨氯地平结晶盐，其是使用低毒性樟脑磺酸制备的，满足用于治疗心血管疾病所要求的药学性质。
Description
技术领域
本发明涉及式1的氨氯地平樟脑磺酸盐及其制备方法。
背景技术
氨氯地平为式2化合物、3-乙基-5-甲基-2-(2-氨基乙氧基-甲基)4-(2-氯苯基)-6-甲基-1，4-二氢-3，5-吡啶二羧酸酯的通称，是用于治疗心血管(cadiovacular)疾病如心绞痛、高血压及充血性心麻痹的长期钙通道阻滞药
欧洲专利公开第89167号公开了各种不同类型的氨氯地平药学可接受盐。通过加入药学可接受酸，形成氨氯地平酸类型的无毒盐，制备药学可接受盐，其实例包括氢氯化物、氢溴化物、硫酸盐、磷酸盐或酸性磷酸盐、乙酸盐、马来酸盐、富马酸盐、乳酸盐、酒石酸盐、柠檬酸盐及葡糖酸盐。这些盐中，马来酸盐是最优选的。
游离碱形式的氨氯地平用于药学用途。然而，因为非晶相氨氯地平显示了低稳定性，优选以药学可接受酸的盐的形式给药。
韩国专利公开第95-6710号建议药学可接受盐必须满足四个物理化学要求：高溶解度、良好稳定性、非吸湿性及片剂配制的可加工性。
多数氨氯地平盐是非晶相的且很难单纯地制备它们。另外，满足所有以上要求的加成酸的氨氯地平盐尚有待发展。例如，已发现即使是建议作为氨氯地平最优选药物形式的氨氯地平马来酸盐在水中具有相对高的溶解度，但其也在几周内在溶液中降解。
韩国专利公开第95-7228号公开了氨氯地平的苯磺酸盐(下文称为“氨氯地平苯磺酸盐”)显示了高溶解度及良好的稳定性，并且具有适合于制备药学制剂的性能。然而，氨氯地平苯磺酸盐衍生自有毒的苯磺酸，因此具有安全问题。
本发明致力于开发一种新型结晶氨氯地平，其满足全部所需性能。
发明内容
因此，本发明的主要目的是提供一种新型氨氯地平结晶盐，其为低毒的且具有药学可接受性质。
根据本发明的一个方面，提供了一种使用比苯磺酸毒性相对低的樟脑磺酸制备氨氯地平结晶盐的方法。
仍根据本发明的另一方面，提供了由本发明方法制备的具有式(1)结构的氨氯地平樟脑磺酸盐。
根据本发明的再一方面，提供了用于治疗心血管疾病的药物组合物，其包括作为作为有效成分的氨氯地平樟脑磺酸盐。
附图说明
当结合附图时，本发明的上述及其他目的经通过以下对本发明的描述而变得明显，所述附图分别为：
图1：本发明的氨氯地平樟脑磺酸盐的X射线衍射扫描图；
图2：氨氯地平苯磺酸盐的X射线衍射扫描图；
图3：本发明的氨氯地平樟脑磺酸盐及氨氯地平苯磺酸盐的粘着性。
具体实施方式
本发明提供了一种使用低毒性樟脑磺酸制备氨氯地平结晶盐的方法。
具体而言，本发明方法包括以下步骤：
1)在有机溶剂中溶解式(2)的氨氯地平；
2)将有机溶剂中的樟脑磺酸溶液加入到氨氯地平溶液中，并搅拌该混合物足够长的时间以形成固体；
3)过滤、洗涤并干燥该固体。
可通过加入酸至氨氯地平溶液中或加入酸至用于制备氨氯地平的反应混合物中来制备本发明的氨氯地平结晶盐。
优选使用浓度为3-60重量％的步骤1)的氨氯地平，有效地促进结晶，更优选10-30重量％。
可在步骤2)中使用的樟脑磺酸包括但不限于式(3)的(1S)-(+)-10-樟脑磺酸、式(4)的(1R)-(-)-10-樟脑磺酸及消旋10-樟脑磺酸。以氨氯地平的量为基准，优选使用樟脑磺酸的量为0.1-5.0当量，更优选1.0-1.3当量。
步骤1)或2)中使用的有机溶剂包括甲醇、乙醇、异丙醇及乙腈。
步骤2中的固体优选形成于-10-50℃，更优选0-25℃。
另外，本发明提供了本发明方法制备的氨氯地平樟脑磺酸盐，其是低毒的且具有药学可接受性能。
已经通过X射线衍射扫描(见图1及2)证实，本发明的氨氯地平结晶盐—氨氯地平樟脑磺酸盐具有不同于非晶相化合物或氨氯地平苯磺酸盐的晶形，并且通过NMR分析证实具有式(1)的结构。
众所周知，氨氯地平苯磺酸盐最适合用于药物制剂的，但是其由于有毒的苯磺酸的使用而具有稳定性问题。为了解决这个问题，本发明使用比苯磺酸具有相对低毒性的樟脑磺酸。
樟脑磺酸的毒性与苯磺酸的毒性根据Registry of Toxic Effects ofChemical Substances(RTECS)数据进行比较，比较结果如表1所示。
表1
