WO2019028877A1 - Composition containing nadh and nadph and application thereof - Google Patents
Composition containing nadh and nadph and application thereof Download PDFInfo
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- WO2019028877A1 WO2019028877A1 PCT/CN2017/097203 CN2017097203W WO2019028877A1 WO 2019028877 A1 WO2019028877 A1 WO 2019028877A1 CN 2017097203 W CN2017097203 W CN 2017097203W WO 2019028877 A1 WO2019028877 A1 WO 2019028877A1
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
Definitions
- composition containing NADH and NADPH and application thereof
- the present invention relates to the technical field of biomedicine and health care products, and in particular to the new use of NADH and NADPH in combination in the fields of medicine and health care products.
- NADH is an abbreviation of reduced nicotinamide Adenine Dinucleotide, a physiology of nicotinamide dinucleotide present in all living cells including human cells.
- Substance a substance that is a cofactor for many enzymes that catalyze oxidation-reduction reactions, is called coenzyme I.
- NADH is produced in the citric acid cycle of glycolysis and respiration in living organisms, and plays a role as a hydrogen donor in enzymatic reactions, which is involved in various physiological activities such as cellular material metabolism, energy synthesis, and cellular DNA repair. , is a control marker in the energy production chain of mitochondria.
- the most important role of NADH is its driving force for cellular respiration.
- the glucose metabolism is very little directly produced by the metabolism of ATP.
- the metabolically produced NADH can produce a large amount of ATP via an electron-transfer oxidative phosphoric acid reaction, thus satisfying The energy needs of the organism.
- NADPH is a reduced nicotinamide adenine dinucleotide phosphate (Nicotinamide Adenine)
- Dinucleotide Phosphate is a very important physiological substance present in biological cells. It is a phosphorylated derivative of the 2'-position of the ribose ring system linked to adenine in NADH. A very important nucleotide coenzyme, called coenzyme.
- NADPH neurodehydrogenase
- the chemical properties, absorption spectra, redox forms, etc. of NADPH are similar to NADH, but the effect in cells is not the same as that of NADH. It passes through 6-phosphate glucose dehydrogenase ( EC.1.11 . 49), 6-phosphogluconate dehydrogenase (EC.1.11.1.4), etc., can be reversibly reduced by many dehydrogenases, but it is not necessarily reactive with many dehydrogenases that utilize NADH.
- the object of the present invention is to express a product in which NADH is used in combination with NADPH in order to obtain a drug or health care product having a special effect.
- the present invention provides a novel composition comprising: the composition comprising the active ingredient NADH or a physiologically acceptable salt thereof, and NADPH or a physiologically acceptable salt thereof, the NADH or a physiologically acceptable salt thereof
- the weight ratio to the NADPH or a physiologically acceptable salt thereof is 1:0.1 to 1:1.
- the weight ratio of NADH or a physiologically acceptable salt thereof to NADPH or a physiologically acceptable salt thereof is from 1:0.3 to 1:0.7.
- the weight ratio of NADH or a physiologically acceptable salt thereof to NADPH or a physiologically acceptable salt thereof in the composition is 1:0.5.
- an antioxidant for preventing oxidation of NADH and NADPH may also be added to the above composition.
- the physiologically acceptable salt of NADH and the physiologically acceptable salt of NADPH in the above composition include all known physiologically acceptable acidic and basic salt-forming substances, such as 1 inorganic acid: hydrogen phthalic acid, sulfuric acid, phosphoric acid; 2 organic acids: aliphatic or aromatic carboxylic acids, including formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, phenylacetic acid, benzoic acid, salicylic acid and ascorbic acid; 3 alkali metal hydrogen Oxide; 4 alkaline earth metal hydroxide.
- 1 inorganic acid hydrogen phthalic acid, sulfuric acid, phosphoric acid
- 2 organic acids aliphatic or aromatic carboxylic acids, including formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, phenylacetic acid, benzoic acid, salicylic acid and ascorbic acid
- the above NADH or a physiologically acceptable salt thereof and NADPH or a physiologically acceptable salt thereof can be prepared into an oral preparation or a parenteral administration by a conventional method using a pharmaceutically acceptable auxiliary substance or a carrier substance or the like.
- the preparation may be a solid preparation such as a tablet, a powder, a capsule, a pill or the like, or may be a liquid preparation such as a solution, a suspension, an injection or the like.
- the above composition is different depending on various conditions such as the condition, age, body weight, and self-traits of the applicator There will be a corresponding change in the dosage administered.
- the above composition may be administered in an amount of 5 to 500 mg/day based on the active ingredient, and when administered as a pharmaceutical, the application dose may be increased to a maximum of 5000 mg/day, the aforementioned administration.
- the dose may be administered once or in divided doses in one day, either by oral administration or by injection.
- the present invention also provides a novel use of the above composition, that is, for the preparation of a medicament or a health care product for treating phenylketonuria.
