Application of glycerophosphoric acid in preparation of composition helpful for improving sleep

Abstract

The invention provides an application of glycerophosphoric acid or pharmaceutically acceptable salts thereof in preparation of a composition helpful for improving sleep. The composition can improve sleep from at least one of three aspects of increasing total sleep duration, preventing sleep fragmentation and increasing sleep depth.

Description

Technical Field

[0001] The invention relates to the technical fields of medicine, food and health food, and in particular to application of glycerophosphoric acid in preparing a composition that helps improve sleep. Background Art

[0002] Sleep is an important physiological process regulated by the brain. It allows the body to rest and restore physical strength. It can also stop brain thinking activities, restore brain power, promote brain function development, and consolidate memory. It plays a vital role in human brain development, physical and mental health, and maintenance of cognitive function.

[0003] Insomnia and other sleep disorders can lead to serious health problems such as anxiety, depression, and cognitive decline. Therefore, it is of great significance to provide a new drug and health food that helps improve sleep. Summary of the invention

[0004] The present invention aims to solve at least one of the above-mentioned technical problems existing in the prior art. To this end, the object of the present invention is to provide a composition that helps improve sleep.

[0005] In order to achieve the above object, the technical solution adopted by the present invention is:

[0006] The present invention provides application of glycerophosphate or a pharmaceutically acceptable salt thereof in preparing a composition that helps improve sleep.

[0007] The pharmaceutically acceptable salts of the present invention refer to salts prepared from pharmaceutically acceptable non-toxic bases or acids (including inorganic or organic bases and inorganic or organic acids). Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese salts, divalent manganese, potassium, sodium, zinc salts, and the like.

[0008] In one or more embodiments of the present invention, improving sleep comprises:

[0009] Treating or preventing sleep disorders; and / or

[0010] Improve sleep quality.

[0011] In one or more embodiments of the present invention, the sleep disorder includes at least one of an intrinsic sleep disorder, an extrinsic sleep disorder, a circadian rhythm disorder, a parasomnia, a sleep disorder associated with an internal or mental disorder, and insomnia.

[0012] In one or more embodiments of the present invention, the intrinsic sleep disorder comprises psychophysiological insomnia.

[0013] In one or more embodiments of the present invention, the circadian rhythm disorder includes at least one of time zone change syndrome (jet lag syndrome), shift work sleep disorder, irregular sleep-wake pattern, delayed sleep phase syndrome, advanced sleep phase syndrome, non-24-hour sleep-wake syndrome, etc.

[0014] In one or more embodiments of the present invention, the sleep disorder associated with internal or mental disorders includes sleep disorder associated with at least one of chronic obstructive pulmonary disease, Alzheimer's disease, Parkinson's disease, cerebrovascular dementia, schizophrenia, depression, and anxiety neurosis.

[0015] In one or more embodiments of the present invention, the sleep disorder refers to insomnia.

[0016] In one or more embodiments of the present invention, the improving sleep comprises at least one of the following:

[0017] Increase total sleep duration;

[0018] Preventing sleep fragmentation;

[0019] Increase sleep depth.

[0020] In one or more embodiments of the present invention, the composition is a medicine and / or a health food.

[0021] In one or more embodiments of the present invention, the medicine and / or health food may further contain other active ingredients that help improve sleep.

[0022] In one or more embodiments of the present invention, other active ingredients that help improve sleep are active ingredients known in the art that can be effectively used to improve sleep quality, prevent and treat sleep disorders, including, for example: sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, antihistamines, benzodiazepines, barbiturates, cyclopyrrolones, GABA agonists, 5HT-2 antagonists (including 5HT-2A antagonists and 5HT-2A / 2C antagonists), histamine antagonists (including histamine H3 antagonists, histamine H3 inverse agonists), imidazopyridines, weak tranquilizers, melatonin agonists and antagonists, melatonin-producing agents, other orexin antagonists, orexin agonists, prokineticin agonists and antagonists, pyrazolopyrimidines, T-type calcium channel antagonists, triazolopyridines, and the like.

[0023] In one or more embodiments of the present invention, the medicine and / or health food may further contain a pharmaceutically acceptable carrier or a carrier acceptable in food or health food.

