Application of Rapamycin in improvement of sleep disorder

Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to application of an mTOR inhibitor to improvement of sleep disorders. Aiming at the defects of the existing hypnotics, the invention finds that the sleep disorder can be improved by using the Rapamycin through researching a new sleep pathway target. The Rapamycin disclosed by the invention is a non-addictive sleeping drug, and can induce natural sleep behaviors; compared with an existing clinical hypnotics which has the side effect of greatly increasing the death rate, the Rapamycin administration disclosed by the invention is beneficial to improving the sleep quality and prolonging the life of animals at the same time. The invention discloses a remarkable effect of Rapamycin in the aspect of improving the sleep disorder, and the discovery has important significance in improving the sleep quality of a patient and preventing the progress of diseases, so that the Rapamycin has a wide medical prospect and a remarkable economic value.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and specifically relates to an application of an mTOR inhibitor in improving sleep disorders. Background Art

[0002] Sleep is a periodic and repetitive physiological activity of the body regulated by the central nervous system. It plays an important role in restoring physical strength, maintaining physical survival, protecting brain function and normal physiological activities. The body's control of sleep depends on the delicate balance between the sleep-wake cycle and the circadian rhythm. The sleep and wake control areas include the preoptic area of ​​the hypothalamus, orexin neurons, and the pons locus coeruleus (French IT, Muthusamy KA. A Review of Sleep and Its Disorders in Patients with Parkinson's Disease in Relation to Various Brain Structures [J]. Frontiers in Aging Neuroscience, 2016, 8: 114.). These areas can regulate the sleep-wake cycle by releasing neurotransmitters such as choline, orexin, and norepinephrine (Mattis J, Sehgal A. Circadian Rhythms, Sleep, and Disorders of Aging [J]. Trends inendocrinology and metabolism: TEM, 2016, 27 (4): 192-203.). Healthy sleep has a positive impact on brain development, cognition, memory, and body immunity, and helps maintain metabolic homeostasis through neural, hormonal, and immune support. However, there are still few physiological data or clinical trials on this. Insufficient sleep time or sleep disorders are common in contemporary society and can affect individual health, including but not limited to a lowered immune system, decreased cognitive function and memory, and interrupted learning and emotional health.

[0003] Sleep disorders are a general term for a large class of diseases with difficulty falling asleep, shallow sleep, and easy awakening as the main clinical features. The 2014 International Classification of Sleep Disorders (ICSD) divides sleep disorders into seven main categories, including insomnia, sleep-related breathing disorders, central hypersomnia, circadian rhythm sleep-wake disorder, sleep-related movement disorder, parasomnias, and other sleep disorders. The occurrence of sleep disorders is related to brain structure, central neurotransmitters, age, and underlying diseases. Studies have shown that compared with normal people, patients with sleep disorders have abnormal brain network connections, which are generally manifested as the dorsolateral prefrontal cortex (DLPFC) being in an abnormally overexcited state and the hypothalamus-pituitary-adrenal axis being more active than in normal people (anza G, Lanuzza B, Aricò D, et al. Impaired short-term plasticity in restless legs syndrome: apilotr TMS study [J]. Sleep Med, 2018, 46: 1-4.). Therefore, people with sleep disorders have higher autonomic nervous system excitability, and their resting heart rate, heart rate variability and metabolic rate are increased. Other studies have shown that the brain network metabolism level of patients with sleep disorders is significantly higher than that of normal people, including varying degrees of metabolic abnormalities in the alertness system, cognitive system, and emotional regulation system. Such patients usually have abnormal connections in the right parietal lobe, changes in the amplitude of low-frequency oscillations in EEG waves, and reduced connectivity between the frontal cortex and the insula (Kong Suli, Gao Cunyou, Yang Zhilei, et al. Effects of transcranial microcurrent stimulation on HPA, BDNF levels and clinical symptoms in patients with mild depression [J]. International Journal of Psychiatry, 2021, 48(1): 22-25.). According to surveys, about one-third of the world's population has varying degrees of sleep disorders, and nearly half of adults in China have varying degrees of sleep disorders, which seriously affects people's physical health and quality of life. (Chinese Society of Neurology, Sleep Disorders Group of the Chinese Society of Neurology. Guidelines for the diagnosis and treatment of insomnia in adults in China (2017 edition) [J]. Chinese Journal of Neurology, 2018, 51(5): 324-335.). Circadian rhythm and sleep dysfunction have been symptom hallmarks of various devastating neurodegenerative diseases. Studies have shown that among the non-motor symptoms of Parkinson's disease, the prevalence of sleep disorders is 60% to 90%, including changes in sleep structure and specific diseases (Lajoie AC, Lafontaine AL, Kaminska M. The Spectrum of Sleep Disorders in Parkinson Disease: A Review. Chest. 2021 Feb; 159(2): 818-827.).In addition, healthy people with insufficient sleep and patients with chronic insomnia have increased cortisol levels, decreased immunity, and enhanced sympathetic nerve activity. Literature has shown that sleep disorders may be related to the development of diabetes, hypertension, and cardiovascular disease (Khan Ms, Aouad R. The effects of insomnia and sleep loss on cardiovascular disease [J]. Sleep Med Clin. 2022, 17 (2): 193-203). Therefore, drug intervention and treatment for diseases related to sleep disorders are particularly important.

