Application of aquilaria sinensis leaf active component 4-phenyl-2-butanone in improvement of sleep disorder
By extracting 4-phenyl-2-butanone from white vermicelli leaves and developing its pharmaceutical preparations, the addictive and adverse reaction problems in the treatment of sleep disorders in the prior art were solved, and the effect of significantly improving sleep quality was achieved.
Patent Information
- Application Number
- CN202411775073.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-05
- Publication Date
- 2025-02-25
AI Technical Summary
The prior art is difficult to effectively solve the problem of sleep disorders, especially due to the adverse reactions such as addictive and rebound insomnia in chemical synthesis drugs.
4-phenyl-2-butanone was extracted from white vermicelli leaves, and pharmacological and pharmacological studies were conducted to develop it as a pharmaceutical preparation to prevent, relieve and treat sleep disorders.
4-phenyl-2-butanone significantly improves sleep quality, has low toxic side effects and high safety, and can provide a highly effective drug for patients with anxiety and sleep disorders.
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of medicines, and in particular to application of 4-phenyl-2-butanone, an active component of Aquilaria sinensis leaves, in improving sleep disorders. Background Art
[0002] Sleep is a spontaneous and reversible resting state that occurs periodically in higher vertebrates, which is characterized by a decrease in the body's responsiveness to external stimuli and a temporary interruption of consciousness. About one-third of a person's life is spent in sleep. When people are in a sleeping state, the brain and body can rest, recuperate and recover, which is helpful for people's daily work and study. Scientifically improving the quality of sleep is the guarantee for people's normal work, study and life. Sleep disorders have caused a considerable number of people to be in a "sub-healthy" state. Sleep disorders often cause low immunity and mental irritability in the human body. At the same time, they are also prone to high blood pressure, neurasthenia, cardiovascular and cerebrovascular accidents, psychological diseases, and even sudden death. The threat that sleep disorders bring to daily work and life is also very terrible. According to statistics, 30-50% of accidents are caused by drowsiness. According to a 5.5-year study of 7,000 people by two American scholars, sleep is an important factor among the seven factors that affect human life span. Sleep disorders can also lead to a lot of economic losses. A survey by the American Sleep Disorders Research Institute shows that the economic losses caused by sleep disorders in the United States reach 43 to 56 billion US dollars a year. Commonly used drugs for treating sleep disorders include chemically synthesized drugs and natural medicines. Chemically synthesized drugs include barbiturates, benzodiazepines, and non-benzodiazepine short-acting drugs. These drugs have definite efficacy, but have serious adverse reactions such as addiction and rebound insomnia.
[0003] Traditional Chinese medicine has the characteristics of multi-target action, has unique therapeutic advantages for insomnia with complex etiology, and its natural source and small side effects have attracted wide attention in modern scientific research and clinical application. White agarwood leaves are commonly used traditional tonic Chinese herbal medicines with multiple pharmacological activities. The prior art only records the possible biological or drug effects of white agarwood leaves on the treatment of sleep disorders, but does not suggest the efficacy of 4-phenyl-2-butanone, a monomer compound, in the treatment of sleep disorders. The present invention explores the pharmacodynamics and pharmacology of 4-phenyl-2-butanone and its corresponding pharmaceutical preparations for relieving and treating sleep disorders, providing new ideas for the development of Chinese medicine monomers for sleep disorders. Summary of the invention
[0004] In order to overcome the above technical defects, the present invention extracts 4-phenyl-2-butanone, an effective ingredient for treating sleep disorders, from the leaves of Aquilaria sinensis, and conducts pharmacodynamic and pharmacological studies on 4-phenyl-2-butanone and its corresponding pharmaceutical preparations for relieving and treating sleep disorders. The results show that the pharmacological effect of treating sleep disorders is clear, the efficacy is significant, the toxic and side effects are low, and the safety is high. A highly effective and low-toxic drug can be provided for patients with anxiety and sleep disorders.
[0005] One of the purposes of the present invention is to provide an application of 4-phenyl-2-butanone in the preparation of a medicine or health food for preventing, alleviating and treating sleep disorders.
