Use of glycerophosphoric acid in the manufacture of a composition to help improve sleep

Abstract

The present application provides the use of glycerophosphoric acid or a pharmaceutically acceptable salt thereof in the preparation of a composition for improving sleep, which can improve sleep from at least one of the following three aspects: increasing total sleep time, preventing sleep fragmentation, and increasing sleep depth.

Description

Technical Field

[0001] This invention relates to the fields of medicine, food, and health food technology, and in particular to the application of glycerophosphate in the preparation of compositions that help improve sleep. Background Technology

[0002] Sleep is an important physiological process regulated by the brain. It allows the body to rest and recover physical strength, and it also allows the brain to stop thinking activities, restore mental capacity, promote brain function development, and consolidate memory. It plays a vital role in human brain development, physical and mental health, and the 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 importance to provide new medications and health foods that can help improve sleep. Summary of the Invention

[0004] The present invention aims to at least solve one of the aforementioned technical problems existing in the prior art. Therefore, the object of the present invention is to provide a composition that helps improve sleep.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0006] This invention provides the use of glycerophosphate or a pharmaceutically acceptable salt thereof in the preparation of compositions that help improve sleep.

[0007] In this invention, pharmaceutically acceptable salts refer to salts prepared from pharmaceutically acceptable non-toxic alkalis 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, etc.

[0008] In one or more embodiments of the present invention, the improvement of sleep includes:

[0009] Treatment or prevention of 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 intrinsic sleep disorder, extrinsic sleep disorder, circadian rhythm disorder, parasomnia, sleep disorder related to internal or mental disorders, and insomnia.

[0012] In one or more embodiments of the present invention, the intrinsic sleep disorder includes 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, and non-24-hour sleep-wake syndrome.

[0014] In one or more embodiments of the present invention, the sleep disorder related to internal or mental disorders includes sleep disorders 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 improvement of sleep includes at least one of the following:

[0017] Increase total sleep duration;

[0018] Prevent 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 also 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 as being effective in improving sleep quality and preventing and treating sleep disorders, including, for example: sedatives, hypnotics, anxiolytics, antipsychotics, anxiolytics, antihistamines, benzodiazepines, barbiturates, cyclopyrrolones, GABA agonists, 5HT-2 antagonists (including 5HT-2A antagonists and 5HT-2A / 2C antagonists), histamine antagonists (including histamine H3 antagonists and histamine H3 inverse agonists), imidazopyridine, weak tranquilizers, melatonin agonists and antagonists, melatonin-producing agents, other orexin antagonists, orexin agonists, prodynein agonists and antagonists, pyrazolopyridine, T-type calcium channel antagonists, triazolopyridine, etc.

[0023] In one or more embodiments of the present invention, the drug and / or health food may also 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 solubilizers, binders, controlled-release polymers, disintegrants, colorants, flavorings, antioxidants, fillers, suspending agents and / or surfactants.

[0025] In one or more embodiments of the present invention, the dosage form of the drug and / or health food may be 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 route of administration of the drug is oral and / or parenteral.

[0027] The beneficial effects of this invention are:

[0028] The present invention provides the use of glycerophosphate or a pharmaceutically acceptable salt thereof in the preparation of compositions that help improve sleep, which may improve sleep by at least one of three aspects: increasing total sleep duration, preventing sleep fragmentation, and increasing sleep depth. Attached Figure Description

[0029] Figure 1 The effect of glycerophosphate on sleep duration in fruit flies. Note: Data are presented as mean ± SEM.

[0030] Figure 2 The effect of glycerophosphate on the number of sleep cycles in Drosophila. Note: Data are presented as mean ± SEM.

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

[0032] Figure 4 The effect of glycerophosphate on the number of nocturnal activities in Drosophila. Note: Data are presented as mean ± SEM. Detailed Implementation

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

[0034] The chemical structural formula of glycerophosphate is

[0035] This invention discovers that glycerophosphate can improve sleep in at least one of three ways: increasing total sleep duration, preventing sleep fragmentation, and increasing sleep depth. Its use in the preparation of pharmaceuticals and / or health foods that improve sleep is also provided.

[0036] The present invention will be further described in detail below through specific embodiments. Unless otherwise specified, the raw materials, reagents, or apparatus used in the embodiments and comparative examples are all available from conventional commercial sources or can be obtained by existing technical methods. Unless otherwise specified, the test or experimental methods are conventional methods in the art.

