CN1219748C - 含有l－肉碱和烷酰基l－肉碱与牛磺酸氯化物和甘氨酸氯化物形成的非吸湿性盐的适合于口服给药的固体组合物 - Google Patents

含有l－肉碱和烷酰基l－肉碱与牛磺酸氯化物和甘氨酸氯化物形成的非吸湿性盐的适合于口服给药的固体组合物 Download PDF

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CN1219748C
CN1219748C CNB018182941A CN01818294A CN1219748C CN 1219748 C CN1219748 C CN 1219748C CN B018182941 A CNB018182941 A CN B018182941A CN 01818294 A CN01818294 A CN 01818294A CN 1219748 C CN1219748 C CN 1219748C
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Abstract

本文描述了L-肉碱和烷酰基L-肉碱与牛磺酸氯化物形成的非吸湿性盐(2-氨基乙磺酸氯化物)和L-肉碱和烷酰基L-肉碱与甘氨酸氯化物形成的非吸湿性盐，它们自身有利于制备适合于口服给药的固体组合物。本文还描述了含有所述盐的固体组合物。

Description

含有L-肉碱和烷酰基L-肉碱与牛磺酸氯化物和 甘氨酸氯化物形成的非吸湿性盐的 适合于口服给药的固体组合物
技术领域
本发明涉及L-肉碱和烷酰基L-肉碱的生理上可接受的盐，其特征在于它们是非吸湿性的和稳定的。所述的盐自身有利于制备适合于口服给药的固体组合物。本发明还涉及含有上述化合物的药物和饮食或营养组合物。
背景技术
众所周知肉碱及其烷酰基衍生物本身用于各种治疗应用。例如，L-肉碱用于治疗急性和慢性心肌缺血、心绞痛、心衰和心律失常的心血管领域。
在肾脏病学领域中，对定期进行血液透析治疗的尿毒症患者给予L-肉碱以对抗肌无力和肌肉痉挛发作。
其它治疗应用涉及恢复正常HDL/LDL+VLDL比和总肠胃外营养。
另外众所周知的是迄今为止了解的L-肉碱及其烷酰基衍生物的盐与所谓的“内盐”具有相同治疗或营养活性且由此可以适当使用，条件是这类盐是“生理上可接受的”，也就是说它们不会产生毒性或不需要的副作用。
然而，实际上迄今为止在内盐与L-肉碱或烷酰基L-肉碱的实际盐之间的选择仅取决于该化合物是否可以更易于或更经济地得到且取决于对制药技术的考虑而不是取决于对治疗或营养活性的考虑。
本文所述的本发明的目的是提供L-肉碱和低级烷酰基L-肉碱类的稳定而非吸湿性盐，它们与相应内盐相比还可产生提高的治疗和/或营养价值。
因此，显然应理解本文所述的本发明盐的有用性不仅包括其非吸湿性及其与相应内盐相比较高的稳定性，而且在于它们的阴离子部分对整个盐的治疗和/或营养价值起一定作用，因此，这样的价值并非仅由该盐的“肉碱”部分所决定。
这些盐的非吸湿性使得它们更易于加工，特别是对制备固体口服给药剂型更是如此。
制药技术领域中的专业技术人员都很了解，吸湿性产品的加工需要在储存和加工过程中使用湿度控制室。
此外，必须将终产品包装在密封的泡罩包装中以避免湿度的不良结果。
所有这些均意味着原料及其加工和包装的储存成本更高。
在工业化国家的人口中，运动员(业余爱好者或专业人员)对食品增补剂或“营养品”的应用在增加且处于良好健康状态的人们对它们的应用也在增加。
运动员应用肉碱或含有肉碱的食品增补剂，因为它有利于脂肪酸类的氧化并使骨骼肌获得更多能量成为可能，由此使运动能力增强并使乳酸在运动员肌肉中的累积较少。
处于良好健康状态的人将这些食品增补剂用作保健食品，即从预防涉及脂质代谢紊乱的疾病的观点来看，这些保健食品用于有利于血清脂肪水平下降和恢复各种胆固醇级分之间的正常比例的目的。
据估计因非处方目的销售的L-肉碱及其衍生物是因处方目的销售的L-肉碱及其衍生物的2倍。
美国市场的保健食品或营养品的份额约占2500亿美元(250billion dollars)，而对欧洲市场的估计数字约为5000亿美元(500billion dollars)(《食品标志新闻》(Food Labeling News)，1994，“营养品”市场是一个巨大的市场(“Nutraceuticals”Market said to be avast one)，3月第2卷N°25；King Communications Group Inc.，1993，全球市场中的“营养品”食品、饮料(“Nutraceuticals”Foods，Drinkin Global Market)-《每日食品和饮料》(Food and Drink Daily)，4月第3卷，N°503)。
许多L-肉碱或烷酰基L-肉碱类的非吸湿性盐已经是已知的。
