CN1121688A - 稳定、可食、易吸收的nadh和nadph治疗组合物 - Google Patents

稳定、可食、易吸收的nadh和nadph治疗组合物 Download PDF

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CN1121688A
CN1121688A CN94191939A CN94191939A CN1121688A CN 1121688 A CN1121688 A CN 1121688A CN 94191939 A CN94191939 A CN 94191939A CN 94191939 A CN94191939 A CN 94191939A CN 1121688 A CN1121688 A CN 1121688A
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乔格·G·D·伯克迈耶
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Abstract

一种药丸形式的稳定、可食且可肠道吸收的治疗组合物，其含有NADH或NADPH或其生理可接受盐，这种药丸的外表面包有一层酸性稳定性保护性包衣。这种NADH/NADPH的口服形式具有很多已知的治疗效果。

Description

说明 书 稳定、可食、易吸收的NADH 和NADPH治疗组合物
本发明涉及一种可作为治疗药口服的稳定的NADH和NADPH组合物。
烟酰胺-腺嘌呤二核苷酸(NADH)和烟酰胺-腺嘌呤-磷酸-二核苷酸(NADPH)都是生理物质，存在于包括人类细胞在内的所有活细胞中。这些物质是很多酶的辅助因子，而这些酶大部分都可催化氧化-还原反应。在最近发现这些化合物的治疗特性之前，它们的主要用途就是在临床生物化学方面作为诊断工具，是反应试剂盒中的必要成分，例如，测量乳酸脱氢酶(LDH)。
NADH最重要的作用是它对细胞呼吸的驱动力。当用氧时，NADH按以下公式形成水和3个ATP分子： 。于是，用一个NADH分子获得3个ATP分子，它具有将近21千卡的能量，这一过程叫做氧化磷酸化。有NADH和/或NADPH使得这工作对生物体来说容易多了，因为它最终可有更多的能量贮备。
最近，NADH和NADPH以及其药理可接受盐已显示出在帕金森病的治疗中有用。这些药对此病的疗效记录在我现存的美国专利4,870,200和5,019,561号文件中，其公开内容并入本文作为参考。
另外，我还发现这些物质对Alzheimer病的治疗有效(即：早老性痴呆)，同时对精神抑郁症的治疗有效，这是我的共同未决专利申请07/815,407的主题，于1991年12月31日在美国专利和商标局提交。
在我的近期发现之前，从没人认为NADH和NADPH有治疗作用，这可能因为人们认为这些化合物太不稳定而不可能被人体肠道吸收、人们料想这些物质在几秒钟内就会在血浆中被水解。
然而，最近应用NADH和NADPH进行的研究证明这些假设是错误的。将NADH和NADPH静脉注入帕金森病患者体内后，观察到一种显著的良性作用至少持续了24小时。详见美国专利4,970,200和5,019,561号。这表明NADH和NADPH在血浆和血液中并没有迅速降解。
静脉内应用NADH和NADPH的一个缺点就是需要注射，而注射必须在医院或由医生进行，这可能会不方便或需依赖于患者的时间。于是人们渴望发现一种稳定的NADH和NADPH的口服形式，患者可以在自己的监督下规律地服用这些物质。
本发明的一个目的就是提供一种存放稳定的NADH和NADPH的口服形式，它足够稳定而不会像前文所述被氧化成失活的NAD+和NADP+，患者可以在他们方便的时候摄入这些物质取得治疗效果。
本发明的另一目的是提供这种稳定的NADH和NADPH口服形式，它能够经受住胃内酸性条件，使这些物质直到肠道内才被吸收。
依照本发明，可提供NADH和/或NADPH的储存稳定性药丸(例如：片剂、胶囊、小药片、小药丸形式)，它包有一层酸性稳定保护膜，可使这些治疗性物质不被胃内酸性环境破坏。在优选的盖仑制剂中，将NADH和/或NADPH和稳定剂和填料压缩在一起。人们惊奇且完全出乎意料地发现口服的NADH和/或NADPH被肠道吸收并进入血流，流至神经系统发挥它已知的治疗作用。