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

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

[0039] Example 1: Effect of glycerophosphate on sleep in fruit flies

[0040] Using the fruit fly (Drosophila melanogaster) to establish human disease research models is gradually becoming a new research highlight. Because fruit fly sleep exhibits significant similarities to human sleep in terms of behavioral patterns, drug responses, and gene expression, it has become a novel model organism for sleep research.

[0041] Continuous monitoring of fruit fly activity was conducted using a Drosophila Activity Monitoring system (DAMS; Trikinetics Inc., USA). The DAMS system primarily consists of a monitor and 32 individual monitoring tubes, each 65 mm long, with one end for food and the other end fitted with a breathable plug. The glass tubes are inserted into a device equipped with an infrared emitter. As each fruit fly moves back and forth within the tube, its movement through the center of the tube interrupts the infrared beam, and the activity is recorded. The fruit fly's sleep state was determined by its behavior, specifically any period of stillness lasting 5 minutes or more. The effects of glycerophosphate on fruit fly sleep were evaluated using nocturnal activity frequency, sleep duration, number of sleep episodes, and duration of each sleep episode as key performance indicators. Monitoring was conducted for three consecutive days in complete darkness.

[0042] Laboratory animals and their rearing

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

[0044] Preparation of Drosophila test culture medium

[0045] The culture medium formula for the Drosophila experiment was 2.5 mL propionic acid, 5 g agar, 25 g sucrose, and 500 mL water. The sucrose and agar were accurately weighed into a beaker and transferred to an iron pot. Water was added, and the mixture was heated to boiling. After boiling, it was cooled, and then propionic acid was added and stirred thoroughly to obtain a blank culture medium. Based on the blank culture medium, a medium containing 0.05% caffeine was prepared according to the specified mass ratio. Based on the caffeine culture medium, a test medium containing 0.08 M glycerophosphate was prepared.

[0046] Fruit fly sleep monitoring

[0047] Newborn male fruit flies within 8 hours were selected and cultured normally for 3 days. After 3 days, the flies were placed into fruit fly activity monitoring tubes containing different intervention media, and then the fruit fly tubes were placed into a fruit fly activity monitoring instrument. A total of 3 groups were set up, as shown in the table below:

[0048]

[0049] Each group was equipped with one monitor, with each monitor corresponding to 32 individual monitoring tubes. One fruit fly was placed in each tube, with culture medium at one end and a vent plug at the other end. The tubes were placed in a temperature- and humidity-controlled incubator and connected to a fruit fly activity monitoring device to continuously monitor the fruit fly's activity and sleep status for 3 days. The fruit fly's sleep status can be defined by its activity behavior; any period of stillness lasting 5 minutes or more is considered as the fruit fly being in a sleep state.

[0050] Each fruit fly activity monitor can simultaneously monitor the activity of 32 fruit flies. The monitor emits an infrared beam from one side and receives it from the other. When a fruit fly moves within the tube, it blocks the reception of the infrared beam. The status of the blocked beam is transmitted back to the computer once per minute to monitor the fruit fly's activity. Monitoring data is transmitted to the corresponding computer in real time. The fruit fly's sleep state is determined by its behavior, specifically any period of stillness lasting 5 minutes or more. Monitoring was conducted for three consecutive days using the number of nocturnal activities, sleep duration, number of sleep episodes, and duration of each sleep episode as evaluation indicators. All monitoring was carried out in a dark environment.

[0051] Data processing and analysis

[0052] For the Drosophila sleep study, GraphPad Prism 9.0 software was used to generate images, and SPSS 20.0 software was used for statistical analysis of the data. Depending on whether the variances were homogeneous, either the Least Significant Difference test or the non-parametric Kruskal-Wallis test in one-way ANOVA was selected. Data are expressed as Mean ± SEM. * indicates p < 0.05 compared to the normal group, ** indicates p < 0.01 compared to the normal group; # indicates p < 0.05 compared to the caffeine group, and ## indicates p < 0.01 compared to the caffeine group.

