WO2021031536A1 - Nadh 和 / 或 nmn 在制备脑功能恢复的药物、保健品中的应用 - Google Patents

Nadh 和 / 或 nmn 在制备脑功能恢复的药物、保健品中的应用 Download PDF

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WO2021031536A1
WO2021031536A1 PCT/CN2020/075632 CN2020075632W WO2021031536A1 WO 2021031536 A1 WO2021031536 A1 WO 2021031536A1 CN 2020075632 W CN2020075632 W CN 2020075632W WO 2021031536 A1 WO2021031536 A1 WO 2021031536A1
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nicotinamide adenine
composition
extract
ginseng
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PCT/CN2020/075632
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English (en)
French (fr)
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陈建生
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泓博元生命科技（深圳）有限公司
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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
    • 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
    • A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/16—Ginkgophyta, e.g. Ginkgoaceae (Ginkgo family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
    • A61K36/258—Panax (ginseng)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/41—Crassulaceae (Stonecrop family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/488—Pueraria (kudzu)
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A61K2236/333—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using mixed solvents, e.g. 70% EtOH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/39—Complex extraction schemes, e.g. fractionation or repeated extraction steps

Definitions

  • the present invention belongs to the field of traditional Chinese medicine compositions, and in particular relates to a composition containing nicotinamide adenine dinucleotide and/or nicotinamide adenine mononucleotide and preparation of a medicine and/or health care product for restoring brain function application.
  • the present invention provides a composition containing nicotinamide adenine dinucleotide (NADH) and/or nicotinamide adenine mononucleotide (NMN) and its use in the preparation of drugs and/or brain function recovery Or the application in health products to improve brain health and brain function, including but not limited to cognition, memory, intelligence, motivation, attention, concentration, learning ability and better communication and reduce cognitive and memory disorders Related diseases and similar diseases.
  • NADH nicotinamide adenine dinucleotide
  • NPN nicotinamide adenine mononucleotide
  • the present invention provides a composition containing NADH/NMN and its application in the preparation of brain function recovery drugs and/or health products for the prevention, control and treatment of brain diseases/disorders, including but not limited to the elderly Dementia, multi-infarct dementia, dyslexia, aphasia, organic brain syndrome, myasthenia gravis, vascular dementia, mild cognitive impairment (MCI), dementia with Lewy bodies, Wernicke-Cole Sakov syndrome, Alzheimer's disease, Parkinson's disease, attention deficit hyperactivity disorder (ADHD), hypoxia, hypoxia, cerebrovascular insufficiency, epilepsy, myoclonus, and low cholinergic nerve function Barriers, slow down memory decline, loss of function, treat memory disorders, neurodegenerative diseases, and control blood pressure and blood circulation in the brain.
  • brain diseases/disorders including but not limited to the elderly Dementia, multi-infarct dementia, dyslexia, aphasia, organic brain syndrome, myasthenia gravis,
  • the present invention provides a composition
  • the raw materials of the composition include: NADH and/or NMN, ginseng, Rhodiola, Panax notoginseng, Ginkgo biloba, Pueraria lobata and Erigeron.
  • the raw materials of the composition include: NADH and/or NMN, ginseng extract, rhodiola extract, notoginseng extract, ginkgo biloba extract, kudzu root extract and erigeron breviscapus extract.
  • the raw materials of the composition include: 1 part to 10 parts of NADH and/or NMN, 1 part to 10 parts of ginseng, 1 part to 10 parts of Panax notoginseng, 1 part to 10 parts of Rhodiola , 1 part to 10 parts of ginkgo biloba, 1 part to 10 parts of kudzu root, and 1 part to 10 parts of breviscapine.
  • the raw materials of the composition include: 5-9 parts of NADH and/or NMN, 5-10 parts of ginseng, 3-7 parts of Panax notoginseng, and 1 ⁇ 2 parts of Rhodiola , Ginkgo biloba leaves 4 ⁇ 8 parts, Pueraria lobata root 1 ⁇ 5 parts and Erigeron 1 ⁇ 4 parts.
  • the raw materials of the composition include: 6 parts to 8 parts of NADH and/or NMN, 6 parts to 9 parts of ginseng, 4 parts to 6 parts of Panax notoginseng, 1 part to 2 parts of Rhodiola , Ginkgo biloba leaves 5 ⁇ 8 servings, Pueraria lobata 2 ⁇ 4 servings, and breviscapine 1 ⁇ 3 servings.