| 物质 | 给药途径 | 试验动物 | 剂量 | 文献 |
| 苯磺酸 | 口服 | 兔 | LD50890μl/kg | AIHAAP23,95,1962 |
| 皮肤 | 猫 | LDLO10g/kg | JPETAB84,358,1945 | |
| 口服 | 野鸟 | LD5075mg/kg | TXAPA921,315,1972 | |
| (1S)-(+)-10-樟脑磺酸 | 皮下 | 鼠 | LD502502mg/kg | PHARAT1,150,1946 |
| (±)-10-樟脑磺酸 | 口服 | 鹌鹑 | LD50＞316mgl/kg | EESADV6,149,1982 |
| #LD50：50％致死量，LDLO：最小致死量 | ||||
如表1所示，因为不可能比较二者之间相同物种的LD50值，所以很难直接比较樟脑磺酸和苯磺酸之间的毒性，然而，可以肯定本发明中所用的樟脑磺酸比苯磺酸显示了更低的毒性。
再者，本发明提供了用于治疗心血管疾病的药物组合物，其包括作为活性成分的本发明的氨氯地平樟脑磺酸盐及药学可接受的赋形剂、载体或稀释剂。
可根据任何常规程序制备药物组合物。在制备该组合物过程中，活性成分优选用载体混合或稀释，或包裹在胶囊、小袋或其他容器形式的载体内。当该载体用作稀释剂时，其可为固体、半固体或液体材料，起运输工具、赋形剂或介质的作用。因此，制剂的形式可为片剂、丸剂、散剂、袋剂、酏剂、混悬剂、乳剂、溶液、糖浆剂、气雾剂、软或硬明胶胶囊、无菌可注射溶液、无菌包装散剂等。
适合的载体、赋形剂及稀释剂的实例为乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖醇、淀粉、阿拉伯树胶、藻朊酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯基吡咯烷酮、水、甲基羟基苯甲酸盐、丙基羟基苯甲酸盐、滑石、硬脂酸镁及矿物油。该组合物可另外包括填料、抗粘结剂、润滑剂、香味剂、乳化剂、防腐剂等。可配制本发明的组合物，以便通过使用本领域的任何公知程序对哺乳动物给药后提供快速、持久或缓释的活性成分。
本发明的药物组合物可经由各种途径给药，包括口服、皮肤、皮下、静脉及肌肉引入。当为人时，氨氯地平樟脑磺酸盐的典型日剂量可为约1.0-10.0mg/kg体重，优选5.0-8.0mg/kg体重，并可以单剂量或分开剂量给药。
然而，应理解实际给药的活性成粉量应取决于各种相关因素，包括每个病人待治疗的情况、所选给药途径、年龄、性别及体重，以及病人病症的严重性；并且因此上述剂量不以任何方式试图限制本发明的范围。
以下实施例及测试例仅用于说明目的，并非用来限制本发明的范围。
实施例1：制备氨氯地平樟脑磺酸盐1
12.25g(0.03mol)的氨氯地平(Hanmi Pharm.Co.Ltd.)溶解于50ml甲醇中，冷却至10℃，然后向其中逐渐加入溶解于19.5ml甲醇中的7.8g(0.336mol)的(1S)-(+)-10-樟脑磺酸(Aldrich)溶液。将反应混合物在室温搅拌2小时后，过滤固体形式化合物，用25ml甲醇洗涤，然后干燥得到16.7g(产率：86.8％)白色晶体形式的题述化合物。
m.p.：198℃～202℃
1H-NMR(300MHz，DMSO-d6)δ(ppm)：8.42(s，1H)，7.82(br，3H)，7.35～7.13(m，4H，ArH)，5.30(s，1H)，4.73～4.55(d.d.，2H)，3.96(q，2H)，3.65(m，2H)，3.50(s，3H)，3.34(s，2H)，3.08(m，2H)，2.90～2.35(d.d.，2H)，2.70(m，1H)，2.31(s，3H)，2.28～2.21(m，1H)，1.95～1.77(m，3H)，1.27(m，2H)，1.26(t，3H)，1.05(s，3H)，0.74(s，3H)
实施例2：制备氨氯地平樟脑磺酸盐2
12.25g(0.03mol)的氨氯地平溶解于50ml甲醇中，冷却至10℃，然后向其中逐渐加入溶解于19.5ml甲醇中的7.8g(0.336mol)的(1R)-(-)-10-樟脑磺酸(Aldrich)溶液。使用与实施例1相同的方法得到15.4g(产率：80.0％)白色晶体形式的题述化合物。