[0004] At present, the treatment methods for sleep disorders include drug therapy, physical therapy and cognitive behavioral therapy, but the actual clinical efficacy of cognitive behavioral therapy is questioned by patients. Drug therapy, including the current commonly used sleeping pills in clinical practice, still has many defects, including ① the past and current sleeping pills cannot induce natural sleep. Diazepam, a commonly used sleeping pill in early clinical practice, and the new generation of sleeping pills such as zolpidem (trade name Ambien) and eszopiclone (trade name Lunesta) are all sedatives, and the characteristics of the sleep EEG waves induced by them are also defective (Arbon, EL, Knurowska, M., & Dijk, D.-J. Randomised clinical trial of the effects of prolonged-release melatonin, temazepam and zolpidem on slow-wave activity during sleep in healthy people [J]. Journal of Psychopharmacology, 2015, 29 (7), 764-776.). ② Past and current sleep medications have many harmful side effects, including next-day drowsiness, daytime amnesia, unconscious movements at night, and possible slowing of reaction time for daytime motor skills (such as driving); newer short-acting sleeping pills on the market also have similar side effects; most prescription sleeping pills are addictive drugs, and drug withdrawal reactions and insomnia rebound will occur when they are discontinued. ③ Past and existing sleep drugs have little effect on improving sleep. A study conducted by a team of top doctors and researchers on the new sedatives taken by most people, including the latest sleeping pill suvorexant (trade name Belsomra) (Huedo-Medina TB, Kirsch I, Middlemass J, et al. Effectiveness of non-benzodiazepine hypnotics in treatment of adult insomnia: meta-analysis of data submitted to the Food and Drug Administration [J]. BMJ. 2012 Dec 17; 345: e8343.), found no statistically significant difference between the two compared with 65 independent placebo drugs.④ People who take commonly used prescription sleeping pills have higher mortality and cancer rates than those who do not use them. An independent study by Daniel Kripke, a doctor at the University of California, San Diego, and other independent research teams evaluated research data on almost all common sleeping pills, including zolpidem (trade name Ambien), eszopiclone (trade name Lunesta), zaleplon (trade name Sonata), temazepam, and sedatives triazolam (trade name Halcion) and flurazepam (trade name Dalmane). People who take prescription sleeping pills have a higher mortality rate (4.6 times) and a higher cancer rate than those who do not use them, and the risk of death varies with the frequency of taking the medicine. Even light users of sleeping pills and those who use them very occasionally (up to 18 pills per year) are still 3.6 times more likely to die during the observation period than those who do not take sleeping pills. (Kripke DF, Langer RD, Kline LE. Hypnotics' association with mortality or cancer: a matched cohort study [J]. BMJ Open. 2012 Feb 27; 2 (1): e000850.). Therefore, the identification of new targets for regulating sleep is of great significance for the development of drugs that induce truly natural deep sleep. Humans are in urgent need of developing new non-addictive drugs that improve meaningful sleep.