  • the raw materials of the composition include: 7 parts of NADH and/or NMN, 7 parts of ginseng, 5 parts of Panax notoginseng, 1 part of Rhodiola, 7 parts of Ginkgo biloba, 3 parts of Pueraria lobata and Erigeron 2 servings.
  • the mass ratio of nicotinamide adenine dinucleotide: nicotinamide adenine mononucleotide is 10:1 to 1:10.
  • the present invention also provides a preparation method of the above composition, which includes the following steps:
  • Panax notoginseng, ginseng, ginkgo biloba, kudzu root, breviscapine, and rhodiola are raw materials, and 8-12 times the amount of ethanol with a mass concentration of 30%-50% is immersed for 10-15 hours. Reflux extraction 3 times, combine the extracts, centrifuge, the filtrate is vacuumed at 60°C-70°C to recover ethanol, and concentrated at 50°C-60°C to obtain extract I;
  • the present invention also provides a preparation comprising the composition described in any one of the above, including:
  • the composition is added with conventional auxiliary materials and prepared into oral preparations and parenteral administration preparations according to conventional techniques.
  • the conventional auxiliary materials include conventional pharmaceutical auxiliary materials or conventional food auxiliary materials.
  • the formulation does not contain lactose.
  • conventional pharmaceutical excipients include but are not limited to:
  • the pharmaceutically or food acceptable excipients, adjuvants, carriers and diluents include but are not limited to glucose, fructose, sucrose, maltose, yellow dextrin, white dextrin, silicon dioxide, microcrystalline cellulose powder, Calcium stearate, magnesium stearate, sorbitol, stevioside, corn syrup, citric acid, tartaric acid, malic acid, succinic acid, lactic acid, L-ascorbic acid, dl- ⁇ -tocopherol, glycerin, propylene glycol, glycerol fat Acid esters, polyglycerin fatty acid esters, sucrose fatty acid esters, sorbitan fatty acid esters, propylene glycol fatty acid esters, gum arabic, carrageenan, casein, gelatin, pectin, agar, nicotinamide, calcium pantothenate, calcium salt , Pigments, flavors, preservatives, distilled water, brine
  • the present invention also provides an application of the composition comprising any one of the above in preparing medicines and/or health care products for restoring brain function.
  • the present invention provides a composition
  • the raw materials of the composition include: NADH and/or NMN, ginseng, Panax notoginseng, Ginkgo biloba, Pueraria lobata, Erigeron, Rhodiola.
  • the invention also provides an application of the above-mentioned composition in the preparation of medicines and/or health products for restoring brain function.
  • Panax notoginseng, ginseng, ginkgo biloba, pueraria lobata, breviscapine, rhodiola, etc. can enhance the improvement of NADH and/or NMN on the neurological function of mice, lower the oxidative stress level of brain tissue, and reduce Apoptosis of brain tissue.
  • it can be determined by animal experiments that after the administration, the brain function of the test animal is improved, and the memory and spatial recognition ability are significantly improved.
  • the embodiment of the present invention provides a composition and its application in the preparation of brain function recovery drugs and/or health products, which are used to solve the poor therapeutic effect of brain function recovery drugs and/or health products in the prior art. And technical defects that have adverse reactions to the human body.
  • This embodiment is a specific embodiment for preparing product 1.
  • composition is made into tablets according to conventional methods and pharmaceutical excipients.
  • This embodiment is a specific embodiment for preparing product 2.
  • composition is made into capsules according to conventional methods and food auxiliary materials.
  • This embodiment is a specific embodiment for preparing product 3.
  • composition is prepared into powder injections according to conventional methods and pharmaceutical excipients.
  • This embodiment is a specific embodiment for preparing product 4.
  • composition is made into pills according to the conventional method and food auxiliary materials.
  • This embodiment is a specific embodiment for preparing product 5.
  • composition is made into an inhalant according to conventional methods and pharmaceutical excipients.
  • Example 1 The products prepared in Example 1 (NADH), Example 3 (NMN) and Example 5 (NADH/NMN 1:1) were mixed into mouse bait and administered to 6-week-old SAMP8 mice. The added amount of each product is 10mg/kg/day. You can freely ingest water. The bait is exchanged once every 3 days and given continuously for 3 months. Then a stepthrough passive evasion test was performed.