[0006] The sleep disorder is insomnia, which is mainly manifested as: reduced sleep time, difficulty falling asleep, insomnia or poor sleep quality.
[0007] The medicine according to the present invention can be composed of 4-phenyl-2-butanone and a pharmaceutically acceptable carrier.
[0008] The drug can be processed into tablets, capsules, pills, powders, granules, syrups, solutions, emulsions, injections, sprays, aerosols, and patches by using methods of the prior art.
[0009] Another object of the present invention is to provide a drug for preventing, alleviating and treating sleep disorders, wherein the drug contains 4-phenyl-2-butanone, or other components with sleep-promoting activity for compound use.
[0010] Another object of the present invention is to provide a method for preventing, alleviating and treating sleep disorders, which comprises administering a therapeutically effective amount of 4-phenyl-2-butanone to a patient.
[0011] In other words, the present invention relates to a new application of 4-phenyl-2-butanone or a medicinal material extract containing 4-phenyl-2-butanone in preventing, alleviating and treating sleep disorders, and provides a new medicinal application of 4-phenyl-2-butanone or a pharmaceutically acceptable salt or solvate thereof or a medicinal material extract containing an effective amount of 4-phenyl-2-butanone, that is, a new application in drugs and health foods for preventing, alleviating and treating sleep disorders.
[0012] To achieve the above-mentioned purpose, the present invention provides an application of 4-phenyl-2-butanone in the preparation of medicines and health foods for preventing, alleviating and treating sleep disorders. The sleep disorders mentioned herein mainly refer to insomnia or early awakening characterized by difficulty in maintaining sleep.
[0013] In the process of screening natural active ingredients with sleep disorder efficacy, the inventors discovered that one of the chemical components in the extract of the traditional Chinese medicine Aquilaria sinensis leaves, paeoniflorin, has a strong pharmacodynamic effect, and also discovered that 4-phenyl-2-butanone has medicinal value in treating and preventing sleep disorders.
[0014] In particular, the pharmaceutically acceptable carriers are generally recognized for this purpose and serve as inactive ingredients of medicaments.
[0015] The carrier includes excipients, such as starch, water, etc.; lubricants, such as magnesium stearate, etc.; disintegrants, such as microcrystalline cellulose, etc.; fillers, such as lactose, etc.; binders, such as pregelatinized starch, dextrin, etc.; sweeteners; antioxidants; preservatives; flavoring agents; spices, etc.
[0016] The drug is in the form of tablets, capsules, pills, powders, granules, syrups, solutions, emulsions, injections, sprays, aerosols, and patches.
[0017] Wherein, the drug is administered via gastrointestinal and parenteral routes.
[0018] Particularly, the non-gastrointestinal administration route is selected from injection, respiratory tract administration, skin administration, mucosal administration or cavity administration.
[0019] Among them, the parenteral preparation is selected from injections, sprays, aerosols, patches and the like.
[0020] Particularly, the gastrointestinal administration preparation is selected from tablets, capsules, powders, granules, pills, solutions, emulsions or syrups.
[0021] Another aspect of the present invention provides an application of a 4-phenyl-2-butanone composition in the preparation of medicines and health foods for preventing, alleviating and treating sleep disorders.
[0022] Wherein, the 4-phenyl-2-butanone composition is selected from pharmaceutically acceptable salts of 4-phenyl-2-butanone and solvates of 4-phenyl-2-butanone.
[0023] In particular, the pharmaceutically acceptable salt of 4-phenyl-2-butanone is a physiologically acceptable salt (especially when administered as a drug to humans and / or mammals).
[0024] Another aspect of the present invention provides a use of a medicinal material containing 4-phenyl-2-butanone or a medicinal material extract containing 4-phenyl-2-butanone in the preparation of medicines and health foods for preventing, alleviating and treating sleep disorders.
[0025] Wherein, the medicinal material containing 4-phenyl-2-butanone is selected from Aquilaria sinensis leaves.
[0026] In particular, the carrier includes excipients such as starch, water, etc.; lubricants such as magnesium stearate, etc.; disintegrants such as microcrystalline cellulose, etc.; fillers such as lactose, etc.; binders such as pregelatinized starch, dextrin, etc.; sweeteners; antioxidants; preservatives; flavoring agents; spices, etc.