[0005] Rapamycin (RAPA), also known as sirolimus, was officially approved by the US FDA as an immunosuppressant for marketing in 1999. The biological activity of RAPA mainly comes from its unique cellular target of rapamycin (mTOR). Mammalian target of rapamycin (mTOR) is a conserved serine-threonine-protein kinase with a molecular weight of 289KD. It belongs to the phosphoinositol kinase-related kinase (PIKK) family and is also a key enzyme in cell signaling pathways that regulates cell survival, proliferation and differentiation (Feng Y, Chen X, Cassady K, et al. The Role of mTOR Inhibitors in Hematologic Disease: From Bench to Bedside [J]. Front Oncol. 2021 Jan 8; 10: 611690.). mTOR mainly exists in the form of two complexes, namely mTORC1 and mTORC2, which control a series of basic cell biological processes, such as cell growth, metabolism and autophagy (Soliman GA, Abzalimov RR, He Y. mTORC1 and mTORC2 Complexes Regulate the Untargeted Metabolomics and Amino Acid Metabolites Profile through Mitochondrial Bioenergetic Functions in Pancreatic Beta Cells [J]. Nutrients. 2022 Jul 22; 14 (15): 3022.). Rapamycin specifically inhibits TOR activity. After entering the cell, it can bind to FK-binding protein 12 (FK-BP12) to form a rapamycin / FK-BP12 complex, which can bind to TOR, block the cellular calcium-dependent and calcium-independent TOR signaling pathways, and regulate multiple processes such as translation, energy regulation, autophagy and cell growth. Currently, no clinical research has been found on the direct use of Rapamycin as a drug to treat sleep disorders such as insomnia. Summary of the invention

[0006] In view of the shortcomings of existing sleeping pills, the present invention has found that the use of Rapamycin can improve sleep disorders through research on new sleep pathway targets. Based on this, the present invention is completed.

[0007] In a first aspect, the present invention provides a pharmaceutical composition for improving sleep disorders, wherein the pharmaceutical composition comprises Rapamycin and another active ingredient, wherein the active ingredient is selected from drugs that promote sleep and wakefulness or active substances that enhance the body's immunity.

[0008] Furthermore, the drugs for promoting sleep and wakefulness include sedative hypnotics and novel hypnotic drugs, orexin receptor antagonists.

[0009] Furthermore, the sedative hypnotic includes benzodiazepine Non-benzodiazepines Class of drugs.

[0010] Furthermore, the benzodiazepine Such drugs include, but are not limited to, one or more of diazepam, flurazepam, triazolam and / or temazepam.

[0011] Further, the novel non-benzodiazepine Drugs in this class include, but are not limited to, one or more of zolpidem, eszopiclone, and / or zaleplon.

[0012] Furthermore, the novel hypnotic drug orexin receptor antagonist includes but is not limited to suovolexin and / or targeted blocking of orexin or one or more thereof.

[0013] Furthermore, the active substances for improving the body's immunity include one or more of trace elements, minerals, vitamins, coenzyme Q, oryzanol and / or melatonin required by the human body.

[0014] Furthermore, the trace elements are one or more of iron (Fe), zinc (Zn), copper (Cu), manganese (Mn), iodine (I) and / or selenium (Se).

[0015] Furthermore, the minerals may be one or more of calcium (Ca), phosphorus (P), potassium (K), sodium (Na), chlorine (Cl) and / or magnesium (Mg).

[0016] Furthermore, the vitamins may be one or more of vitamin A (VA), B vitamins (VB), vitamin C (VC), vitamin D (VD), vitamin E (VE) and / or vitamin K (VK).

[0017] Furthermore, one or more pharmaceutically acceptable carriers may be added to the pharmaceutical composition.