[0053] Test results

[0054] Effects of glycerophosphate on sleep duration in fruit flies

[0055] Regarding sleep duration ( Figure 1 On day 1, compared with the normal group, the nighttime sleep duration of fruit flies in the caffeine group was significantly reduced (p < 0.01); compared with the caffeine group, the nighttime sleep duration of fruit flies in the GP group showed an increasing trend, but the increase was not significant. On day 2, compared with the normal group, the nighttime sleep duration of fruit flies in the caffeine group was significantly reduced (p < 0.01). Compared with the caffeine group, the nighttime sleep duration of fruit flies in the GP group was significantly increased (p < 0.05). On day 3, compared with the normal group, the nighttime sleep duration of fruit flies in the caffeine group was significantly reduced (p < 0.01). Compared with the caffeine group, the nighttime sleep duration of fruit flies in the GP group was significantly increased (p < 0.01). These results indicate that GP, at a specific dose, can reverse the caffeine-induced shortening of sleep duration in fruit flies and has a significant effect on prolonging the nighttime sleep duration of insomniac fruit flies.

[0056] Effect of glycerophosphate on the number of sleep cycles in fruit flies

[0057] In terms of the number of sleeps ( Figure 2 On day 1, compared with the normal group, the number of sleep episodes in the caffeine group was significantly increased (p < 0.01), indicating that caffeine intervention fragmented the sleep of fruit flies, leading to decreased sleep quality. Compared with the caffeine group, the number of sleep episodes in the GP group was not significantly different. On day 2, compared with the normal group, the number of sleep episodes in the caffeine group was significantly increased (p < 0.01), while the number of sleep episodes in the GP group was significantly reduced (p < 0.01). On day 3, compared with the normal group, the number of sleep episodes in the caffeine group was significantly increased (p < 0.01), while the number of sleep episodes in the GP group was significantly reduced (p < 0.01). These results indicate that GP, at a specific dose, can reverse caffeine-induced sleep fragmentation in fruit flies, significantly reduce the number of nighttime sleep episodes in insomniac fruit flies, improve sleep fragmentation, and thus improve sleep.

[0058] Effect of glycerophosphate on single sleep time in fruit flies

[0059] For the duration of a single sleep episode ( Figure 3 On day 1, compared with the normal group, the single sleep duration 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). On day 2, compared with the normal group, the single sleep duration 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 day 3, compared with the normal group, the single sleep duration 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, at a specific dose, can increase the single sleep duration and sleep depth of insomniac fruit flies, thereby improving sleep.

[0060] Effect of glycerophosphate on the number of nocturnal activities in fruit flies

[0061] Regarding the number of nighttime activities ( Figure 4 On day 1, compared with the normal group, the number of nocturnal activities in the caffeine group showed an increasing trend. Compared with the caffeine group, the number of nocturnal activities in the GP group was significantly reduced (p < 0.05). On day 2, compared with the normal group, the number of nocturnal activities in the caffeine group showed a significant increasing trend (p < 0.05). Compared with the caffeine group, the number of nocturnal activities in the GP group was significantly reduced (p < 0.05). On day 3, compared with the normal group, the number of nocturnal activities in the caffeine group showed an increasing trend. Compared with the caffeine group, the number of nocturnal activities in the GP group showed a decreasing trend. These results indicate that GP, at a specific dose, can reduce the number of nocturnal activities in insomniac fruit flies to a certain extent, thereby inducing sleep.

[0062] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. The use of glycerophosphate or a pharmaceutically acceptable salt thereof as the sole active ingredient in the preparation of compositions that help improve sleep.

2. The application according to claim 1, characterized in that, The improvement in sleep includes: Treatment or prevention of sleep disorders; and / or Improve sleep quality.

3. The application according to claim 2, characterized in that, The sleep disorders include at least one of the following: intrinsic sleep disorders, extrinsic sleep disorders, circadian rhythm disorders, parasomnias, sleep disorders related to internal or mental disorders, and insomnia.

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

5. The application according to claim 1, characterized in that, The composition is a drug and / or health food.

6. The application according to claim 5, characterized in that, The drug and / or health food also contain a pharmaceutically acceptable carrier or a carrier acceptable in food or health food.

7. The application according to claim 6, characterized in that, The carrier is selected from at least one of solubilizers, binders, controlled-release polymers, disintegrants, colorants, flavorings, antioxidants, fillers, suspending agents, and / or surfactants.

8. The application according to claim 5, characterized in that, The dosage form of the drug and / or health food is selected from any one of tablets, pills, capsules, granules, powders, chewable gums, suspensions, emulsions, suppositories, or solutions.

9. The application according to claim 5, characterized in that, The drug is administered orally and / or via parenteral route.

Images