- Phenylketonuria is an autosomal recessive disorder involving a defect in the phenylalanine hydroxylase gene located on the long arm of chromosome 12, such that phenylalanine cannot be converted to tyrosine, resulting in Phenylalanine and its ketoacids accumulate and are excreted in large amounts from the urine, so it is called "phenylketonuria", and its incidence in China is about 1/1118.
- phenylketonuria the most powerful measure for the treatment of phenylketonuria is to control the intake of phenylalanine, that is, to give patients a special diet with low phenylalanine or phenylalanine (commonly known as "special diet"), and to adhere to A lifelong diet, and this special diet is usually very expensive and imposes a heavy financial burden on the patient's family.
- the present invention also provides another novel use of the above composition, i.e., for the preparation of a medicament or a health care product for treating tinnitus.
- Tinnitus is a common disease in otological diseases, which refers to abnormal sound sensations produced by patients without any external stimuli, such as squeaking, insects, clocks, winds, machine roars, etc. Monotonous or mixed sound, but in fact there is no corresponding sound in the surrounding environment, which means that tinnitus is only a subjective feeling. There are many reasons for tinnitus, but the mechanism of tinnitus is still unclear. The upset, anxiety and even depression accompanying tinnitus often cause great psychological and psychological problems for patients. In recent years, the clinical incidence rate has been increasing. At present, the common treatment method for tinnitus at home and abroad is to use vasodilators for control, but this method is applicable to a narrow population and has a large side effect.
- NADH and NADPH are combined in a certain ratio, which has the effect of treating phenylketonuria and tinnitus, and the efficacy is unachievable regardless of whether NADH or NADPH is used alone. Beneficial effect.
- both NADH and NADPH are self-produced substances in the human body, so that no toxic side effects occur after administration of the composition.
- the following weight ratio of NADH or a physiologically acceptable salt thereof, and NADPH or a physiologically acceptable salt thereof, and a pharmaceutically acceptable auxiliary substance or carrier substance are prepared into a suitable oral form by a conventional method in the field of pharmacy and health care products. Formulation.
- test drug was administered in an amount of 5 mg per kg of body weight, of which One group was given NAD H, and the remaining six groups were each given the composition of the present invention in the ratio 1 to ratio 6 in Example 1, and each patient continued to receive a special diet for limiting phenylalanine daily.
- Daily detection of blood phenylalanine concentration per child According to the concentration change, the dietary formula is adjusted appropriately, so that the blood phenylalanine concentration is always controlled within the range of 360 ⁇ 15 ⁇ mol/L, and on the 10th day after taking the medicine, each child is determined to have a phenylpropanoid in the diet.
- the tolerable amount of the level of the acid is adjusted appropriately, so that the blood phenylalanine concentration is always controlled within the range of 360 ⁇ 15 ⁇ mol/L, and on the 10th day after taking the medicine, each child is determined to have a phenylpropanoid in the diet.
- the composition of the present invention is more effective in treating phenylketonuria than the simple treatment of NADH;
- the weight ratio of NADH or a physiologically acceptable salt thereof to NADPH or a physiologically acceptable salt thereof in the composition of the present invention is 1:0.5 ⁇ , it is most effective for the treatment of phenylketonuria.
- composition of the present invention has a good therapeutic effect on tinnitus.
Abstract
A composition containing nicotinamide adenine dinucleotide (NADH) and nicotinamide adenine dinucleotide phosphate (NADPH) and an application thereof, wherein the composition comprises an active ingredient NADH or a physiologically acceptable salt thereof and NADPH or a physiologically acceptable salt thereof; the weight ratio of NADH or the physiologically acceptable salt thereof to NADPH or the physiologically acceptable salt thereof is 1:0.1-1:1. The described composition may be used to prepare a drug or healthcare product for the treatment of phenylketonuria and tinnitus.
Description
一种含有 NADH和 NADPH的组合物及其应用 技术领域 Composition containing NADH and NADPH and application thereof
[0001] 本发明涉及生物医药和保健品的技术领域， 特别涉及 NADH和 NADPH联合使 用在医药和保健品领域的新用途。 [0001] The present invention relates to the technical field of biomedicine and health care products, and in particular to the new use of NADH and NADPH in combination in the fields of medicine and health care products.
背景技术 Background technique
[0002] NADH是还原型烟酰胺腺嘌呤二核苷酸 （Nicotinamide Adenine Dinucleotide) 的英文缩写形式， 烟酰胺腺嘌呤二核苷酸是存在于包括人类细胞在内的所有活 细胞中的一种生理物质， 这种物质是很多可催化氧化 _还原反应的酶的辅助因 子， 被称为辅酶 I。 [0002] NADH is an abbreviation of reduced nicotinamide Adenine Dinucleotide, a physiology of nicotinamide dinucleotide present in all living cells including human cells. Substance, a substance that is a cofactor for many enzymes that catalyze oxidation-reduction reactions, is called coenzyme I.