[0018] Furthermore, the carrier material includes, but is not limited to, one or more of a water-soluble carrier material, a poorly soluble carrier material and / or an enteric carrier material.

[0019] Furthermore, the water-soluble carrier material includes, but is not limited to, one or more of polyethylene glycol, polyvinyl pyrrolidone and / or organic acid.

[0020] Furthermore, the poorly soluble carrier material includes but is not limited to one or more of ethyl cellulose and / or cholesterol stearate.

[0021] Furthermore, the enteric carrier material includes but is not limited to one or more of cellulose acetate phthalate and / or carboxymethyl ethyl cellulose.

[0022] Furthermore, the pharmaceutical composition can be prepared into a variety of dosage forms, including but not limited to one or more of tablets, capsules, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal agents and / or suppositories.

[0023] Furthermore, the preparation can be one or more of a conventional preparation, a sustained-release preparation, a controlled-release preparation and / or various microparticle delivery systems.

[0024] Furthermore, the tablets may widely use various carriers known in the art, including one or more of diluents and absorbents, wetting agents and binders, disintegrants, disintegration inhibitors, absorption promoters and / or lubricants.

[0025] Furthermore, the diluent and absorbent include, but are not limited to, one or more of starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose and / or aluminum silicate.

[0026] Furthermore, the wetting agent and adhesive include, but are not limited to, one or more of water, glycerol, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, glucose solution, acacia gum slurry, gelatin slurry, sodium carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate and / or polyvinyl pyrrolidone.

[0027] Furthermore, the disintegrant includes, but is not limited to, one or more of dry starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene, sorbitan fatty acid ester, sodium dodecyl sulfate, methyl cellulose and / or ethyl cellulose.

[0028] Furthermore, the disintegration inhibitor includes but is not limited to sucrose, tristearin, cocoa butter and / or hydrogenated oil.

[0029] Furthermore, the absorption enhancer includes but is not limited to one or more of quaternary ammonium salts and / or sodium lauryl sulfate.

[0030] Furthermore, the lubricant includes, but is not limited to, one or more of talc, silicon dioxide, corn starch, stearate, boric acid, liquid paraffin and / or polyethylene glycol.

[0031] Furthermore, the tablets can be further made into coated tablets, including sugar-coated tablets, film-coated tablets, enteric-coated tablets, double-layer tablets and multi-layer tablets.

[0032] Furthermore, the pills may be prepared using a wide variety of carriers known in the art, including diluents and absorbents, binders and / or disintegrants.

[0033] Furthermore, the diluent and absorbent include, but are not limited to, one or more of glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinyl pyrrolidone, Gelucire, kaolin and / or talc.

[0034] Furthermore, the adhesive includes, but is not limited to, one or more of gum arabic, gum tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste and / or batter.

[0035] Furthermore, the disintegrant includes, but is not limited to, one or more of agar powder, dry starch, alginate, sodium dodecyl sulfate, methyl cellulose and / or ethyl cellulose.

[0036] Furthermore, the suppository may be made of a wide variety of carriers known in the art, including but not limited to one or more of polyethylene glycol, lecithin, cocoa butter, higher alcohols, esters of higher alcohols, gelatin and / or semi-synthetic glycerides.

[0037] Furthermore, the injectable preparation includes, but is not limited to, one or more of a solution, an emulsion, a lyophilized powder injection and / or a suspension.

[0038] Furthermore, the injectable preparation may use all diluents commonly used in the art, including but not limited to one or more of water, ethanol, polyethylene glycol, 1,3-propylene glycol, ethoxylated isostearyl alcohol, polyoxygenated isostearyl alcohol and / or polyoxyethylene sorbitan fatty acid esters.

[0039] Furthermore, in order to prepare an isotonic injection solution, the injection preparation may be added with an appropriate amount of one or more of sodium chloride, glucose, glycerol, conventional cosolvents, buffers and / or pH regulators.