例如，1990年12月21日提交的欧洲专利0 434 080(Lonza)中描述了L-肉碱与L(+)-酒石酸的非吸湿性盐(已经由Múller和Strack在Hoppe-Seyler Z.的《生理学与化学》(Physiol.Chem.)，353，618-622，1972年4月中描述的盐)在制备固体口服给药剂型中的应用。
然而，该盐存在许多缺点，诸如：例如在长期储存后释放三甲胺，因这种胺的腥臭味道而产生不良的气味。
此外，L(+)-酒石酸不能与诸如例如乙酰基L-肉碱这样的烷酰基L-肉碱类形成非吸湿性盐。
还应注意酒石酸盐的阴离子不能单独提高肉碱的治疗和/或营养价值。
美国专利US4,602,039(Sigma Tau)中描述了L-肉碱、乙酰基L-肉碱和丙酰基L-肉碱的富马酸盐。
尽管L-肉碱富马酸盐是高度非吸湿性的，甚至比L-肉碱酒石酸盐更耐高相对湿度含量的周围环境，但是这种特性似乎在增加烷酰基的重量时会减少。
WO98/43945中描述了适合于口服给药的含有L-肉碱和烷酰基L-肉碱类与2-氨基乙磺酸(牛磺酸)形成的非吸湿盐的固体组合物。
WO98/45250中描述了适合于口服给药的含有L-肉碱和烷酰基L-肉碱酒石酸镁的固体组合物。
WO98/44918中描述了适于口服给药的含有烷酰基L-肉碱酒石酸镁的固体组合物
WO98/47857中描述了适合于口服给药的含有L-肉碱胆碱酒石酸盐或烷酰基L-肉碱胆碱酒石酸盐的固体组合物。
WO98/49134中描述了适合于口服给药的含有L-肉碱或烷酰基L-肉碱富马酸镁的固体组合物。
发明内容
因此，本文所述的本发明上述目的形成了L-肉碱和低级烷酰基L-肉碱类的新型药物上可接受的非吸湿性的稳定盐，其中阴离子部分对该盐的治疗和/或营养价值起一定作用。
因此，本文所述的本发明的目的是通式(I)的L-肉碱与牛磺酸氯化物形成的盐(2-氨基-乙磺酸的氯化物盐)：
Figure C0181829400061
其中R是氢或具有2-5个碳原子的直链或支链低级烷酰基。
优选其中R选自乙酰基、丙酰基、丁酰基、戊酰基或异戊酰基组成的组的盐。
如上所述，以本申请人的名义提交的国际专利申请WO98/43945中描述了含有与2-氨基乙磺酸形成的非吸湿性肉碱盐的适合于口服给药的固体组合物，而本文所述的本发明的盐是含有2-氨基乙磺酸的氯化物盐的肉碱盐。
预计本领域技术人员通过阅读WO98/43945会得到与2-氨基-乙磺酸的氯化物盐形成的肉碱盐，其具有的吸湿性与WO98/43945中所述盐的吸湿性相似。
与WO98/43945中所述盐相比，本文所述的本发明盐的令人意外的较低吸湿性使得它们特别适用于制备适合于上述目的的固体口服组合物。
本文所述的本发明的另一个目的是通式(II)的L-肉碱与甘氨酸氯化物形成的盐：
其中R是氢或具有2-5个碳原子的直链或支链低级烷酰基。优选其中R选自乙酰基、丙酰基、丁酰基、戊酰基或异戊酰基组成的组的盐。
牛磺酸是身体内最丰富的氨基酸之一且在中枢神经系统和骨骼肌中被发现并且集中在大脑和心脏中。目前一段时间已知牛磺酸在哺乳动物生长和发育过程中是必不可少的营养物；实际上，它存在于母乳中且对小脑和视网膜的发育尤为重要。牛磺酸还具有极其重要的代谢功能：在胆汁中，胆汁酸与牛磺酸结合而分别形成甘氨胆酸和牛磺胆酸。
胆汁酸的盐具有降低溶液表面张力的重要特性。由于这一原因，所以它们是极佳的乳化剂且在肠中具有吸收和消化脂类的重要功能。
这些重要的代谢和营养特性意味着当牛磺酸与L-肉碱结合时，牛磺酸具有补充L-肉碱具有的功能的特性。实际上，牛磺酸通过促进脂肪酸类的乳化和消化而补充随后由L-肉碱产生的代谢活性，即为能量产生而氧化脂肪酸类。
甘氨酸是广泛用作人体营养和家畜和宠物饲喂中的食品增补剂的重要氨基酸。因此，肉碱与甘氨酸形成的非吸湿性盐还提供了比相应内盐提高的治疗和/或营养价值，即如上所述，阴离子部分(甘氨酸)提供了所述的治疗和/或营养价值，因此这一价值不再仅由所述盐的“肉碱”部分来决定。
本文所述的本发明的非吸湿性盐是在生理条件下人或动物营养中、即健康状态良好的受试者中和在儿童和成年人中观察到的吸收障碍中有用的活性剂。
本文所述的本发明L-肉碱和低级烷酰基L-肉碱类的盐是非吸湿性的、易于加工且在储存时高度稳定。
本文下面给出了制备本发明非吸湿性盐的实施例。
实施例1
制备乙酰基L-肉碱与牛磺酸氯化物形成的盐(ST 1805)的步骤
将2.5g的牛磺酸[0.02mol]和4.78g的乙酰基L-肉碱氯化物[0.02mol]溶于最少量的水并在40℃下进行真空浓缩。用丙酮提取由此获得的残余物并在搅拌条件下保持过夜且然后过滤并干燥。
得到7.1g的非吸湿性白色结晶固体。
产率：76％。
DSC＝186℃(分解)。
固相NMR 13C
ppm 67.0(CH-O)；63.6(N+-CH2-CH)，54.1((CH3)3N+)；46.6(N+CH2-CH2)；36.4(CH2CO，CH2S)；21.9(CH3)