[0003] NADH在生物体内产生于糖酵解和呼吸作用的柠檬酸循环中， 在酶促反应中起 递氢体的作用， 其参与细胞物质代谢、 能量合成、 细胞 DNA修复等多种生理活 动， 是线粒体中能量产生链中的控制标志物。 NADH最重要的作用是它对细胞呼 吸的驱动力， 葡萄糖代谢吋直接经代谢所产生的 ATP是十分少的， 而代谢产生的 NADH经由一个电子传递的氧化磷酸反应可产生大量的 ATP， 从而满足生物体的 能量需要。 [0003] NADH is produced in the citric acid cycle of glycolysis and respiration in living organisms, and plays a role as a hydrogen donor in enzymatic reactions, which is involved in various physiological activities such as cellular material metabolism, energy synthesis, and cellular DNA repair. , is a control marker in the energy production chain of mitochondria. The most important role of NADH is its driving force for cellular respiration. The glucose metabolism is very little directly produced by the metabolism of ATP. The metabolically produced NADH can produce a large amount of ATP via an electron-transfer oxidative phosphoric acid reaction, thus satisfying The energy needs of the organism.
[0004] NADPH是还原型烟酰胺腺嘌呤二核苷酸磷酸 （Nicotinamide Adenine [0004] NADPH is a reduced nicotinamide adenine dinucleotide phosphate (Nicotinamide Adenine)
Dinucleotide Phosphate) 的英文缩写形式， 与 NADH—样， NADPH也是存在于生 物细胞内的非常重要的生理物质， 它是 NADH中与腺嘌呤相连的核糖环系 2'-位的 磷酸化衍生物， 是一种极为重要的核苷酸类辅酶， 被称为辅酶 Π。 The abbreviated form of Dinucleotide Phosphate), like NADH, is a very important physiological substance present in biological cells. It is a phosphorylated derivative of the 2'-position of the ribose ring system linked to adenine in NADH. A very important nucleotide coenzyme, called coenzyme.
[0005] NADPH的化学性质、 吸收光谱、 氧化还原形式等均类似于 NADH, 但是在细 胞内的作用与 NADH并不相同， 它通过 6-磷酸葡萄糖脱氢酶 （EC . 1 . 1 . 1 . 49 ) ， 6-磷酸葡萄糖酸脱氢酶 （EC . 1 . 1 . 1 . 44) 等， 可被许多脱氢酶进行可逆 的还原， 但是与很多利用 NADH的脱氢酶不一定能进行反应。 [0005] The chemical properties, absorption spectra, redox forms, etc. of NADPH are similar to NADH, but the effect in cells is not the same as that of NADH. It passes through 6-phosphate glucose dehydrogenase ( EC.1.11 . 49), 6-phosphogluconate dehydrogenase (EC.1.11.1.4), etc., can be reversibly reduced by many dehydrogenases, but it is not necessarily reactive with many dehydrogenases that utilize NADH.
[0006] 目前关于 NADH或者 NADPH各自在药物以及保健品领域中的应用的报道已经 屡见不鲜， 但是却鲜有见到关于将 NADH与 NADPH联合使用的报道， 如果能幵 发一种兼容 NADH与 NADPH的组合物， 或许能为人类的医药和保健品领域带来
意外惊喜。 [0006] At present, reports on the application of NADH or NADPH in the field of drugs and health care products are common, but few reports on the combination of NADH and NADPH have been reported, if a NADH- and NADPH-compatible method can be expressed. Composition, perhaps for human medicine and health care products unexpected surprise.
技术问题 technical problem
[0007] 针对上述背景技术中提到的现状， 本发明的目的在于幵发将 NADH与 NADPH 联合使用的产品， 以期获得一种具有特殊功效的药物或者保健品。 In view of the status quo mentioned in the above background art, the object of the present invention is to express a product in which NADH is used in combination with NADPH in order to obtain a drug or health care product having a special effect.
问题的解决方案 Problem solution
技术解决方案 Technical solution
[0008] 为实现上述目的， 发明人进行了大量的试验研究， 最终摸索出了 NADH与 NAD PH的最佳配比， 并惊喜地发现该配比下的组合物具有治疗苯丙酮尿症及耳鸣的 功效， 并且该功效是 NADH或者 NADPH单独使用吋无法达到的效果。 因此， 本 发明提供了一种新的组合物， 其特征在于： 所述组合物中包含活性成分 NADH或 其生理可接受盐以及 NADPH或其生理可接受盐， 所述 NADH或其生理可接受盐 与所述 NADPH或其生理可接受盐的重量比为 1 : 0.1〜1： 1。 [0008] In order to achieve the above object, the inventors conducted a large number of experimental studies, and finally found the best ratio of NADH and NAD PH, and surprisingly found that the composition under the ratio has treatment for phenylketonuria and tinnitus. The efficacy, and this effect is not achieved by NADH or NADPH alone. Accordingly, the present invention provides a novel composition comprising: the composition comprising the active ingredient NADH or a physiologically acceptable salt thereof, and NADPH or a physiologically acceptable salt thereof, the NADH or a physiologically acceptable salt thereof The weight ratio to the NADPH or a physiologically acceptable salt thereof is 1:0.1 to 1:1.