m.p.：198℃～204℃
1H-NMR(300MHz，DMSO-d6)δ(ppm)：8.42(s，1H)，7.82(br，3H)，7.35～7.13(m，4H，ArH)，5.30(s，1H)，4.73～4.55(d.d.，2H)，3.96(q，2H)，3.65(m，2H)，3.50(s，3H)，3.34(s，2H)，3.08(m，2H)，2.90～2.35(d.d.，2H)，2.70(m，1H)，2.31(s，3H)，2.28～2.21(m，1H)，1.95～1.77(m，3H)，1.27(m，2H)，1.26(t，3H)，1.05(s，3H)，0.74(s，3H)
实施例3：制备氨氯地平樟脑磺酸盐3
12.25g(0.03mol)的氨氯地平溶解于50ml甲醇中，冷却至10℃，然后向其中逐渐加入溶解于19.5ml甲醇中的7.8g(0.336mol)的(±)-10-樟脑磺酸(Aldrich)溶液。使用与实施例1相同的方法得到16.0g(产率：83.2％)白色晶体形式的题述化合物。
m.p.：198℃～202℃
1H-NMR(300MHz，DMSO-d6)δ(ppm)：8.42(s，1H)，7.82(br，3H)，7.35～7.13(m，4H，ArH)，5.30(s，1H)，4.73～4.55(d.d.，2H)，3.96(q，2H)，3.65(m，2H)，3.50(s，3H)，3.34(s，2H)，3.08(m，2H)，2.90～2.35(d.d.，2H)，2.70(m，1H)，2.31(s，3H)，2.28～2.21(m，1H)，1.95～1.77(m，3H)，1.27(m，2H)，1.26(t，3H)，1.05(s，3H)，0.74(s，3H)
实验例1：溶解度试验
氨氯地平盐优选在水中的溶解度为在pH1-7.5时为超过1mg/ml，特别在血液pH值为7.4时。因此测试实施例1及2的每种氨氯地平樟脑磺酸盐的溶解度及饱和pH值，并与氨氯地平苯磺酸盐(韩国专利公开第95-7228号)比较。根据韩国药典(Korean Ministry ofHealth and Welfare，Gereral principle of medical supplies，Vol.1，Clause29，the 7th revision)描述的程序实施测量，其包括以下步骤：将每种化合物溶解于蒸馏水中至饱和，用液相色谱分析饱和溶液，然后测量每种化合物以氨氯地平为基准的溶解量。
表2
| 盐 | 溶解度(mg/ml) | 饱和pH |
| 氨氯地平苯磺酸盐 | 1.398 | 6.2 |
| 实施例1的氨氯地平樟脑磺酸盐(S) | 1.225 | 6.0 |
| 实施例2的氨氯地平樟脑磺酸盐(R) | 1.250 | 6.2 |
如表2所示，本发明的氨氯地平樟脑磺酸盐的饱和pH类似于氨氯地平苯磺酸盐的值，但是其溶解度略低于氨氯地平苯磺酸盐的值，可能是由于氨氯地平樟脑磺酸盐分子量(M.W＝641.18)及氨氯地平苯磺酸盐分子量(M.W＝559.06)之间的差异。
实验例：稳定性试验
测量实施例1及2中制备的本发明的氨氯地平樟脑磺酸盐的时间相关稳定性，并与氨氯地平苯磺酸盐比较。具体而言，每种化合物在55℃、相对湿度约50％下储存，并在1、2、3及4周后，用液相色谱测定活性氨氯地平的残留量。
表3
| 盐 | 初始 | 1周 | 2周 | 3周 | 4周 |
| 氨氯地平苯磺酸盐 | 1 | 0.99 | 0.996 | 0.993 | 0.993 |
| 实施例1的氨氯地平樟脑磺酸盐(S) | 1 | 1 | 0.998 | 1 | 1 |
| 实施例2的氨氯地平樟脑磺酸盐(R) | 1 | 1 | 1 | 1.002 | 1 |
如表3所示，氨氯地平苯磺酸盐在1周后具有微小但显著的降解，而本发明的氨氯地平樟脑磺酸盐在4周时间内是稳定的。因此，相比于氨氯地平苯磺酸盐，本发明的氨氯地平樟脑磺酸盐更稳定。
实验例3：无吸湿性试验
当配制固体形式药品时，药品不吸湿是重要的。因此，测量本发明的氨氯地平樟脑磺酸盐的吸湿性并与氨氯地平苯磺酸盐的吸湿性进行比较。