NADH和NADPH在pH值低于7时都是很不稳定的，而胃内都是这种环境。所以，依照本发明，这些物质必须包被一层酸性稳定保护层，使它们可以通过胃内环境继而进入肠道被吸收。合适的酸性稳定包衣是本领域中已知的，而且可以在活性成分制成片剂或胶囊之后通过传统包衣工艺完成。合适的包衣例子是：纤维素醋酸酯邻苯二甲酸酯；聚乙酸乙烯酯邻苯二甲酸酯；羟基-丙基-甲基纤维素邻苯二甲酸酯；甲基丙烯酸共聚物；脂-蜡；虫胶；玉米蛋白；水衣和surerelease。一种优选的包衣基质见下文实例1中。制成包衣的另一种可能性是一种邻苯二甲酸酯和一种乏干性物质的异丙醇溶液。一种合适的乏干性物质在Rohm Pharma出售，名为EU-DRAGITTM。其他的，可使用一种水介质中的蛋白衣。然而，不能应用糖衣，因为它会使NADH失稳定。
尽管NADH和/或NADPH可以它们的纯净形式应用(当避光时，它们的压缩型相当稳定)，但优选与稳定剂结合，更优选与稳定剂和填料一起结合成盖仑制剂。已经发现以下这些稳定剂是有效的，而且可使NADH和NADPH具有最强的储存稳定性。它们是：NaHCO3，抗坏血酸和抗坏血酸钠；生育酚和生育酚醋酸酯；聚乙烯吡咯烷酮(PVP)12(12代表分子量为12000)；PVP25；PVP40；PVPPF17(意思是分子量从17000开始的聚合物)和PVPPF60。含有这些稳定剂的NADH/NADPH制剂可稳定达两年。其他各种稳定剂对本领域技术人员将是显而易见的。
用于NADH和NADPH的合适的填料包括：甘露醇，微晶纤维素，羧甲基纤维素和磷酸氢钙。其他合适的填料对本领域技术人员将是显而易见的。应该避免用乳糖作为填料，因为它会和NADH发生反应。
总之，一种优选制剂包括约3—10％重的NADH和/或NAD-PH；约1—10％重的稳定剂，其余为填料。这样的配方，经压缩成药丸并包衣后可稳定保存24个月。
NADH和/或NADPH，加上可选择的稳定剂和填料按照制丸领域中已知的方法可制成片剂、胶囊、小药片或小药丸。片剂可通过直接压缩制成或先制粒后压缩制成。胶囊剂可通过混合各种成分并随后应用传统的自动填充设备将混合物填入胶囊中。小片剂的制成是将粉状或颗粒状的成分压缩成例如直径2mm的药片。
在直接压缩制成片剂的实例中，其特别优选配方是：NADH占5％，抗坏血酸钠占5％，硬脂酸镁占3％，油石粉占4％，二氧化硅占1％，甘露酸占82％。
在胶囊制作实例中，一个特别优选的配方是：NADH占5％，抗坏血酸钠占5％，聚乙烯吡咯烷酮(PVP)占5％，微晶纤维素占77％，硬脂酸镁占3％，α-生育酚醋酯占1％，滑石粉占3％，二氧化硅占1％。
口服NADH和/或NADPH的合适单一剂量是5到500mg，优选是25到100mg。合适的日口服用量为5到1500mg，优选是25到300mg。这种剂量可改善帕金森病患者的运动系统。
辅酶NADH和NADPH的适当的生理可接受盐包括所有已知的生理可接受酸性和碱性成盐物质，例如：无机酸有：氢卤酸，硫酸，磷酸；有机酸有：脂肪族或芳香族羧酸，如：甲酸，醋酸，琥珀酸，乳酸，苹果酸，酒石酸，柠檬酸，马来酸，苯乙酸，苯甲酸，水杨酸或抗坏血酸；或者是碱金属氢氧化物或碱土金属氢氧化物或盐。
NADH，NADPH或它们的生理相容性盐可用药理学可接受辅助物和载体物质通过常用方法制成。在必要的时候，它们也可以和其他活性成分结合使用，例如：突触后多巴胺激动剂，如：Lisuride或Amorphine。实例1：
配制按重量比组成为：5％NADH，5％的稳定剂聚-(1-乙烯基-2-吡咯烷酮)和90％的填料D-甘露醇的治疗组合物。混合物制粒，然后压缩成100mg的片剂。
通过混合以下各种成分制成一种包衣悬液：0.91kg纤维素醋酸酯邻苯二甲酸酯；0.05kg硬脂酸镁；0.28kg邻苯二甲酸乙酯；6.0g丙酮和0.03kg水。然后用这种悬浮液包被每个药片形成酸性保护衣。
然后检测这些药片溶解在正常胃内环境中的时间(即：“溶解时间”)。这一步使用Erweka公司(德国)的溶解检测仪2T3设备。从每一组抽出的12片药都在0.1％盐酸中移动2小时，经过这一处理后在显微镜下检查这些药片的完整性。所有药片的表面都是完整的，于是得出结论溶解时间至少为2小时，这段时间足够使NADH穿过胃内酸性环境到达肠道被吸收。
通过给415例帕金森病患者口服10mg药片证实了NADH可被肠道吸收。有相同数量的帕金森病患者静脉内注入相同剂量的NADH，口服用药和静脉用药的所有病人都有症状缓解表现。而且口服用药的病人症状缓解程度比得上静脉用药病人症状的缓解程度，它们的长期治疗效果也证实是相似的。