[0009] 优选地， 所述组合物中， NADH或其生理可接受盐与 NADPH或其生理可接受 盐的重量比为 1 : 0.3—1： 0.7。 Preferably, in the composition, the weight ratio of NADH or a physiologically acceptable salt thereof to NADPH or a physiologically acceptable salt thereof is from 1:0.3 to 1:0.7.
[0010] 更优选地， 所述组合物中， NADH或其生理可接受盐与 NADPH或其生理可接 受盐的重量比为 1 : 0.5。 More preferably, the weight ratio of NADH or a physiologically acceptable salt thereof to NADPH or a physiologically acceptable salt thereof in the composition is 1:0.5.
[0011] 优选地， 上述组合物中还可加入用于防止 NADH及 NADPH被氧化的抗氧化剂 [0011] Preferably, an antioxidant for preventing oxidation of NADH and NADPH may also be added to the above composition.
[0012] 上述组合物中的 NADH的生理可接受盐以及 NADPH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， 如①无机酸： 氢¾酸、 硫酸、 磷酸； ② 有机酸： 脂肪族或芳香族羧酸， 包括甲酸、 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、 水杨酸和抗坏血酸； ③碱金属氢氧化 物； ④碱土金属氢氧化物。 The physiologically acceptable salt of NADH and the physiologically acceptable salt of NADPH in the above composition include all known physiologically acceptable acidic and basic salt-forming substances, such as 1 inorganic acid: hydrogen phthalic acid, sulfuric acid, phosphoric acid; 2 organic acids: aliphatic or aromatic carboxylic acids, including formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, phenylacetic acid, benzoic acid, salicylic acid and ascorbic acid; 3 alkali metal hydrogen Oxide; 4 alkaline earth metal hydroxide.
[0013] 上述 NADH或其生理可接受盐以及 NADPH或其生理可接受盐可按常规方法用 药学上可接受的辅助物质或者载体物质等制备成口服制剂或者肠道外给药的制 齐 ij， 该制剂可以是固体制剂， 如片剂、 散剂、 胶囊剂、 丸剂等， 也可以是液体 制剂， 如溶液剂、 悬浮剂、 注射剂等。 The above NADH or a physiologically acceptable salt thereof and NADPH or a physiologically acceptable salt thereof can be prepared into an oral preparation or a parenteral administration by a conventional method using a pharmaceutically acceptable auxiliary substance or a carrier substance or the like. The preparation may be a solid preparation such as a tablet, a powder, a capsule, a pill or the like, or may be a liquid preparation such as a solution, a suspension, an injection or the like.
[0014] 根据施用者的病情、 年齢、 体重以及自身特质等种种条件的不同， 上述组合物
的施用剂量会有相应的改变。 一般来说， 对一个成人而言， 上述组合物的施用 剂量按有效成分计可以为 5〜500mg/天， 而在作为药品施用吋， 可以将其施用剂 量提高至最高 5000mg/天， 前述的施用剂量在一天内可以一次或者分多次施用， 施用方式可以是口服或者注射。 [0014] The above composition is different depending on various conditions such as the condition, age, body weight, and self-traits of the applicator There will be a corresponding change in the dosage administered. In general, for an adult, the above composition may be administered in an amount of 5 to 500 mg/day based on the active ingredient, and when administered as a pharmaceutical, the application dose may be increased to a maximum of 5000 mg/day, the aforementioned administration. The dose may be administered once or in divided doses in one day, either by oral administration or by injection.
[0015] 本发明还提供了上述组合物的一种新用途， 即用于制备治疗苯丙酮尿症的药物 或保健品。 The present invention also provides a novel use of the above composition, that is, for the preparation of a medicament or a health care product for treating phenylketonuria.