[0027] The drug can be prepared into various dosage forms by methods known in the art, such as tablets, capsules, pills, powders, granules, syrups, solutions, emulsions, injections, sprays, aerosols, patches, etc.
[0028] The present invention also provides a method for treating sleep disorders, comprising administering to a subject a therapeutically effective amount of a pharmaceutical composition of 4-phenyl-2-butanone, wherein the therapeutically effective amount is 0.5-5 mg / kg / d, preferably 1.2-4 mg / kg / d, and further preferably 2-3.5 mg / kg / d.
[0029] Unless otherwise specified, the term "therapeutically effective amount" as used herein is the amount of a drug required to produce an effective effect; the "therapeutically effective amount" can be adjusted and varied and is ultimately determined by medical personnel, taking into account factors including the route of administration and the nature of the preparation, the recipient's general condition such as weight and age, and the nature and severity of the disease being treated.
[0030] The present invention finds that 4-phenyl-2-butanone can increase the content of 5-HT and GABA in serum and / or hippocampal tissue, has significant effects of preventing, alleviating and treating sleep disorders, is one of the main effective components of Aquilaria sinensis leaves and Aquilaria sinensis leaf extracts for treating sleep disorders, explores its new medicinal value, prepares it into a medicine or health food for preventing, alleviating and treating sleep disorders, has significant efficacy, few toxic and side effects, good safety, can be taken for a long time, has high drugability and good medicinal prospects. DETAILED DESCRIPTION
[0031] In order to make those skilled in the art better understand the technical scheme of the present invention, the present invention is described in detail below in conjunction with specific embodiments. The experimental methods for which specific conditions are not indicated in the following examples are usually carried out under normal conditions or according to the conditions recommended by the manufacturer. The test materials used in the following examples, unless otherwise specified, are purchased from conventional biochemical reagent stores. Unless otherwise specified, percentages and parts are calculated by weight. Unless otherwise defined, all professional and scientific terms used in the text have the same meaning as those familiar to those skilled in the art. In addition, any method and material similar to or equal to the recorded content can all be applied to the present invention. The preferred implementation methods and materials described in the text are only for demonstration purposes.
[0032] The endpoints and any values of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values should be understood to include values close to these ranges or values. For numerical ranges, the endpoint values of each range, the endpoint values of each range and the individual point values, and the individual point values can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.
[0033] All experiments in the following examples and experimental examples were repeated three times, and the data were expressed as Mean ± SEM. GraphPad Prism 7.0 software was used for statistical analysis, and t-test was used for comparison between two groups, and oneway-ANOWA was used for comparison between multiple groups, with P < 0.05 being considered statistically significant.
[0034] The technical solution of the present invention is further described in detail below in conjunction with specific embodiments and appended tables. It should be understood that the following embodiments are only used to explain the present invention and are not used to limit the present invention.
[0035] Example 1: Exploring the effects of Aquilaria sinensis leaves on the treatment of sleep disorders
[0036] The leaves of Aquilaria sinensis were extracted with 12 times the amount of hot water (100°C) for 3 times, 60 minutes each time, filtered, the filtrate was combined, and concentrated under reduced pressure to a relative density of 1.10 to obtain an extract. The extract was analyzed by GC-MS, and a variety of active components with autonomic inhibition and sedative effects were obtained (see Table 1). Among them, there may be three key components with higher qualitative values, namely 4-phenyl-2-butanone, valeric acid, and valeric alcohol. In addition, there are 5 benzodiazepine compounds, three of which have no qualitative values. It may be due to technical limitations that there are false positives or the existence of similar compounds.
[0037] Further quality control research was conducted on the monomer components, and 4-phenyl-2-butanone, the key ingredient in Aquilaria sinensis leaves for treating insomnia, was discovered.