  • This test is a test method that uses the memory and learning ability of mice that like the dark habit. It is a method of using electrical stimulation to make it remember when transferred from a bright room to a dark room, and after 24 hours, the method of "remembering how much dark room is dangerous" is evaluated based on the length of stay in the bright room. That is, the length of stay in the bright room indicates the level of memory learning ability.
  • the software ShutAvoid (PanLab Corporation) was used for analysis.
  • the time before entering the dark room (the incubation period) is set to a maximum of 2 minutes. After 1 minute of light room acclimatization, open the shield door, transfer to the dark room, close the door, and give 2 seconds 0.4mA electrical stimulation . After electrical stimulation, the mice were quickly returned to the cage. In the official test on the next day, the incubation period was set to 5 minutes at most, and the time spent in the bright room was measured. The incubation period of the individual who stayed in the bright room for 5 minutes the next day was set to 5 minutes for calculation.
  • the staying time in the bright room on the second day was averaged by group, and the ratio was calculated with the control group (no intake group) as 1.0.
  • the number of individuals in each group is as follows: 24 in the control group, 8 in the NADH group (product in Example 1), 8 in the NMN group (product in Example 3), and 8 in the NADH/NMN group (product in Example 5).
  • the results of the control group and each product group are shown in Table 1.
  • each product group has a higher passive evasion effect than the control group.
  • the passive evasion effect was 1.4 times that of the control group.
  • the control ratio of the passive evasion effect of the NADH group was 1.2 better than that of the NMN group alone. This result indicates that the product of the present invention has a brain function improvement effect.
  • the elevated radial arm maze method was used to test the effect of mice on improving learning and memory:
  • the animal research protocol has been approved by the Institutional Animal Ethics Committee.
  • the 6-week-old mice were adapted to the environment for one week and healthy mice were selected for research.
  • the selected mice were pre-trained in the elevated radial arm maze (RAM), and the adapted mice were assigned to different treatment groups, each group containing 8 mice.
  • the animals were subjected to the same treatment as Experimental Example 1 every day for two weeks. During the treatment, the mice were placed on the RAM for 10 minutes each time to recognize the food pellets present on the three arms of different colors.
  • the spatial learning ability is tested by calculating different parameters such as the number of days to learn the task, the latency period of finding food, and the number of wrong entries/attempts.
  • the trained mice were given a one-week (third week) rest without treatment or training.
  • the mice were tested for memory retention by testing the latency and the number of false entries in the same room. Analyze the data by ANOVA and appropriate post-hoc comparisons. The results are shown in Table 2:
  • each product group significantly (P ⁇ 0.01) reduced the number of days that mice need to learn under the set conditions, and significantly (P ⁇ 0.05) reduced the number of learning mice in the elevated RAM model The time it takes to find food.
  • each product group showed a significant improvement in spatial learning ability, represented by reducing the latency and the number of false entries.
  • the NADH/NMN group has the most significant effect.
  • Ginseng can reduce brain cell apoptosis by regulating the expression of Bax and Bcl-2 proteins, and its mechanism of action is related to the up-regulation of NAIP and Bcl-2 Protein expression is related to the decrease of Bax protein expression.
  • Panax notoginseng can inhibit the apoptosis of cerebral vascular endothelial cells, up-regulate the expression of VEGF, and promote angiogenesis. It can also upregulate glial fibrillary acidic protein (glial fibrillary acidic protein (GFAP), basic fibroblast growth factor (BFGF) expression, improve brain autologous neural stem cells (neural stem cells) Cells (NSCs) living microenvironment promotes the proliferation of brain autologous neural stem cells, thereby improving the brain nerve function of mice.
  • GFAP glial fibrillary acidic protein
  • BFGF basic fibroblast growth factor
  • NSCs brain autologous neural stem cells
  • Ginkgo biloba can significantly reduce the apoptosis of brain tissue in mice, inhibit the expression of c-fos protein in brain tissue, and promote brain nerve repair.
  • Pueraria lobata can significantly reduce the neurological deficit score, significantly reduce the volume of brain necrosis and the number of apoptosis-positive cells. Its neuroprotective mechanism is related to the inhibition of the phosphorylation level of STAT3, the reduction of the expression of P53 and the abnormal activation of the JAK2/STAT3 signaling pathway.
  • Erigeron breviscapus has a significant inhibitory effect on neuronal apoptosis in the brain tissue of newborn mice. Its mechanism is related to the regulation of Bax /Bcl-2 gene expression, down-regulation of caspase-3 and NF-kB And Fas protein expression and so on.