[0040] Furthermore, the various preparations may also add colorants, preservatives, spices, flavoring agents, sweeteners or other materials to the pharmaceutical preparations as needed.

[0041] Furthermore, the pharmaceutical composition can be administered by injection, cavity administration, respiratory tract administration or mucosal administration.

[0042] Furthermore, the injection administration includes subcutaneous injection, intravenous injection, intramuscular injection and intracavitary injection, etc.; the cavity administration includes rectal or vaginal administration; and the respiratory tract administration includes nasal administration.

[0043] In a second aspect, the present invention provides the use of Rapamycin in the preparation of a medicament for improving diseases related to sleep disorders.

[0044] Furthermore, the sleep disorder-related diseases include but are not limited to depression, anxiety, schizophrenia, Parkinson's disease, periodic leg movements, diabetes, hypertension and cardiovascular disease.

[0045] Furthermore, the sleep disorders include insomnia, central hypersomnia, circadian rhythm sleep-wake disorder, sleep-related movement disorder, parasomnias and other types of sleep disorders.

[0046] Furthermore, the medicine may also contain another active ingredient, which is selected from drugs that promote sleep and wakefulness or active substances that improve the body's immunity.

[0047] Furthermore, the active substances for improving the body's immunity include one or more of trace elements, minerals, vitamins, coenzyme Q, oryzanol and / or melatonin required by the human body.

[0048] Furthermore, the trace elements are one or more of iron (Fe), zinc (Zn), copper (Cu), manganese (Mn), iodine (I) and / or selenium (Se).

[0049] Furthermore, the minerals may be one or more of calcium (Ca), phosphorus (P), potassium (K), sodium (Na), chlorine (Cl) and / or magnesium (Mg).

[0050] Furthermore, the vitamins may be one or more of vitamin A (VA), B vitamins (VB), vitamin C (VC), vitamin D (VD), vitamin E (VE) and / or vitamin K (VK).

[0051] Furthermore, the drug can be prepared into a variety of dosage forms, including but not limited to one or more of tablets, capsules, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal agents and / or suppositories.

[0052] Furthermore, the preparation can be one or more of a conventional preparation, a sustained-release preparation, a controlled-release preparation and / or various microparticle delivery systems.

[0053] Furthermore, the drug can be introduced into the body by injection, penetration, absorption, physical or chemical mediation.

[0054] Furthermore, the injection administration includes subcutaneous injection, intravenous injection, intramuscular injection and intracavitary injection, etc.; the cavity administration includes rectal or vaginal administration; and the respiratory tract administration includes nasal administration.

[0055] Beneficial Effects

[0056] 1. Rapamycin of the present invention is a non-addictive hypnotic drug that can induce natural sleep behavior, and various evaluation indicators are effective and significantly improved.

[0057] 2. Compared with existing sleeping pills that cause a significant increase in mortality, the administration of Rapamycin in the present invention can prolong the life span of animals.

[0058] 3. After administration of Rapamycin of the present invention, the sleep behavior indicators of normal and humanized nematode models of Parkinson's disease at different stages were improved, indicating that Rapamycin helps to improve the sleep quality of normal and Parkinson's patients at different stages.

[0059] 4. The present invention reveals the remarkable effect of Rapamycin in improving sleep disorders. This discovery is of great significance for improving patients' sleep quality and preventing the progression of diseases, and thus has broad medical prospects and significant economic value. BRIEF DESCRIPTION OF THE DRAWINGS

[0060] Figure 1 The figure shows the changes in the number of pharyngeal pumps and the delay time of the awakening response, the sleep indicators of nematodes, after treatment with different concentrations of Rapamycin, and the drug dose-effect curve.

[0061] Figure 2 Changes in sleep indicators such as pharyngeal pump frequency and wake-up response latency in wild-type nematodes and Parkinson's disease model nematodes on the first, second, and seventh days of adulthood after treatment with Rapamycin DETAILED DESCRIPTION

[0062] The specific embodiments of the present invention are further described below. It should be noted that the description of these embodiments is used to help understand the present invention, but does not constitute a limitation of the present invention. In addition, the technical features involved in the embodiments described below can be combined with each other as long as they do not conflict with each other.