[0038] Table 1
[0039] serial number Compound Chinese name Molecular formula Molecular weight Retention time Qualitative value 1 4-Phenylbutan-2-one 4-Phenyl-2-butanone C10H12O 148.088 5.767 0.9491 2 Valerenic acid Valerenic acid C15H22O2 234.161 7.487 0.8723 3 Baldrinal Valerianol C12H10O4 218.057 3.435 0.5321 4 Nitrazepam Nitrazepam C15H11N3O3 281.080 1.382 - 5 Tetrazepam Tetrahydrodiazepam C16H17C1N2O 288.102 4.789 - 6 Estazolam Estazolam C16H11C1N4 294.067 3.384 - 7 Limazepine B2 Rimazepine B2 C15H18N2O4 290.126 5.339 0.6911 8 Limazepine C Rimazepine C C15H16N2O3 272.116 5.841 0.5683
[0040] Example 2 Investigating the effect of 4-phenyl-2-butanone on improving sleep
[0041] Animal dosing and grouping: 40 SPF adult male SD rats were selected to eat and drink freely. All mice were first adapted to the environment for one week (7 days) before the experiment. Then they were randomly divided into four groups for dosing, with 10 mice in each group, namely blank control group, model group, positive drug group, GABA group, and 4-phenyl-2-butanone group. The details are as follows:
[0042] Blank group: daily gavage with pure water;
[0043] Positive drug group: daily diazepam dosage was 1 mg / kg / d, twice a day;
[0044] GABA group: daily dosage was 83.3 mg / kg; the maximum dosage of GABA for human use is 500 mg / 60 kg, which is converted to the corresponding dosage for mice: 83.3 mg / kg;
[0045] 4-Phenyl-2-butanone group: daily administration dose was 3 mg / kg body weight.
[0046] Except for the blank group, the other groups were intraperitoneally injected with 300 mg / kg of 4-Chloro-DL-phenylalanine (PCPA) once a day for three consecutive days to establish a rat insomnia model. From the fourth day, the drug was administered for 6 consecutive days. The experiment started 30 minutes after the last administration. At the beginning of the last administration of mice, a stopwatch was used to count down for 30 minutes, and then 42 mg / kg of sodium pentobarbital was intraperitoneally injected into the four groups of mice, and the disappearance and recovery of the righting reflex of the mice were observed. The disappearance time and recovery time of the righting reflex of the mice were recorded, and the sleep latency and sleep duration were calculated. The results are shown in Table 2.
[0047] Criteria for judging sleep latency and sleep duration: If the mouse remains in dorsal recumbency for more than 1 minute, it is considered that the mouse's righting reflex has disappeared. After the mouse automatically turns over, the mouse is immediately placed in dorsal recumbency. If the mouse turns over within 1 minute, it is considered that the mouse's righting reflex has recovered. The disappearance time and recovery time of the mouse's righting reflex are recorded. The time period from intraperitoneal injection of sodium pentobarbital to the disappearance of the mouse's righting reflex is recorded as the sleep latency. The time period from the disappearance of the mouse's righting reflex to the recovery of the mouse's righting reflex is recorded as the sleep duration.
[0048] Table 2
[0049] Blank control group Positive drug group GABA group 4-Phenyl-2-butanone group Sleep latency, min 5.43±1.51 3.68±0.84* 5.83±1.72 4.17±0.58 Sleep duration, min 26.43±9.21 89.63±7.76* 42.78±18.13** 40.74±5.29*
[0050] Note: *P<0.05, **P<0.01 compared with the blank group
[0051] As can be seen in the table above, diazepam can significantly shorten the sleep latency of mice and prolong the sleep time of mice. The GABA group and the 4-phenyl-2-butanone group were both proven to significantly prolong the sleep time of mice (p<0.01), and there was no significant difference between the two effects. Compared with the GABA group, the 4-phenyl-2-butanone group could also significantly shorten the sleep latency of mice (p<0.05), and its effect was better than that of the GABA group.