[0024] In one or more embodiments of the present invention, the carrier is selected from at least one of a solubilizer, a binder, a controlled release polymer, a disintegrant, a colorant, a flavoring agent, an antioxidant, a filler, a suspending agent and / or a surfactant.

[0025] In one or more embodiments of the present invention, the drug and / or health food can be prepared in a dosage form selected from any one of tablets, pills, capsules, granules, powders, chewing gums, suspensions, emulsions, suppositories or solutions.

[0026] In one or more embodiments of the present invention, the drug is administered orally and / or parenterally.

[0027] The beneficial effects of the present invention are:

[0028] The present invention provides the use of glycerophosphoric acid or a pharmaceutically acceptable salt thereof in the preparation of a composition that helps improve sleep. Glycerophosphoric acid can improve sleep in at least one of the three aspects of increasing total sleep time, preventing sleep fragmentation, and increasing sleep depth. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 Effects of glycerol phosphate on sleep duration of Drosophila. Note: Data are presented as mean±SEM.

[0030] Figure 2 The effect of glycerol phosphate on the sleep frequency of Drosophila. Note: Data are presented as mean±SEM.

[0031] Figure 3 The effect of glycerol phosphate on the single sleep time of Drosophila. Note: Data are presented as mean±SEM.

[0032] Figure 4 Effects of glycerol phosphate on the number of nocturnal activities of Drosophila. Note: Data are presented as mean±SEM. DETAILED DESCRIPTION

[0033] Glycerophosphate, also known as glycerol phosphate, glycerol-3 phosphate or 3-glycerol phosphate, is an important biochemical molecule with good biocompatibility and safety, and is involved in cellular energy metabolism and signal transduction.

[0034] The chemical structure of glycerophosphate is

[0035] The present invention finds that glycerophosphate can improve sleep from at least one of the three aspects of increasing total sleep duration, preventing sleep fragmentation, and increasing sleep depth, and provides an application of the glycerophosphate in the preparation of a drug and / or health food for improving sleep.

[0036] The present invention is further described in detail below by specific examples. Unless otherwise specified, the raw materials, reagents or devices used in the examples and comparative examples can be obtained from conventional commercial sources or can be obtained by prior art methods. Unless otherwise specified, the experiments or test methods are conventional methods in the art.

[0037] The materials and equipment used in the embodiments of the present invention are as follows:

[0038] Glycerophosphate was selected from Shanghai MacLean Biochemical Technology Co., Ltd. (GP, catalog number G887797), agar (Biofroxx), sucrose (commercially available), propionic acid (Shanghai Sinopharm Group), and Drosophila activity monitor (Trikinetics, USA, model DAM5).

[0039] Example 1 Effect of glycerophosphate on Drosophila sleep

[0040] Using Drosophila melanogaster to establish a human disease research model has gradually become a new research highlight. Since the sleep of fruit flies shows great similarities with human sleep in terms of behavioral performance, drug response, gene expression, etc., fruit flies have become a new model organism for sleep research.

[0041] The Drosophila Activity Monitoring System (DAMS; Trikinetics Inc. USA) was used to continuously monitor the activity of fruit flies. The DAMS system mainly consists of a monitor and 32 separate monitoring tubes, each of which is 65 mm long, with one end for placing food and the other end as a breathable plug. The glass tube can be inserted into a device with an infrared emission source. When each fruit fly moves back and forth inside, it passes through the middle of the glass tube and is recorded due to the cutting of the infrared column. The sleep state of fruit flies is determined by their behavior, that is, any period of inactivity lasting 5 minutes or more. The number of fruit fly nighttime activities, sleep duration, number of sleeps and single sleep time were used as evaluation indicators to evaluate the effect of glycerophosphate on fruit fly sleep. The monitoring was carried out for 3 consecutive days, and all monitoring was carried out in a dark environment.

[0042] Experimental animals and feeding

[0043] Wild-type Drosophila melanogaster (Canton S) was obtained from the Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences. The fruit flies were raised in an artificial climate chamber (temperature set at 25°C, relative humidity set at 60%), with 12 hours of day and 12 hours of night, with a day-night reciprocating cycle.