  • Rhodiola can improve the brain nerve function damage of MCAO mice and inhibit nerve cell apoptosis, mainly by activating the PI3K/AKT signaling pathway, promoting the phosphorylation of AKT, activating the nuclear transcription of NRF2, and promoting the protein expression of HO-1. And then inhibit nerve cell apoptosis and improve nerve function.
  • the panax notoginseng, ginseng, ginkgo biloba, kudzu root, breviscapine, rhodiola, etc. in the present invention can enhance the improvement of NADH and/or NMN on brain nerve function, lower the oxidative stress level of brain tissue, and reduce brain tissue Apoptosis.
  • the present invention takes ginseng and ginkgo biloba as the king, soothes the nerves, nourishes the mind, promotes blood circulation and dredges the collaterals, takes notoginseng and pueraria lobata as the ministers, dredges the collaterals and relaxes the tendons, and also nourishes the yin and promotes the body fluid.
  • breviscapine and rhodiola as assistants, promote blood circulation and relax muscles, dissipate bruises and reduce swelling. Combining the three, it has the effects of activating blood and dredging collaterals, replenishing qi and promoting fluid, which can significantly improve brain nerve function, reduce brain cell apoptosis, and promote brain function recovery.
  • the present invention adopts specific ingredients and specific proportions, the formula is reasonable, the compatibility is appropriate, the selected ingredients of the present invention are compatible, conform to the theory of combining traditional Chinese medicine and modern medicine, are convenient to use, have good absorption effects, and have no adverse or side effects. After clinical verification, it can effectively improve and improve brain function and promote the recovery of brain function.
  • the present invention provides a composition
  • the raw materials of the composition include: NADH and/or NMN, ginseng, Panax notoginseng, Ginkgo biloba, Pueraria lobata, Erigeron, Rhodiola.