每种化合物暴露于两种条件：37℃、75％相对湿度、24小时(条件1)以及30℃、95％相对湿度、3天(条件2)，并且然后根据韩国专利公开第1995-7228号描述的方法测量每种化合物的含湿量。
表4
| 盐 | 原始湿度 | 条件1(％) | 条件2(％) |
| 氨氯地平苯磺酸盐 | 0.05 | 0.05 | 0.15 |
| 实施例1的氨氯地平樟脑磺酸盐(S) | 0.05 | 0.05 | 0.15 |
| 实施例2的氨氯地平樟脑磺酸盐(R) | 0.05 | 0.05 | 0.15 |
表4中结果表明无论本发明的氨氯地平樟脑磺酸盐，还是氨氯地平苯磺酸盐都不是吸湿的。
实验例4：对比粘合性试验
测量本发明的氨氯地平樟脑磺酸盐的粘合性，并与如下的氨氯地平苯磺酸盐的粘合性进行比较。
每种化合物根据韩国专利公开第95-7228号制成片剂，粘合在制片剂冲床的残留化合物用甲醇以多种片剂量萃取，并用分光计测量其量。
多次测量的平均值由图3的直线的斜率来确定。
图5
| 片剂吸附量(μg) | ||||||
| 氨氯地平苯磺酸盐 | 氨氯地平樟脑磺酸盐 | 樟脑磺酸盐/苯磺酸盐 | ||||
| 片剂量 | AVG. | S.D | AVG. | S.D | AVG. | S.D |
| 50 | 32.9 | 5.6 | 33.0 | 8.2 | 1.00 | 0.08 |
| 100 | 60.6 | 2.5 | 60.6 | 9.1 | 0.99 | 0.11 |
| 150 | 102.7 | 15.7 | 101.1 | 14.6 | 0.99 | 0.01 |
| 220 | 183.8 | 1.1 | 177.1 | 2.1 | 0.96 | 0.01 |
| 250 | 235.1 | 5.3 | 234.8 | 13.3 | 1.00 | 0.03 |
| 300 | 242.7 | 2.6 | 235.4 | 1.4 | 0.97 | 0.02 |
由表5可看出，本发明的氨氯地平樟脑磺酸盐及氨氯地平苯磺酸盐在粘度抑制性能方面是相同的(图3)。
当本发明用上述具体实施方案描述时，应认识到本令技术人员可对本发明作出的各种改变及变化也落入所附权利要求限定的本发明的保护范围。
Claims (8)
1.具有式1结构的氨氯地平樟脑磺酸盐。
2.一种制备权利要求1的氨氯地平樟脑磺酸盐的方法，其包括以下步骤：
1)在有机溶剂中溶解式2的氨氯地平；
2)加入溶于有机溶剂中的樟脑磺酸溶液至所述氨氯地平溶液中，并搅动该混合物足够长的时间以形成固体；
3)过滤、洗涤并干燥该固体。
3.如权利要求2的方法，其中所述樟脑磺酸选自以下组中：式(3)的(1S)-(+)-10-樟脑磺酸、式(4)的(1R)-(-)-10-樟脑磺酸及消旋10-樟脑磺酸。
4.如权利要求2的方法，其中步骤2)中所用混合物的氨氯地平浓度为3-60重量％。
5.如权利要求2的方法，其中以氨氯地平的量为基准，所用樟脑磺酸的量为0.1-5.0当量。
6.如权利要求2的方法，其中步骤1)或2)中所用有机溶剂选自以下组中：甲醇、乙醇、异丙醇及乙腈。
7.如权利要求2的方法，其中所述固体形成于-10-50℃。
8.一种用于治疗心血管疾病的药物组合物，其包括作为活性成分的权利要求1的氨氯地平樟脑磺酸盐。
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| US20070135488A1 (en) * | 2002-04-13 | 2007-06-14 | Chung You S | Amlodipine nicotinate and process for the preparation thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101495451B (zh) * | 2006-07-21 | 2012-07-25 | 韩美药品株式会社 | (s)-(-)-氨氯地平樟脑磺酸盐或其水合物及包含其的药物组合物 |
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