[0016] 苯丙酮尿症是一种常染色体隐性遗传病， 涉及位于第 12号染色体长臂上的苯丙 氨酸羟化酶基因缺陷， 使得苯丙氨酸不能转变成为酪氨酸， 导致苯丙氨酸及其 酮酸蓄积并从尿中大量排出， 故称"苯丙酮尿症"， 其在中国的发病率约为 1/1118 0。 目前治疗苯丙酮尿症最有力的措施是控制苯丙氨酸的摄入量， 即给予患者低 苯丙氨酸或无苯丙氨酸的特殊饮食 （俗称"特供饮食"） ， 并且要坚持终身饮食治 疗， 而这种特供饮食通常价格非常昂贵， 给患者家庭带来沉重的经济负担。 [0016] Phenylketonuria is an autosomal recessive disorder involving a defect in the phenylalanine hydroxylase gene located on the long arm of chromosome 12, such that phenylalanine cannot be converted to tyrosine, resulting in Phenylalanine and its ketoacids accumulate and are excreted in large amounts from the urine, so it is called "phenylketonuria", and its incidence in China is about 1/1118. At present, the most powerful measure for the treatment of phenylketonuria is to control the intake of phenylalanine, that is, to give patients a special diet with low phenylalanine or phenylalanine (commonly known as "special diet"), and to adhere to A lifelong diet, and this special diet is usually very expensive and imposes a heavy financial burden on the patient's family.
[0017] 本发明还提供了上述组合物的另一种新用途， 即用于制备治疗耳鸣的药物或保 健品。 The present invention also provides another novel use of the above composition, i.e., for the preparation of a medicament or a health care product for treating tinnitus.
[0018] 耳鸣是耳科疾病中的常见病， 是指患者在没有任何外界刺激条件下所产生的异 常声音感觉， 如感觉耳内有蝉鸣、 虫叫、 钟表响、 风声、 机器轰鸣声等单调或 混杂的响声， 但实际上周围环境中并无相应的声音， 也就是说耳鸣只是一种主 观感觉。 引起耳鸣的原因很多， 但耳鸣的发生机理至今尚不明确。 耳鸣伴随的 心烦、 焦虑甚至抑郁等常给患者的生理和心理造成极大困扰， 近年临床发病率 有不断上升的趋势。 目前国内外针对耳鸣常用的治疗方法是采用血管扩张剂进 行控制， 但是这种方法适用的人群窄， 而且副作用大。 [0018] Tinnitus is a common disease in otological diseases, which refers to abnormal sound sensations produced by patients without any external stimuli, such as squeaking, insects, clocks, winds, machine roars, etc. Monotonous or mixed sound, but in fact there is no corresponding sound in the surrounding environment, which means that tinnitus is only a subjective feeling. There are many reasons for tinnitus, but the mechanism of tinnitus is still unclear. The upset, anxiety and even depression accompanying tinnitus often cause great psychological and psychological problems for patients. In recent years, the clinical incidence rate has been increasing. At present, the common treatment method for tinnitus at home and abroad is to use vasodilators for control, but this method is applicable to a narrow population and has a large side effect.
发明的有益效果 Advantageous effects of the invention
有益效果 Beneficial effect
[0019] 发明人通过实验发现， 将 NADH与 NADPH按照一定的配比联合使用吋， 其兼 具治疗苯丙酮尿症以及耳鸣的功效， 并且该功效是无论 NADH还是 NADPH单独 使用吋都无法达到的有益效果。 而且 NADH和 NADPH均属人体内自产的物质， 故服用该组合物后不会出现任何毒副作用。
本发明的实施方式 [0019] The inventors discovered through experiments that NADH and NADPH are combined in a certain ratio, which has the effect of treating phenylketonuria and tinnitus, and the efficacy is unachievable regardless of whether NADH or NADPH is used alone. Beneficial effect. Moreover, both NADH and NADPH are self-produced substances in the human body, so that no toxic side effects occur after administration of the composition. Embodiments of the invention
[0020] 下面结合具体实施例对本发明做进一步的详细说明， 以下实施例是对本发明的 解释， 本发明并不局限于以下实施例。 The present invention will be further described in detail with reference to the preferred embodiments thereof. The following examples are illustrative of the invention, and the invention is not limited to the following examples.
[0021] 实施例 1 Embodiment 1
[0022] 采用药学及保健品领域的常规方法， 将以下重量配比的 NADH或其生理可接受 盐以及 NADPH或其生理可接受盐与药学上可接受的辅助物质或者载体物质等制 备成适宜口服的剂型。 The following weight ratio of NADH or a physiologically acceptable salt thereof, and NADPH or a physiologically acceptable salt thereof, and a pharmaceutically acceptable auxiliary substance or carrier substance are prepared into a suitable oral form by a conventional method in the field of pharmacy and health care products. Formulation.