  • the invention also provides an application of the above-mentioned composition in the preparation of medicines and/or health products for restoring brain function.
  • Panax notoginseng, ginseng, ginkgo biloba, pueraria lobata, breviscapine, rhodiola, etc. can enhance the improvement of NADH and/or NMN on the neurological function of mice, lower the oxidative stress level of brain tissue, and reduce Apoptosis of brain tissue.
  • it can be determined by animal experiments that after the administration, the brain function of the test animal is improved, and the memory and spatial recognition ability are significantly improved.

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Abstract

公开了一种组合物、制备方法、制剂以及制备脑功能恢复的药物和/或保健品的应用，其中所述组合物的原料包括烟酰胺腺嘌呤二核苷酸和/或烟酰胺腺嘌呤单核苷酸、人参、三七、银杏叶、葛根、灯盏花、红景天。

Description

NADH和/或NMN在制备脑功能恢复的药物、保健品中的应用 技术领域
本发明属于中药组合物领域，尤其涉及一种含烟酰胺腺嘌呤二核苷酸和/或烟酰胺腺嘌呤单核苷酸的组合物及其制备脑功能恢复的药物和/或保健品中的应用。
 背景技术
世界范围的人口老龄化增加了脑功能下降的发生，容易引起健忘、焦虑性障碍、欲望的降低、睡眠质量的降低等，严重的甚至会产生记忆障碍及老年性痴呆，这使得受影响的人的生活受到巨大的破坏性影响。
 技术问题
但是脑功能减低的成因极其复杂，目前大部分研究仅针对具体脑损伤性疾病，所研究的药物对人体损害较大，副作用较多，并且对于因衰老或身体其他原因引起的脑功能下降的日常预防、改善和治疗的药品和饮食品，基本没有。
 技术解决方案
有鉴于此，本发明提供了一种含烟酰胺腺嘌呤二核苷酸（NADH）和/或烟酰胺腺嘌呤单核苷酸（NMN）的组合物及其在制备脑功能恢复的药物和/或保健品中的应用，用于改善大脑健康及大脑功能，包括但不限于认知、记忆、智力、动机、注意力、专注力、学习能力和更好的沟通及减轻与认知和记忆障碍相关的疾病及类似疾病。
本发明提供了一种含NADH/NMN的组合物及其在制备脑功能恢复的药物和/或保健品中的应用，用于预防、控制及治疗与大脑疾病/障碍，其包括但不限于老年性痴呆、多发梗塞性痴呆症、阅读障碍、失语症、器质性脑综合征、重症肌无力、血管性痴呆、轻度认知功能障碍（MCI）、路易体痴呆症、韦尼克-科尔萨科夫综合征、阿尔茨海默氏症、帕金森氏症、注意缺陷多动障碍（ADHD）、低氧、缺氧、脑血管功能不全、癫痫、肌阵挛和低胆碱能神经功能障碍，减缓记忆力衰退、功能丧失和治疗记忆障碍疾病、神经退行性疾病，并在大脑中控制血压和血液循环。
本发明提供了一种组合物，所述组合物的原料包括：NADH和/或NMN、人参、红景天、三七、银杏叶、葛根以及灯盏花。
优选地，所述组合物的原料包括：NADH和/或NMN、人参提取物、红景天提取物、三七提取物、银杏叶提取物、葛根提取物以及灯盏花提取物。
优选地，以质量份计，所述组合物的原料包括：NADH和/或NMN 1份~10份、人参1份~10份、三七1份~10份、红景天1份~10份、银杏叶1份~10份、葛根1份~10份以及灯盏花1份~10份。
优选地，以质量份计，所述组合物的原料包括：NADH和/或NMN 5份~9份、人参5份~10份、三七3份~7份、红景天1份~2份、银杏叶4份~8份、葛根1份~5份以及灯盏花1份~4份。
优选地，以质量份计，所述组合物的原料包括：NADH和/或NMN 6份~8份、人参6份~9份、三七4份~6份、红景天1份~2份、银杏叶5份~8份、葛根2份~4份以及灯盏花1份~3份。
优选地，以质量份计，所述组合物的原料包括：NADH和/或NMN 7份、人参7份、三七5份、红景天1份、银杏叶7份、葛根3份以及灯盏花2份。