[0063] The experimental methods in the following examples are conventional methods unless otherwise specified, and the experimental materials used in the following examples are commercially available unless otherwise specified.

[0064] Explanation of terms

[0065] Insomnia: refers to persistent difficulty sleeping, insufficient sleep opportunities, and related daytime function impairment. It is the most common type of sleep disorder. ICSD-3 divides insomnia into three categories: chronic insomnia, short-term insomnia, and other insomnia disorders.

[0066] Central hypersomnia disorders: include diseases with daytime sleepiness as the main complaint and other sleep disorders as the cause are excluded. ICSD-3 divides them into narcolepsy type 1, narcolepsy type 2, idiopathic hypersomnia, Kleine-Levin syndrome, disease-related excessive sleepiness, excessive sleepiness caused by drugs or substance abuse, excessive sleepiness related to mental disorders, and insufficient sleep syndrome.

[0067] Circadian rhythm sleep-wake disorder: a chronic or recurrent sleep disorder caused by changes in physiological rhythms or environmental factors that cause imbalances between personal sleep-wake cycles. ICSD-3 divides it into delayed sleep-wake phase disorder, delayed sleep-wake phase disorder, non-24h sleep-wake rhythm disorder, irregular sleep-wake rhythm disorder, shift work sleep-wake disorder, and jet lag sleep disorder.

[0068] Sleep-related movement disorders: ICSD-3 divides them into restless legs syndrome, periodic limb movement disorder, sleep-related leg cramps, sleep-related bruxism, sleep-related rhythmic movement disorder, benign sleep myoclonus of infancy, and intrinsic spinal myoclonus during sleep onset.

[0069] Parasomnias: refers to adverse physical events (complex movements, behaviors) or experiences (emotions, perceptions, dreams) that occur when falling asleep, sleeping, or waking up from sleep. ICSD-3 divides them into three categories: non-rapid eye movement-related parasomnias, rapid eye movement-related parasomnias, and other parasomnias.

[0070] 1-octanol: 1-octanol is an organic compound, a colorless, transparent, oily liquid with a strong grease and citrus smell.

[0071] The structural formula of rapamycin is as follows:

[0072]

[0073] Example 1 Rapamycin promotes sleep in nematodes

[0074] Behaviorally, sleep can be characterized by five indicators: (i) prolonged behavioral quiescence, (ii) reversibility upon stimulation (to distinguish it from torpor or coma), (iii) species-specific posture, (iv) increased arousal threshold in response to external stimuli, and (v) rebound after sleep deprivation. The sleep of Caenorhabditis elegans also has sleep characteristics such as behavioral quiescence, arousal threshold, and sleep homeostasis, so the behavioral changes of nematodes can be used to judge sleep quality.

[0075] 1.1 Materials and methods

[0076] Wild-type nematodes

[0077] Rapamycin Compounds

[0078] 1.2 Steps

[0079] Rapamycin solutions of 0.04 μM, 0.4 μM, 4 μM, 40 μM, and 400 μM were prepared, and after inducing the nematodes to sleep, various behavioral indicators of the nematodes' sleep were evaluated.

[0080] Pharyngeal pumping times: One up and down movement of the pharyngeal muscles relative to the head under the stereoscope is counted as one time, and each worm is counted for 20 seconds.

[0081] Response latency: Stimulate the nematode with 1-octanol odor, start timing from when the worm approaches its head, and stop timing when the worm shows an evasive behavior of retreating for half a cycle of the sine wave. The time taken is the reaction time, in seconds.

[0082] 1.3 Experimental Results

[0083] like Figure 1 As shown in the figure, after treatment with rapamycin at concentrations of 0.04μM, 0.4μM, 4μM, 40μM, and 400μM, the sleep indicators of nematodes, the number of pharyngeal pumps and the delay time of the awakening response, were evaluated, and the drug dose-effect curve was drawn. The EC value of rapamycin affecting the delay time of the awakening response in nematodes was calculated. 50 The concentration of 45.21 μM affects the number of pharyngeal pumps IC 50 The concentration is 5.21 μM.