[0023] 配比 1 NADH: NADPH = 1： 0.1 [0023] Proportion 1 NADH: NADPH = 1: 0.1
[0024] 配比 2 NADH: NADPH = 1： 0.3 [0024] Proportion 2 NADH: NADPH = 1: 0.3
[0025] 配比 3 NADH: NADPH = 1： 0.5 [0025] Proportion 3 NADH: NADPH = 1: 0.5
[0026] 配比 4 NADH: NADPH = 1： 0.7 Proportion 4 NADH: NADPH = 1: 0.7
[0027] 配比 5 NADH: NADPH = 1： 1 [0027] Proportion 5 NADH: NADPH = 1: 1
[0028] 酉己比 6 NADH Na 2： NADPH Na 4= 1： 0.5 [0028] 酉Heng ratio 6 NADH Na 2 : NADPH Na 4 = 1: 0.5
[0029] 实施例 2 [0029] Example 2
[0030] 本发明的组合物对苯丙酮尿症的治疗作用 Therapeutic effect of the composition of the invention on phenylketonuria
[0031] 临床试验资料 [0031] Clinical Trial Data
[0032] 1、 试验对象 [0032] 1. Test object
[0033] 从已被确诊为患有苯丙酮尿症的所有经监护人同意参加试验的患儿中选择年齢 在 6〜9岁的患儿 56名， 男女不限， 这 56名患儿在加入该临床试验之前每日均需 通过给予限制苯丙氨酸的特供饮食将其血苯丙氨酸浓度控制在理想范围之内。 [0033] 56 children aged 6 to 9 years old were selected from all children who had been diagnosed as having phenylketonuria and agreed to participate in the trial. The 56 children were admitted to the clinic. Before the test, the blood phenylalanine concentration should be controlled within the ideal range by giving a special diet for limiting phenylalanine.
[0034] 2、 试验方法 [0034] 2 test method
[0035] 试验幵始吋， 记录每名患儿的年齢及体重信息， 并根据每名患儿的年齢及体重 每曰给予限制苯丙氨酸的特供饮食， 使每名患儿的血苯丙氨酸浓度控制在 360±1 5 mol/L， 同吋记录每名患儿对饮食中苯丙氨酸水平的可耐受量。 之后将参与试 验的 56名患儿随机分成七组， 每组 8名， 每组患儿均于每日早晨空腹口服试验药 物， 试验药物的服用量为每公斤体重服用 5mg活性成分， 其中， 第一组给予 NAD H， 其余六组分别给予实施例 1中的配比 1至配比 6的本发明的组合物， 每名患儿 每日继续给予限制苯丙氨酸的特供饮食。 每日检测每名患儿的血苯丙氨酸浓度
， 并根据浓度变化适吋调整饮食配方， 使其血苯丙氨酸浓度始终控制在 360±15μ mol/L范围内， 待到服药后的第 10天， 测定每名患儿对饮食中苯丙氨酸水平的可 耐受量。 [0035] At the beginning of the trial, the age and weight information of each child was recorded, and a special diet for limiting phenylalanine was given according to the age and weight of each child, so that the blood benzene of each child was given. The alanine concentration was controlled at 360 ± 15 mol/L, and the tolerable dose of phenylalanine in the diet was recorded for each child. The 56 children enrolled in the trial were then randomly divided into seven groups of 8 patients in each group. Each group received oral test drugs on an empty stomach every morning. The test drug was administered in an amount of 5 mg per kg of body weight, of which One group was given NAD H, and the remaining six groups were each given the composition of the present invention in the ratio 1 to ratio 6 in Example 1, and each patient continued to receive a special diet for limiting phenylalanine daily. Daily detection of blood phenylalanine concentration per child According to the concentration change, the dietary formula is adjusted appropriately, so that the blood phenylalanine concentration is always controlled within the range of 360±15 μmol/L, and on the 10th day after taking the medicine, each child is determined to have a phenylpropanoid in the diet. The tolerable amount of the level of the acid.
[0036] 3、 试验结果 [0036] 3, test results
[0037] 对比服药前后每名患儿对饮食中苯丙氨酸水平的可耐受量， 计算每名患儿在服 药第 10天后每公斤体重对饮食中苯丙氨酸水平可耐受量的提高值， 再对每组患 儿取平均值。 参与试验的七组患儿在服药第 10天后每公斤体重对饮食中苯丙氨 酸水平可耐受量的提高值的平均值如表 1所示。 [0037] Comparing the tolerable dose of phenylalanine in each diet before and after taking the drug, calculating the tolerable amount of phenylalanine in the diet per kilogram of body weight per patient after the 10th day of taking the drug Increase the value and average each group of children. The average value of the increase in the tolerance of phenylalanine in the diet per kg body weight after the 10th day of the trial was shown in Table 1.
[0038] 表 1 Table 1
[] [表 1] [] [Table 1]
[0039] 4、 结果讨论 [0039] 4, the results of the discussion
[0040] 上述试验结果对比可以看出： 在服用量相同的情况下， 在相同的吋间内， 服用 本发明的组合物对苯丙酮尿症的治疗效果要好于单纯服用 NADH的治疗效果； 而 且当本发明的组合物中 NADH或其生理可接受盐与 NADPH或其生理可接受盐的 重量配比为 1 : 0.5吋， 其对苯丙酮尿症的治疗效果最佳。 [0040] The above test results can be seen: in the same amount of taking, in the same day, the composition of the present invention is more effective in treating phenylketonuria than the simple treatment of NADH; When the weight ratio of NADH or a physiologically acceptable salt thereof to NADPH or a physiologically acceptable salt thereof in the composition of the present invention is 1:0.5 Å, it is most effective for the treatment of phenylketonuria.