NMR：D2O Hδ 5.6-5.5(1H，m，-CH-)；3.8-3.6(2H，m，N-CH2)；3.4-3.3(2H，t，H2N-CH2)；3.2-3.1(2H，t，CH2-SO3-)；3(9H，s，(CH3)3-N)；2.8-2.7(2H，d，CH2-COOH)；2(3H，s，COCH3)
实施例2
制备丙酰基L-肉碱与牛磺酸氯化物形成的盐(ST 1806)的步骤
Figure C0181829400082
将2.5g的牛磺酸[0.02mol]和5.1g的丙酰基L-肉碱氯化物[0.02mol]溶于最少量的水并在40℃下进行真空浓缩。用丙酮提取由此获得的残余物、在搅拌条件下保持过夜且然后过滤并干燥。
得到7.2g的非吸湿性白色结晶固体。
产率：98％。
DSC＝175℃(分解)。
固相NMR 13C
ppm 69.5(CH-O)；66.4(N+CH2-CH)，53.9((CH3)3)；46.5(N+CH2-CH2)；36.1(CH2CO，CH2S)；29.6(OCOCH2)；10.4(CH3)
NMR：D2O Hδ 5.6-5.5(1H，m，-CH-)；3.8-3.6(2H，m，N-CH2)；3.4-3.3(2H，t，H2N-CH2)；3.2-3.1(2H，t，CH2-SO3-)；3.1(9H，s，(CH3)3-N)；2.7-2.6(2H，m，CH2-COOH)；2.4-2.3(2H，q，CH2CH3)；1-0.9(3H，t，CH2-CH3)
实施例3
制备乙酰基L-肉碱与甘氨酸氯化物形成的盐ST 1803的步骤
将2.2g的盐酸甘氨酸(吸湿产品)[0.02mol]和4.06g的乙酰基L-肉碱内盐(吸湿产品)[0.02mol]溶于50ml水并进行真空浓缩。
用丙酮提取由此获得的残余物并在搅拌条件下保持过夜且过滤。
将滤液在30℃下进行真空干燥。
得到6.1g的非吸湿性白色结晶固体形式的盐酸甘氨酸乙酰基L-肉碱盐。
产率：95％。
DSC＝177℃(分解)。
固相NMR 13C
ppm 67.0(CH-O)；63.8(N+-CH2)，54.5((CH3)3N+)；42.6(N-CH2-CO)；36.3(CH2CO)；27.1(CH3)
NMR：D2O Hδ 5.6-5.5(1H，m，-CH-)；3.7-3.5(2H，m，N-CH2)；3.5(2H，s，H2N-CH2)；3.1(9H，s，(CH3)3-N)；2.6-2.4(2H，m，CH2-COOH)；2(3H，s，CO-CH3)
实施例4
制备丙酰基L-肉碱与甘氨酸氯化物形成的盐ST 1804的步骤
Figure C0181829400101
将2.2g[0.02mol]的盐酸甘氨酸(吸湿产品)和4.35g的丙酰基L-肉碱内盐(吸湿产品)[0.02mol]溶于最少量的水并进行真空浓缩。用丙酮提取由此获得的残余物并在搅拌条件下保持过夜且然后过滤并干燥。
得到6.2g的非吸湿性白色结晶固体。
产率：94％。
DSC＝163℃(分解)。
固相NMR 13C
ppm 69.5(CH-O)；66.4(N+-CH2)，53.8((CH3)3N+)；43.1(N-CH2-CO)；35.1(CH2CO)；29.6(OCOCH2)；13.3(CH3)
NMR：D2O Hδ＝5,6-5,5(1H，m，-CH-)；3.7-3.5(2H，m，N-CH2)；3.5(2H，s，H2N-CH2)；3.1(9H，s，(CH3)3-N-)；2.7-2.6(2H，m，CH2-COOH)；2.4-2.3(2H，q，CH2-CH3)；1-0.9(3H，t，CH2CH3)
上述实施例中的化合物是非吸湿性的且非常稳定。
本文所述的本发明还包括含有药物和食品技术人员众所周知的至少一种上述药物上可接受的非吸湿性盐和可能的一种或多种其它活性组分的组合物作为其活性组分。
特别优选的是适合于制备如片剂、咀嚼片或胶囊这样的口服给药剂型的固体形式的组合物，它含有相当于50-2000mg、优选100-1000mg以内盐表示的L-肉碱或烷酰基L-肉碱的通式(I)或(II)的L-肉碱或烷酰基L-肉碱的盐。
例如，适合于生产片剂的组合物如下：
本发明L-肉碱的非吸湿性盐           500mg
          淀粉                     20mg
          滑石                     10mg
          硬脂酸钙                 1mg
                                   共531mg
适合于生产胶囊的组合物如下：
本发明L-肉碱的非吸湿性盐           500mg
          乳糖                     50mg
          淀粉                     20mg
          滑石                     5mg
          硬脂酸钙                 2mg
                                   共577mg