优选地，所述烟酰胺腺嘌呤二核苷酸:烟酰胺腺嘌呤单核苷酸的质量比例为10:1~1:10。
本发明还提供上述组合物的制备方法，包括如下步骤：
将配比量的三七、人参、银杏叶、葛根、灯盏花、红景天为原料，加8-12倍量的质量浓度为30 %-50%的乙醇水溶液浸渍10小时-15小时后，回流提取3次，合并提取液，离心，滤液真空60℃-70℃回收乙醇，50℃-60℃浓缩得到提取液I；
将提取液I中，加入配比量的烟酰胺腺嘌呤二核苷酸和/或烟酰胺腺嘌呤单核苷酸，在室温下充分搅拌混匀，升温至50℃-70℃真空浓缩后，得到组合物。
本发明还提供了一种包括以上任意一项所述的组合物的制剂，包括：
所述组合物加入常规辅料，按照常规工艺，制成口服制剂和肠道外给药制剂。所述常规辅料包括常规药用辅料或常规食品用辅料。
优选地，所述制剂中不含有乳糖。
优选地，常规药用辅料包括但不限于：
所述药学上或食品上可接受的赋形剂、辅料、载体及稀释剂包括但不限于葡萄糖、果糖、蔗糖、麦芽糖、黄糊精、白糊精、二氧化硅、微晶纤维素粉末、硬脂酸钙、硬脂酸镁、山梨糖醇、甜菊苷、玉米糖浆、柠檬酸、酒石酸、苹果酸、琥珀酸、乳酸、L-抗坏血酸、dl-α-生育酚、甘油、丙二醇、甘油脂肪酸酯、聚甘油脂肪酸酯、蔗糖脂肪酸酯、山梨醇酐脂肪酸酯、丙二醇脂肪酸酯、阿拉伯胶、卡拉胶、酪蛋白、明胶、果胶、琼脂、烟酰胺、泛酸钙、钙盐、色素、香精、防腐剂、蒸馏水、盐水、含水葡萄糖溶液、乙醇、丙二醇和聚乙二醇、各种动物油和植物油、白软石蜡、石蜡和蜡。
本发明还提供了一种包括以上任意一项所述的组合物在制备脑功能恢复的药物和/或保健品中的应用。
 有益效果
综上所述，本发明提供了一种组合物，所述组合物的原料包括：NADH和/或NMN、人参、三七、银杏叶、葛根、灯盏花、红景天。本发明还提供了一种上述组合物在制备脑功能恢复的药物和/或保健品中的应用。本发明提供的技术方案中，三七、人参、银杏叶、葛根、灯盏花、红景天等可以增强NADH和/或NMN对小鼠神经功能的改善，下调脑组织的氧化应激水平，减少脑组织的细胞凋亡。进一步地，经动物实验测定可得，给药后，受试动物脑功能改善较好，记忆力和空间识别能力都有显著提高。
 本发明的实施方式
下面将对本申请实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本申请一部分实施例，而不是全部的实施例。基于本申请中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本申请保护的范围。
本发明实施例提供了一种组合物及其在制备脑功能恢复的药物和/或保健品中的应用，用于解决现有技术中，脑功能恢复药物和/或保健品存在着治疗效果差以及对人体存在不良反应的技术缺陷。
为了更详细说明本发明，下面结合实施例对本发明提供的一种组合物及其在制备脑功能恢复的药物和/或保健品中的应用，进行具体地描述。
实施例1
本实施例为制备产品1的具体实施例。
取5g人参、1g红景天、3g三七、4g银杏叶、1g葛根以及1g灯盏花混合，经粉碎、膨化处理后备用；加8倍量的质量浓度为30%的乙醇水溶液浸渍10小时后，回流提取3次，合并提取液，离心，滤液真空60℃-70℃回收乙醇，50℃真空浓缩得到提取液I。
将提取液I中，加入5g的NADH，在室温下充分搅拌混匀后升温至50℃真空浓缩后，得到组合物。将组合物按常规方法与药用辅料制成片剂。
实施例2
本实施例为制备产品2的具体实施例。
取10g人参、2g红景天、7g三七、8g银杏叶、5g葛根以及4g灯盏花混合，经粉碎、膨化处理后备用；加12倍量的质量浓度为40%的乙醇水溶液15小时后，回流提取3次，合并提取液，离心，滤液真空60℃-70℃回收乙醇，60℃真空浓缩得到提取液I。
将提取液I中，加入9g的NADH，在室温下充分搅拌混匀后升温至50℃真空浓缩后，得到组合物。将组合物按常规方法与食品用辅料制成胶囊剂。
实施例3
本实施例为制备产品3的具体实施例。
取6g人参、1g红景天、4g三七、5g银杏叶、2g葛根以及1g灯盏花混合，经粉碎、膨化处理后备用；加9倍量的质量浓度为35%的乙醇水溶液浸渍12小时后，回流提取3次，合并提取液，离心，滤液真空60℃-70℃回收乙醇，真空浓缩得到提取液I。
将提取液I中，加入6g的NMN，在室温下充分搅拌混匀后升温至50℃真空浓缩后，得到组合物。将组合物按常规方法与药用辅料制成粉针剂。
实施例4
本实施例为制备产品4的具体实施例。
取9g人参、2g红景天、6g三七、8g银杏叶、4g葛根以及3g灯盏花混合，经粉碎、膨化处理后备用；加10倍量的质量浓度为45%的乙醇水溶液浸渍12小时后，回流提取3次，合并提取液，离心，滤液真空60℃-70℃回收乙醇，50℃真空浓缩得到提取液I。