[0041] 实施例 3 Embodiment 3
[0042] 本发明的组合物对耳鸣的治疗作用 Therapeutic effect of the composition of the invention on tinnitus
[0043] 临床试验资料 [0043] Clinical trial data
[0044] 1、 试验对象 [0044] 1. Test object
[0045] 随机选择自 2014年 3月至 2015年 2月期间自愿参加该临床试验的被确诊为耳鸣的 患者， 排除由外伤、 肿瘤及全身性疾病所导致的耳鸣患者， 共收治试验对象 76 例， 性别不限， 年齢为 28-69岁， 平均年齢为 52.3岁， 所有患者均有不同程度的
耳鸣症状， 且已对工作及生活造成了影响， 病程最短者 1个月， 最长者 5.5年。 [0045] Randomly selected patients who were diagnosed with tinnitus who volunteered to participate in the clinical trial from March 2014 to February 2015, excluded patients with tinnitus caused by trauma, tumor and systemic diseases, and treated 76 patients in total. , gender is not limited, the age is 28-69 years old, the average age is 52.3 years old, all patients have different degrees The symptoms of tinnitus have affected work and life. The shortest course is 1 month and the longest is 5.5 years.
[0046] 2、 试验方法 [0046] 2. Test method
[0047] 所有参与试验的患者均于每日早晨空腹口服实施例 1中配比 3的本发明的组合物 ， 温水送服， 服用量为每人每日一次性服用 20mg活性成分， 连续服用到耳鸣症 状完全消失或者症状不再改善为止。 [0047] All the patients participating in the trial were orally administered with the composition of the present invention in Formulation 1 in Example 1 on an empty stomach every morning, and were taken in warm water. The dosage was 20 mg of the active ingredient per person per day, and was continuously administered. The tinnitus symptoms disappear completely or the symptoms no longer improve.
[0048] 3、 疗效评定标准 [0048] 3, efficacy evaluation criteria
[0049] 疗效观察指标参照 《中药新药治疗耳鸣临床研究指导原则》 如下： [0049] The efficacy observation indicators refer to the "Guidelines for the Clinical Research of New Chinese Medicine for the Treatment of Tinnitus" as follows:
[0050] (1)显效： 耳鸣症状完全消失或仅在夜间及安静环境下偶尔出现， 听力基本恢复 到未得病吋状态或无明显听力障碍， 维持半个月以上不复发； [0050] (1) markedly effective: the tinnitus symptoms completely disappeared or occasionally appeared in the night and quiet environment, the hearing basically recovered to the state of no disease or no obvious hearing impairment, and maintained no recurrence for more than half a month;
[0051] (2)有效： 耳鸣症状稍有缓解， 发作由持续性转为仅在安静环境下或仅在嘈杂环 境下出现； [0051] (2) Effective: The symptoms of tinnitus are slightly relieved, and the onset changes from continuous to only in a quiet environment or only in a heterocyclic environment;
[0052] (3)无效： 耳鸣症状与服药前无明显改变， 体征亦无改变甚至出现恶化。 [0052] (3) Invalid: The symptoms of tinnitus did not change significantly before taking the drug, and the signs did not change or even deteriorated.
[0053] 4、 试验结果 [0053] 4, test results
[0054] 参与试验的 76例耳鸣患者在服用本发明的组合物一段吋期以后， 经回访统计结 果为： 显效者 33例， 有效者 28例， 无效者 15例， 显效率 43.4%， 总有效率 80.3% [0054] 76 patients with tinnitus participating in the trial after taking the composition of the present invention for a period of time, the return visit statistics were: 33 cases were effective, 28 cases were effective, 15 cases were ineffective, the effective rate was 43.4%, there was always 80.3% efficiency
。 说明本发明的组合物对耳鸣具有较好的治疗效果。
. It is indicated that the composition of the present invention has a good therapeutic effect on tinnitus.
Claims
[权利要求 1] 一种组合物， 其特征在于： 所述组合物中包含活性成分 NADH或其生 理可接受盐以及 NADPH或其生理可接受盐， 所述 NADH或其生理可 接受盐与所述 NADPH或其生理可接受盐的重量比为 1 : 0.1〜1： 1。 [Claim 1] A composition comprising: the active ingredient NADH or a physiologically acceptable salt thereof, and NADPH or a physiologically acceptable salt thereof, the NADH or a physiologically acceptable salt thereof The weight ratio of NADPH or a physiologically acceptable salt thereof is 1:0.1 to 1:1.
[权利要求 2] 根据权利要求 1所述的组合物， 其特征在于： 所述 NADH或其生理可 接受盐与所述 NADPH或其生理可接受盐的重量比为 1 : 0.3-1： 0.7。 [Claim 2] The composition according to claim 1, wherein the weight ratio of the NADH or a physiologically acceptable salt thereof to the NADPH or a physiologically acceptable salt thereof is from 1:0.3 to 1:0.7.