[0084] Example 2 Rapamycin improves sleep disorder symptoms in the Parkinson's nematode model

[0085] 2.1 Materials and methods

[0086] Wild-type nematodes, humanized Parkinson's disease model nematodes

[0087] Rapamycin

[0088] 2.2 Steps

[0089] Rapamycin solutions of 0.04 μM, 0.4 μM, 4 μM, 40 μM, and 400 μM were prepared, and after inducing the nematodes to sleep, various behavioral indicators of the nematodes' sleep were evaluated.

[0090] Pharyngeal pumping times: One up and down movement of the pharyngeal muscles relative to the head under the stereoscope is counted as one time, and each worm is counted for 20 seconds.

[0091] Response latency: Stimulate the nematode with 1-octanol odor, start timing from when the worm approaches its head, and stop timing when the worm shows an evasive behavior of retreating for half a cycle of the sine wave. The time taken is the reaction time, in seconds.

[0092] 2.3 Experimental Results

[0093] like Figure 2 As shown, after treatment with Rapamycin, the sleep behavior indicators of wild-type nematodes and humanized Parkinson's disease nematode models, such as the number of pharyngeal pumps and the latency of awakening responses, were improved, indicating that Rapamycin helps improve sleep quality.

Claims

1. A pharmaceutical composition for improving sleep disorders, comprising Rapamycin and another active ingredient, wherein the active ingredient is selected from drugs that promote sleep and wakefulness or active substances that enhance the body's immunity.

2. The pharmaceutical composition as claimed in claim 1, wherein the other drug for promoting sleep and wakefulness comprises a sedative hypnotic and a novel hypnotic orexin receptor antagonist; and the active substance for improving the body's immunity comprises one or more of trace elements, minerals, vitamins, coenzyme Q, oryzanol and / or melatonin required by the human body.

3. The pharmaceutical composition according to any one of claims 1 or 2, wherein the sedative hypnotic includes but is not limited to one or more of diazepam, flurazepam, triazolam, temazepam, zolpidem, eszopiclone and / or zaleplon; the novel hypnotic orexin receptor antagonist includes but is not limited to one or more of suovolexin and / or targeted orexin blockade.

4. The pharmaceutical composition according to any one of claims 1 to 3, which can be prepared into a variety of dosage forms, including but not limited to one or more of tablets, capsules, pellets, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal agents, buccal tablets, suppositories and / or lyophilized powder injections.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition can be administered by injection, cavity administration, respiratory tract administration or mucosal administration; the injection administration includes subcutaneous injection, intravenous injection, intramuscular injection and intracavitary injection, etc.; the cavity administration includes rectal or vaginal administration; the respiratory tract administration includes nasal administration.

6. Application of Rapamycin in the preparation of drugs for improving diseases related to sleep disorders.

7. The use as claimed in claim 6, wherein the sleep disorder-related diseases include but are not limited to depression, anxiety, schizophrenia, Parkinson's disease, periodic leg movement, diabetes, hypertension and cardiovascular disease; the sleep disorders include insomnia, central hypersomnia, circadian rhythm sleep-wake disorder, sleep-related movement disorder, parasomnia and other sleep disorders.

8. The use according to any one of claims 6 or 7, wherein the medicine may further contain another active ingredient, the active ingredient being selected from drugs that promote sleep and wakefulness or active substances that enhance the body's immunity.

9. The use according to any one of claims 6 to 8, wherein the drug can be prepared into a variety of dosage forms, including but not limited to one or more of tablets, capsules, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal agents and / or suppositories.

10. The use according to any one of claims 6 to 9, wherein the injection administration includes subcutaneous injection, intravenous injection, intramuscular injection and intracavitary injection, etc.; the cavity administration includes rectal or vaginal administration; and the respiratory tract administration includes nasal administration.

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