[0044] Preparation of Drosophila Experimental Culture Medium

[0045] The medium formula for the fruit fly test is 2.5mL of propionic acid, 5g of agar, 25g of sucrose, and 500mL of water. Accurately weigh sucrose and agar with a beaker, transfer them into an iron pot, add water, heat to boiling, cool after cooking, add propionic acid, and stir evenly to obtain a blank medium. Based on the blank medium, according to the mass ratio, a medium containing 0.05% caffeine is prepared. Based on the caffeine medium, a test medium containing 0.08M glycerophosphate is prepared.

[0046] Drosophila sleep monitoring

[0047] Select male fruit flies born within 8 hours, culture them normally for 3 days, and then put them into fruit fly activity monitoring tubes containing different intervention culture media, and then put the fruit fly tubes into the fruit fly activity monitor. A total of 3 groups were set up, as shown in the following table:

[0048]

[0049] Each group is equipped with a monitor, and each monitor corresponds to 32 separate monitoring tubes. A fruit fly is placed in each tube, with culture medium placed at one end and a breathable plug at the other end. The tube is placed in a constant temperature and humidity incubator and connected to a fruit activity monitoring device to continuously monitor the activity and sleep state of the fruit flies for 3 days. The sleep state of fruit flies can be defined by their activity behavior, that is, any period of inactivity lasting 5 minutes or more is considered to be a sleep state.

[0050] Each fruit fly activity monitor can monitor the activities of 32 fruit flies at the same time. The fruit fly activity monitor emits infrared beams from one side and receives infrared beams from the other side. When the fruit flies are active in the tube, they will block the reception of infrared beams. Whether the infrared beam is blocked will be transmitted back to the computer at a frequency of 1 time / 1 minute to monitor the activity status of the fruit flies. The monitoring data is transmitted to the corresponding computer in real time. The sleep state of fruit flies is determined by their behavior, that is, any period of inactivity lasting 5 minutes or more. The number of fruit flies' nighttime activities, sleep duration, number of sleeps and single sleep duration are used as evaluation indicators for continuous monitoring for 3 days, and all monitoring is carried out in a dark environment.

[0051] Data processing and analysis

[0052] For the Drosophila sleep research experiment, GraphPad Prism 9.0 software was used to draw pictures, and SPSS20.0 software was used for statistical analysis of the data. Depending on whether the variance was homogeneous, the LeastSignificant Difference test in the one-way analysis of variance or the non-parametric Kruskal-Wallis test was selected. Data are expressed as Mean±SEM, * indicates p<0.05 compared with the normal group, ** indicates p<0.01 compared with the normal group; # indicates p<0.05 compared with the caffeine group, and ## indicates p<0.01 compared with the caffeine group.

[0053] Test results

[0054] Effects of glycerol phosphate on sleep duration in Drosophila

[0055] For sleep duration ( Figure 1 ), on the first day, compared with the normal group of fruit flies, the night sleep duration of fruit flies in the caffeine group was significantly reduced (p < 0.01); compared with the caffeine group, the night sleep duration of fruit flies in the GP group showed an increasing trend, but did not increase significantly. On the second day, compared with the normal group of fruit flies, the night sleep duration of fruit flies in the caffeine group was significantly reduced (p < 0.01). Compared with the caffeine group, the night sleep duration of fruit flies in the GP group was significantly increased (p < 0.05). On the third day, compared with the normal group of fruit flies, the night sleep duration of fruit flies in the caffeine group was significantly reduced (p < 0.01). Compared with the caffeine group, the night sleep duration of fruit flies in the GP group was significantly increased (p < 0.01). These results indicate that GP can reverse the caffeine-induced shortening of fruit fly sleep duration at a specific dose, and has the effect of significantly prolonging the night sleep duration of insomniac fruit flies.

[0056] Effects of glycerol phosphate on sleep frequency in Drosophila

[0057] For sleep frequency ( Figure 2 ), on the first day, compared with the normal group of fruit flies, the sleep times of fruit flies in the caffeine group increased significantly (p < 0.01), indicating that caffeine intervention caused the fruit flies' sleep to be fragmented, resulting in a decrease in their sleep quality; compared with the caffeine group, the sleep times of GP fruit flies did not change significantly. On the second day, compared with the normal group of fruit flies, the sleep times of fruit flies in the caffeine group increased significantly (p < 0.01), and compared with the caffeine group, the intervention of GP significantly reduced the sleep times of fruit flies (p < 0.01). On the third day, compared with the normal group of fruit flies, the sleep times of fruit flies in the caffeine group increased significantly (p < 0.01), and compared with the caffeine group, the intervention of GP significantly reduced the sleep times of fruit flies (p < 0.01). These results indicate that GP can reverse caffeine-induced fruit fly sleep fragmentation at a specific dose, has the effect of significantly reducing the number of nighttime sleeps of insomniac fruit flies, improves fruit fly sleep fragmentation, and thus improves sleep.