[权利要求 3] 根据权利要求 2所述的组合物， 其特征在于： 所述 NADH或其生理可 接受盐与所述 NADPH或其生理可接受盐的重量比为 1 : 0.5。 [Claim 3] The composition according to claim 2, wherein the weight ratio of the NADH or a physiologically acceptable salt thereof to the NADPH or a physiologically acceptable salt thereof is 1:0.5.
[权利要求 4] NADH和 NADPH在制备治疗苯丙酮尿症的组合物中的应用， 其特征 在于： 所述组合物中的 NADH或其生理可接受盐与 NADPH或其生理 可接受盐的重量比为 1 : 0.1〜1： 1。 [Claim 4] The use of NADH and NADPH in the preparation of a composition for treating phenylketonuria, characterized by: weight ratio of NADH or a physiologically acceptable salt thereof to NADPH or a physiologically acceptable salt thereof in the composition For 1: 0.1~1: 1.
[权利要求 5] 根据权利要求 4所述的应用， 其特征在于： 所述组合物中的 NADH或 其生理可接受盐与 NADPH或其生理可接受盐的重量比为 1 : 0.3〜1：[Claim 5] The use according to claim 4, wherein the weight ratio of NADH or a physiologically acceptable salt thereof to NADPH or a physiologically acceptable salt thereof in the composition is 1: 0.3 to 1:
0.7。 0.7.
[权利要求 6] 根据权利要求 5所述的应用， 其特征在于： 所述组合物中的 NADH或 其生理可接受盐与 NADPH或其生理可接受盐的重量比为 1 : 0.5。 [Claim 6] The use according to claim 5, wherein the weight ratio of NADH or a physiologically acceptable salt thereof to NADPH or a physiologically acceptable salt thereof in the composition is 1:0.5.
[权利要求 7] NADH和 NADPH在制备治疗耳鸣的组合物中的应用， 其特征在于： 所述组合物中的 NADH或其生理可接受盐与 NADPH或其生理可接受 盐的重量比为 1 : 0.1—1： 1。 [Claim 7] The use of NADH and NADPH in the preparation of a composition for treating tinnitus, characterized in that the weight ratio of NADH or a physiologically acceptable salt thereof to NADPH or a physiologically acceptable salt thereof in the composition is 1: 0.1-1: 1.
[权利要求 8] 根据权利要求 7所述的应用， 其特征在于： 所述组合物中的 NADH或 其生理可接受盐与 NADPH或其生理可接受盐的重量比为 1 : 0.3〜1：[Claim 8] The use according to claim 7, wherein the weight ratio of NADH or a physiologically acceptable salt thereof to NADPH or a physiologically acceptable salt thereof in the composition is 1: 0.3 to 1:
0.7。 0.7.
[权利要求 9] 根据权利要求 8所述的应用， 其特征在于： 所述组合物中的 NADH或 其生理可接受盐与 NADPH或其生理可接受盐的重量比为 1 : 0.5。
[Claim 9] The use according to claim 8, wherein the weight ratio of NADH or a physiologically acceptable salt thereof to NADPH or a physiologically acceptable salt thereof in the composition is 1:0.5.
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| CN105456286A (en) * | 2016-01-27 | 2016-04-06 | 邦泰生物工程(深圳)有限公司 | Application of nicotinamide mononucleotide to preparing of drugs or health care products for preventing and curing hearing losses |
| CN105535009A (en) * | 2016-01-27 | 2016-05-04 | 邦泰生物工程(深圳)有限公司 | Drug or health care product for preventing and treating hearing loss |
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| US5332727A (en) * | 1993-04-29 | 1994-07-26 | Birkmayer U.S.A. | Stable, ingestable and absorbable NADH and NADPH therapeutic compositions |
| US5668114A (en) * | 1996-05-08 | 1997-09-16 | Birkmayer Pharmaceuticals | NADH and NADPH pharmaceuticals for treating hypertension |
| US20040115629A1 (en) * | 2002-01-09 | 2004-06-17 | Panzer Scott R | Molecules for diagnostics and therapeutics |
| EP2166010A1 (en) * | 2008-09-23 | 2010-03-24 | Genkyo Tex Sa | Pyrazolo pyridine derivatives as NADPH oxidase inhibitors |
| CN105331589A (en) * | 2015-11-02 | 2016-02-17 | 太原理工大学 | Water type NADH oxidase of reproducible coenzyme NAD+ and encoding gene and application thereof |
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| CN105456286A (en) * | 2016-01-27 | 2016-04-06 | 邦泰生物工程(深圳)有限公司 | Application of nicotinamide mononucleotide to preparing of drugs or health care products for preventing and curing hearing losses |
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