Claims (7)

1.通式(I)的L-肉碱或烷酰基L-肉碱与牛磺酸氯化物的盐：
其中R是氢或具有2-5个碳原子的直链或支链低级烷酰基。
2.权利要求1的盐，其中R选自乙酰基、丙酰基、丁酰基、戊酰基和异戊酰基。
3.含有如权利要求1或2中所定义的通式(I)的化合物作为其活性组分的组合物。
4.权利要求3的组合物，另外含有一种或多种选自药物上可接受的赋形剂和活性组分的物质。
5.权利要求3或4的组合物，它是片剂、咀嚼片、胶囊、颗粒或粉剂形式。
6.权利要求3的组合物，它是含有通式(I)的L-肉碱或烷酰基L-肉碱的盐作为其活性组分的单位剂型，该单位剂型含有50-2000mg以内盐表示的L-肉碱或烷酰基L-肉碱。
7.权利要求6的组合物，其中所述单位剂型含有100-1000mg以内盐表示的L-肉碱或烷酰基L-肉碱。
CNB018182941A 2000-10-31 2001-09-28 含有l－肉碱和烷酰基l－肉碱与牛磺酸氯化物和甘氨酸氯化物形成的非吸湿性盐的适合于口服给药的固体组合物 Expired - Lifetime CN1219748C (zh)

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