[0058] Effect of glycerol phosphate on the duration of a single sleep bout in Drosophila

[0059] For a single sleep period ( Figure 3 ), on the first day, compared with the normal group of fruit flies, the single sleep time of fruit flies in the caffeine group was significantly reduced (p < 0.01). Compared with the caffeine group, the single sleep time of fruit flies in the GP group was significantly increased (p < 0.05). On the second day, compared with the normal group of fruit flies, the single sleep time of fruit flies in the caffeine group was significantly reduced (p < 0.01). Compared with the caffeine group, the single sleep duration of fruit flies in the GP group was significantly increased (p < 0.01). On the third day, compared with the normal group of fruit flies, the single sleep time of fruit flies in the caffeine group was significantly reduced (p < 0.01). Compared with the caffeine group, the single sleep duration of fruit flies in the GP group was significantly increased (p < 0.05). These results indicate that GP can increase the single sleep time of insomniac fruit flies at a specific dose, increase the depth of sleep of fruit flies, and thus improve sleep.

[0060] Effects of glycerol phosphate on the frequency of nocturnal activity in Drosophila

[0061] For the number of nighttime activities ( Figure 4 ), on the first day, compared with the normal group of fruit flies, the number of nocturnal activities of fruit flies in the caffeine group showed an increasing trend. Compared with the caffeine group, the number of nocturnal activities of fruit flies in the GP group was significantly reduced (p < 0.05). On the second day, compared with the normal group of fruit flies, the number of nocturnal activities of fruit flies in the caffeine group was significantly increased (p < 0.05). Compared with the caffeine group, the number of nocturnal activities of fruit flies in the GP group was significantly reduced (p < 0.05). On the third day, compared with the normal group of fruit flies, the number of nocturnal activities of fruit flies in the caffeine group showed an increasing trend. Compared with the caffeine group, the number of nocturnal activities of fruit flies in the GP group showed a decreasing trend. These results indicate that GP can reduce the number of nocturnal activities of insomnia fruit flies to a certain extent at a specific dose, thereby inducing the occurrence of sleep.

[0062] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. Use of glycerophosphoric acid or a pharmaceutically acceptable salt thereof in preparing a composition that helps improve sleep.

2. The use according to claim 1, characterized in that: Improved sleep includes: Treat or prevent sleep disorders; and / or Improve sleep quality.

3. The use according to claim 2, characterized in that: The sleep disorder includes at least one of an intrinsic sleep disorder, an extrinsic sleep disorder, a circadian rhythm disorder, a parasomnia, a sleep disorder associated with an internal or mental disorder, and insomnia.

4. The use according to claim 1, characterized in that: The sleep improvement includes at least one of the following: Increase total sleep duration; Preventing sleep fragmentation; Increase sleep depth.

5. The use according to claim 1, characterized in that: The composition is a medicine and / or a health food.

6. The use according to claim 5, characterized in that: The medicine and / or health food may also contain other active ingredients that help improve sleep.

7. The use according to claim 5, characterized in that: The medicine and / or health food may further contain a pharmaceutically acceptable carrier or a carrier acceptable in food or health food.

8. The use according to claim 7, characterized in that: The carrier is selected from at least one of a solubilizer, a binder, a controlled release polymer, a disintegrant, a colorant, a flavoring agent, an antioxidant, a filler, a suspending agent and / or a surfactant.

9. The use according to claim 5, characterized in that: The drug and / or health food can be prepared in a dosage form selected from any one of tablets, pills, capsules, granules, powders, chewing gums, suspensions, emulsions, suppositories or solutions.

10. The use according to claim 5, characterized in that: The drug is administered orally and / or parenterally.

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