Claims (11)

1.一种稳定、可食且可肠道吸收的治疗组合物，它包括NADH或NADPH，或其生理可接受盐，和一种稳定剂，稳定剂选自NaHCO3，抗坏血酸，抗坏血酸钠，生育酸，生育酚乙酸酯和聚乙烯吡咯烷酮，这种治疗组合物为药丸形式，外层包被有一层酸性稳定性保护性包衣。
2.权利要求1的治疗组合物，其中组合物呈选自片剂型，胶囊剂型，小片剂型和小药丸剂型的药丸形式。
3.权利要求的治疗组合物，其中稳定剂选自NaHCO3，抗坏血酸钠，生育酚乙酸酯和聚乙烯吡咯烷酮。
4.权利要求1的治疗组合物，其还含有一种填料。
5.权利要求4的治疗组合物，其中填料选自甘露醇，微晶纤维素，羧甲基纤维素和磷酸氢钙。
6.权利要求1的治疗组合物，其具有下列配方：占3％-10％重的NADH或NADPH或NADH和NADPH的混合物；约占1％-10％重的稳定剂，其余是填料。
7.权利要求5的治疗组合物，其具有下列配方：约占3％-10％重的NADH和NADPH或NADH和NADPH的混合物，约占1％-10％重的稳定剂；其余是填料。
8.权利要求1的治疗组合物，其中包衣中包括一种蛋白质。
9.权利要求1的治疗组合物，其中包衣中包括纤维素醋酸酯邻苯二甲酸酯。
10.权利要求9的治疗组合物，其中包衣中还包括邻苯二甲酸乙酯。
11.权利要求1的治疗组合物，其特征在于其在正常胃环境中溶解时间至少为2小时。
CN94191939A 1993-04-29 1994-03-25 稳定、可食、易吸收的nadh和nadph治疗组合物 Expired - Fee Related CN1072483C (zh)

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CN104758307A (zh) * 2015-03-16 2015-07-08 邦泰生物工程(深圳)有限公司 Nadh和nmn在制备帕金森病药物或保健品的应用
CN109562120A (zh) * 2017-08-11 2019-04-02 邦泰生物工程(深圳)有限公司 一种含有nadh和nadph的组合物及其应用
CN109893510A (zh) * 2019-02-28 2019-06-18 合肥康诺药物开发有限公司 一种辅酶i肠溶片及其制备方法

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CA2735293A1 (en) * 1995-01-17 1996-07-18 Menuco Corp. Nadh and nadph therapeutic agents for dermal administration
US5712259A (en) * 1996-04-22 1998-01-27 Birkmayer Pharmaceuticals NADH and NADPH pharmaceuticals for treating chronic fatigue syndrome
US5668114A (en) * 1996-05-08 1997-09-16 Birkmayer Pharmaceuticals NADH and NADPH pharmaceuticals for treating hypertension
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DK0697859T3 (da) 1997-12-29
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WO1994025007A1 (en) 1994-11-10
CA2161641A1 (en) 1994-11-10
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CA2161641C (en) 1999-06-15
US5332727A (en) 1994-07-26
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DE69403656T2 (de) 1997-10-16
CN1072483C (zh) 2001-10-10
EP0697859A4 (en) 1996-06-26
EP0697859A1 (en) 1996-02-28
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IL109186A0 (en) 1994-06-24
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JPH08512021A (ja) 1996-12-17
AU674583B2 (en) 1997-01-02

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