将提取液I中，加入8g的NMN，在室温下充分搅拌混匀后升温至50℃真空浓缩后，得到组合物。将组合物按常规方法与食品用辅料制成丸剂。
实施例5
本实施例为制备产品5的具体实施例。
取7g人参、1g红景天、5g三七、7g银杏叶、3g葛根以及2g灯盏花混合，经粉碎、膨化处理后备用；加12倍量的质量浓度为50%的乙醇水溶液浸渍12小时后，回流提取3次，合并提取液，离心，滤液真空60℃-70℃回收乙醇，50℃真空浓缩得到提取液I。
将提取液I中，加入7g的NADH和NMN的混合物（1:1），在室温下充分搅拌混匀后升温至50℃真空浓缩后，得到组合物。将组合物按常规方法与药用辅料制成吸入剂。
实验例1
将实施例1（NADH）、实施例3（NMN）和实施例5（NADH/NMN 1:1）制备的产品混合到小鼠饵料中，给予6周龄的SAMP8小鼠。各产品的加入量为10mg/kg/day。可自由摄取水。饵料3天交换一次，持续给予3个月。之后进行步入(stepthrough)型被动逃避试验。本试验是利用了小鼠喜欢黑暗的习性的记忆学习能力的一个试验方法。是从明室转移到暗室时通过电刺激让其记忆并在24小时后以明室停留时间的长短来评价“记住多少暗室危险”的方法。即，明室停留时间的长短表示记忆学习能力的高低。分析使用软件ShutAvoid(PanLab公司)。
第一天的预备学习中，将进入暗室前的时间(潜伏期)设为最大2分钟，1分钟的明室驯化后打开遮蔽门，转移到暗室后关上门，给予2秒钟0.4mA的电刺激。电刺激后迅速将小鼠放回笼子。第二天的正式试验中，将潜伏期最大设为5分钟，测定在明室停留的时间。将第二天在明室持续停留5分钟的个体的潜伏期设为5分钟进行计算。
第二天的明室停留时间按组取平均，以对照组(无摄取组)为1.0，计算其比率。每组的个体数如下：对照组 24只、NADH组(实施例1产品) 8只、NMN组(实施例3产品) 8只、NADH/NMN组(实施例5产品)8只。对照组和各产品组的结果如表1所示。
Figure dest_path_image001
从表1可知，各产品组与对照组相比，具有高的被动逃避效果。其中，NADH/NMN组中可观察到比对照组1.4倍的被动逃避效果。此外，NADH组的被动逃避效果的对照比为1.2比单独的NMN组要好。该结果表明本发明的产品具有脑功能改善效果。
实验例2
采用高架放射臂迷宫方法测试小鼠对改善学习及记忆的功效：动物研究方案已得到机构动物伦理委员会的批准。将6周龄的小鼠适应环境一周并选择健康小鼠进行研究。将选择的小鼠在高架放射臂迷宫（RAM）中预先训练，将适应的小鼠分配于不同的处理组，每组包含8只小鼠。完成预训练后，对动物每天进行如实验例1相同的处理持续并持续至两周。在处理期间，小鼠置于RAM上，每次10分钟以认识存在于三个不同颜色臂上的食物丸。在训练过程中，通过计算不同的参数如需要学习任务的天数、发现食物的潜伏期、错误进入/尝试的次数来测试空间学习能力。在这样处理后，给予所训练的小鼠一个星期（第三周）的休息而不需要处理或训练。在第四周，对小鼠采用相同的同屋通过测试潜伏期及错误进入的数量来进行记忆保持测试。通过ANOVA及适当的事后比较来分析数据。结果如表2所示：
Figure 59979dest_path_image002
如表2所示，各产品组显著（P< 0.01）地减少了在所设置条件下小鼠需要学习的天数，并且显著地（P< 0.05）降低了学习后的小鼠在高架RAM模型中找到食物所需要的时间。与对照组相比，各产品组显示出了显著的空间学习能力的提高，以减少潜伏期及错误进入的数量为代表。其中尤以NADH/NMN组效果最为显著。这些结果都证实本发明产品能够提高了空间学习及记忆保持。
从上述实施例可以得出，本发明提供的技术方案，具有以下优点：
1、人参可通过调节Bax、Bcl-2 蛋白表达来减少脑细胞凋亡，其作用机制与上调NAIP 和Bcl-2 蛋白表达和降低Bax蛋白表达有关。
三七可抑制脑血管内皮细胞凋亡，上调VEGF 表达，促进血管再生。同时还可上调胶质纤维酸性蛋白( glial fibrillary acidic protein，GFAP) 、碱性成纤维细胞生长因子( Basic fibroblastgrowth factor，BFGF) 的表达，改善脑自体神经干细胞( neural stem cells，NSCs) 的生存微环境，促进脑自体神经干细胞的增殖，进而改善小鼠的脑神经功能。
银杏叶可显著减少小鼠脑组织细胞凋亡，抑制脑组织c -fos蛋白表达，促进脑神经修复。