[0052] Example 2 Investigating the Effect of 4-phenyl-2-butanone on Serum Levels of 5-HT and GABA
[0053] Animal dosing and grouping: 40 SPF adult male SD rats were selected to eat and drink freely. All mice were first adapted to the environment for one week (7 days) before the experiment. Then they were randomly divided into four groups for dosing, with 10 mice in each group, namely blank control group, model group, positive drug group, GABA group, and 4-phenyl-2-butanone group. The details are as follows:
[0054] Blank group: daily gavage with pure water;
[0055] Positive drug group: daily diazepam dosage was 1 mg / kg / d, twice a day;
[0056] 4-Phenyl-2-butanone group: daily administration dose was 3 mg / kg body weight.
[0057] Except for the blank group, the other groups were intraperitoneally injected with 300 mg / kg of 4-Chloro-DL-phenylalanine (PCPA) once a day for three consecutive days to establish a rat insomnia model. From the fourth day, the drug was administered for 4 consecutive days. One hour after the last administration, the mice were euthanized, blood was collected from the eyeballs, plasma was collected, centrifuged at 3000 rpm, 4°C for 15 minutes, the supernatant was collected, and frozen in a -80°C refrigerator for subsequent analysis of changes in sleep-related neurotransmitters in serum. At the same time, the mouse brain was collected and placed at -80°C for subsequent analysis of changes in sleep-related neurotransmitters in mouse brain tissue. The results are shown in Table 3.
[0058] The occurrence of sleep is closely related to changes in neurotransmitters in the brain. 5-HT, also known as serotonin, is an important inhibitory neurotransmitter widely present in mammals. Its level is very high in the cerebral cortex and synapses, mainly distributed in the pineal gland and hypothalamus. An increase in the content of 5-HT can have a certain sedative and sleep-promoting effect; GABA is an important inhibitory neurotransmitter in the brain, and it activates GABA receptors to cause Cl - Channels open, increasing cell membrane resistance to Cl - The permeability of Cl - Flowing into nerve cells causes cell membrane hyperpolarization, inhibiting the excitement of neuronal cells, thereby achieving a calming and hypnotic effect.
[0059] Table 3
[0060] 5-HT GABA Blank control group 23.45±0.46 1.57±0.04 Positive drug group 22.71±0.35 1.51±0.05 Model Group 19.84±0.72 1.26±0.07 4-Phenyl-2-butanone group 23.19±0.69 1.56±0.06
[0061] Note: *P<0.05, **P<0.01
[0062] As can be seen in the table above, compared with the normal group, the serum 5-HT and GABA in the model group decreased. Compared with the model group, the serum 5-HT and GABA in the positive drug group and the 4-phenyl-2-butanone group increased to varying degrees. Moreover, the 5-HT and GABA levels in the brain of mice treated with 4-phenyl-2-butanone were significantly better than those in the positive drug group. The results show that 4-phenyl-2-butanone can improve the sleep quality of insomnia rats by increasing the expression of 5-HT and GABA in the hippocampus tissue.
[0063] Finally, it should be noted that the above description is only a preferred embodiment of the present invention. Under the guidance of the present invention, those skilled in the art can make a variety of similar expressions without violating the purpose and claims of the present invention. Such changes all fall within the scope of protection of the present invention.
Claims
1. Application of 4-phenyl-2-butanone in improving sleep disorders.
2. The use according to claim 1, characterized in that: The 4-phenyl-2-butanone is used for increasing the expression levels of 5-HT and GABA in serum and / or hippocampal tissue.
3. The use according to claim 1, characterized in that: The invention is used in preparing food, health care products or medicines for preventing, improving or treating sleep disorders.
4. The use according to claim 1, characterized in that: The sleep disorders include: reduced sleep time, difficulty falling asleep, insomnia or poor sleep quality.
5. The use according to claim 3, characterized in that The 4-phenyl-2-butanone can be used alone in the preparation of the food, health care product or medicine, or can be used in combination with other components having sleep-aiding activity.
6. A composition for improving sleep disorders, characterized in that: The invention comprises the 4-phenyl-2-butanone as an active ingredient and pharmaceutically acceptable auxiliary materials.
7. The composition according to claim 6, characterized in that Other ingredients with sleep-inducing activity are also included.
8. The composition according to claim 6 or 7 is in oral dosage form or injection form, and can also adopt controlled release or sustained release forms known in the modern pharmaceutical industry.