葛根能显著降低神经功能缺损评分，明显减少脑坏死体积与凋亡阳性细胞数，其神经保护作用机制与抑制STAT3的磷酸化水平、降低P53 的表达及JAK2 /STAT3 信号通路异常激活有关。
灯盏花对新生小鼠脑组织神经细胞凋亡均具有明显的抑制作用，其机制与调节Bax /Bcl-2 基因表达、下调caspase-3 、NF-kB 及Fas蛋白表达等有关。
红景天能够改善MCAO 小鼠的脑神经功能损伤，抑制神经细胞凋亡，主要是通过激活PI3K/AKT信号通路，促进AKT 的磷酸化，激活NＲF2 的核转录，促进HO-1 的蛋白表达，进而抑制神经细胞凋亡，改善神经功能。
因此，本发明中的三七、人参、银杏叶、葛根、灯盏花、红景天等可以增强NADH和/或NMN对脑神经功能的改善，下调脑组织的氧化应激水平，减少脑组织的细胞凋亡。
本发明以人参、银杏叶为君，安神益智，活血通络，以三七、葛根为臣，通络舒筋，兼养阴生津。以灯盏花、红景天为佐使，活血舒筋，散淤消肿。三者相伍，具有活血通络，益气生津的功效，能明显改善脑神经功能，减少脑细胞凋亡，从而促进脑功能恢复。
本发明采用特定的成分特定的配比，组方合理，配伍得当，本发明所选成分配伍相宜，符合中医药和现代医药相结合的理论，使用方便，吸收效果好，无不良及毒副作用，经临床验证，能有效的提高和改善脑功能，促进脑功能的恢复。
综上所述，本发明提供了一种组合物，所述组合物的原料包括：NADH和/或NMN、人参、三七、银杏叶、葛根、灯盏花、红景天。本发明还提供了一种上述组合物在制备脑功能恢复的药物和/或保健品中的应用。本发明提供的技术方案中，三七、人参、银杏叶、葛根、灯盏花、红景天等可以增强NADH和/或NMN对小鼠神经功能的改善，下调脑组织的氧化应激水平，减少脑组织的细胞凋亡。进一步地，经动物实验测定可得，给药后，受试动物脑功能改善较好，记忆力和空间识别能力都有显著提高。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (10)

  1. 一种组合物，其特征在于，所述组合物的原料包括：烟酰胺腺嘌呤二核苷酸和/或烟酰胺腺嘌呤单核苷酸、人参、三七、银杏叶、葛根、灯盏花、红景天。
  2. 根据权利要求1所述的组合物，其特征在于，所述组合物的原料包括：烟酰胺腺嘌呤二核苷酸和/或烟酰胺腺嘌呤单核苷酸、人参提取物、三七提取物、银杏叶提取物、葛根提取物、灯盏花提取物以及红景天提取物。
  3. 根据权利要求1所述的组合物，其特征在于，以质量份计，所述组合物的原料包括：烟酰胺腺嘌呤二核苷酸和/或烟酰胺腺嘌呤单核苷酸 1份~10份、人参1份~10份、三七1份~10份、红景天1份~10份、银杏叶1份~10份、葛根1份~10份以及灯盏花1份~10份。
  4. 根据权利要求3所述的组合物，其特征在于，以质量份计，所述组合物的原料包括：烟酰胺腺嘌呤二核苷酸和/或烟酰胺腺嘌呤单核苷酸 5份-9份、人参5份~10份、三七3份~7份、红景天1份~2份、银杏叶4份~8份、葛根1份~5份以及灯盏花1份~4份。
  5. 根据权利要求4所述的组合物，其特征在于，以质量份计，所述组合物的原料包括：烟酰胺腺嘌呤二核苷酸和/或烟酰胺腺嘌呤单核苷酸 6份~8份、人参6份~9份、三七4份~6份、红景天1份~2份、银杏叶5份~8份、葛根2份~4份以及灯盏花1份~3份。
  6. 根据权利要求1所述的组合物，其特征在于，所述烟酰胺腺嘌呤二核苷酸:烟酰胺腺嘌呤单核苷酸的质量比例为10:1~1:10。
  7. 一种权利要求1-6任一项所述的组合物的制备方法，其特征在于，包括如下步骤:
    将配比量的三七、人参、银杏叶、葛根、灯盏花、红景天为原料，加8-12倍量的质量浓度为30-50%的乙醇水溶液浸渍10小时-15小时后，回流提取3次，合并提取液，离心，滤液真空60℃-70℃回收乙醇，50℃-60℃浓缩得到提取液I；
    将提取液I中，加入配比量的烟酰胺腺嘌呤二核苷酸和/或烟酰胺腺嘌呤单核苷酸，在室温下充分搅拌混匀，升温至50℃-70℃真空浓缩后，得到组合物。
  8. 包括权利要求1-6任一项所述的组合物的制剂，其特征在于，
    所述组合物加入常规辅料，按照常规工艺，制成口服制剂和肠道外给药制剂，所述常规辅料包括常规药用辅料或常规食品用辅料。
  9. 根据权利要求8所述的制剂，其特征在于，所述制剂中不含有乳糖。
  10. 权利要求1-6任一项所述的组合物在制备脑功能恢复的药物和/或保健品中的应用。
PCT/CN2020/075632 2019-08-20 2020-02-18 Nadh 和 / 或 nmn 在制备脑功能恢复的药物、保健品中的应用 WO2021031536A1 (zh)

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