Application of medicine in improving 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] This invention belongs to the field of biomedical technology, specifically relating to the application of an mTOR inhibitor in improving sleep disorders. Background Technology

[0002] Sleep is a periodic and repetitive physiological activity regulated by the central nervous system, playing a vital role in restoring physical strength, maintaining bodily survival, protecting brain function, and ensuring normal physiological activities. The body's control over sleep depends on a delicate balance between the sleep-wake cycle and the circadian rhythm. Areas controlling sleep and wakefulness include the preoptic area of ​​the hypothalamus, orexin neurons, and the locus coeruleus of the pons (French IT, Muthusamy K A. A Review of Sleep and Its Disorders in Patients with Parkinson's Disease in Relation to Various BrainStructures[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 the body's immune function, and helps maintain metabolic homeostasis through neural, hormonal, and immune support; however, relevant physiological data or clinical trials are still scarce. Insufficient sleep or sleep disorders are prevalent in contemporary society and can affect individual health, including but not limited to a weakened immune system, decreased cognitive function and memory, and disruption of learning and emotional well-being.

[0003] Sleep disorders are a broad category of diseases characterized by difficulty falling asleep, shallow sleep, and frequent awakenings. 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 disorders, sleep-related motor disorders, 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 individuals, patients with sleep disorders exhibit abnormal brain network connectivity, generally characterized by an abnormally overexcited state in the dorsolateral prefrontal cortex (DLPFC) and increased activity of the hypothalamus-pituitary-adrenal axis (anza G, Lanuzza B, Aricò D, et al. Impaired shortterm plasticity inrestless legs syndrome: a pilot rTMS study[J]. Sleep Med, 2018, 46:1-4.). Therefore, individuals with sleep disorders have higher autonomic nervous system excitability, increased resting heart rate, heart rate variability, and metabolic rate. Other studies have shown that the brain network metabolic level of patients with sleep disorders is significantly higher than that of normal people. The alert system, cognitive system and emotional regulation system all have different degrees of metabolic abnormalities. These patients usually have abnormal connectivity in the right parietal lobe of the brain, changes in low-frequency oscillation amplitude in the electroencephalogram, 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 global population has different degrees of sleep disorders. Nearly half of the adults in China have different degrees of sleep disorders, which seriously affect people's physical health and quality of life. (Chinese Society of Neurology, Sleep Disorders Group of Chinese Society of Neurology. Guidelines for the Diagnosis and Treatment of Insomnia in Chinese Adults (2017 Edition) [J]. Chinese Journal of Neurology, 2018, 51(5):324-335.). Disorders of circadian rhythms and sleep function have long been symptom markers of various destructive neurodegenerative diseases.Studies have shown that sleep disorders account for 60%–90% of non-motor symptoms of Parkinson's disease, including changes in sleep structure and specific diseases (Lajoie AC, Lafontaine AL, Kaminska M. The Spectrum of Sleep Disorders in ParkinsonDisease: A Review. Chest. 2021 Feb;159(2):818-827.). Furthermore, healthy individuals with insufficient sleep and patients with chronic insomnia exhibit elevated cortisol levels, decreased immunity, and enhanced sympathetic nerve activity. Literature suggests that sleep disorders may be associated with the development of diabetes, hypertension, and cardiovascular disease (Khan Ms, Aouad R. The effects of insomnia and sleep loss on cardiovascular disease [J]. Sleep MedClin. 2022, 17(2):193-203). Therefore, drug intervention and treatment targeting sleep disorders are particularly important.

[0004] Currently, treatments for sleep disorders include medication, physical therapy, and cognitive behavioral therapy. However, the clinical efficacy of cognitive behavioral therapy is often questioned by patients. Medication, including commonly used sleeping pills, still has many shortcomings, including: ① Past and current sleep medications cannot induce natural sleep. Early clinically used sleeping pills like diazepam, and newer generation sleeping pills such as zolpidem (trademark name Ambien) and eszopiclone (trademark name Lunesta), are all sedatives, and the sleep EEG characteristics they induce 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 existing sleep medications have many harmful side effects, including drowsiness the next day, daytime forgetfulness, unconscious movements at night, and potentially delayed 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, and withdrawal symptoms and rebound insomnia can occur upon discontinuation. ③ Past and existing sleep medications have minimal effect on improving sleep. A study by a team of leading physicians and researchers on new sedatives taken by most people (including the latest sleeping pill, Belsomra) found no statistically significant difference between these drugs and 65 independent placebo drugs. (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.)④ People who take commonly prescribed sleeping pills have higher mortality and cancer rates than those who do not. An independent study by Dr. Daniel Kripke of the University of California, San Diego, along with other independent research teams, evaluated data from studies on almost all common sleeping pills, including zolpidem (brand name Ambien), eszopiclone (brand name Lunesta), zaleplon (brand name Sonata), temazepam, and the sedatives triazolam (brand name Halcion) and flurazepam (brand name Dalmane). Those taking prescription sleeping pills had a 4.6 times higher mortality rate and cancer rate than those who did not use them, and the risk of death varied with the frequency of medication use. Even among light users and very occasional users (maximum 18 pills per year), the likelihood of death during the observation period was still 3.6 times higher than those who did 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 urgently need to develop new non-addictive drugs to improve meaningful sleep.

[0005] Rapamycin (RAPA), also known as sirolimus, was officially approved by the US FDA in 1999 as an immunosuppressant. RAPA's biological activity primarily derives from its unique mammalian target of rapamycin (mTOR) as its cellular target. The mammalian target of rapamycin (mTOR) is a conserved serine-threonine protein kinase with a molecular weight of 289 KD, belonging to the phosphoinositol kinase-related kinase (PIKK) family. It is also a key enzyme in cell signaling pathways regulating 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, 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 the rapamycin / FK-BP12 complex. This complex can bind to TOR, block calcium-dependent and non-calcium-dependent TOR signaling pathways, and regulate multiple processes such as translation, energy regulation, autophagy, and cell growth. Currently, there are no clinical studies that have found that use Rapamycin directly as a drug to treat sleep disorders such as insomnia. Summary of the Invention

[0006] To address the shortcomings of existing sleeping pills, this invention, through research on novel sleep pathway targets, discovered that rapamycin can improve sleep disorders. Based on this, this invention was completed.

[0007] In a first aspect, the present invention provides the use of Rapamycin in the preparation of medicaments for improving sleep disorder-related diseases.

[0008] Furthermore, the sleep disorder-related diseases include, but are not limited to, depression, anxiety, schizophrenia, Parkinson's disease, Alzheimer's disease, periodic limb movement, diabetes, hypertension, and cardiovascular disease.

[0009] Furthermore, the sleep disorders include insomnia, central hypersomnia, circadian rhythm sleep-wake disorders, sleep-related motor disorders, parasomnias, and other types of sleep disorders.

[0010] Furthermore, the drug may also contain another active ingredient selected from sleep-promoting drugs or active substances that enhance the body's immunity.

[0011] Furthermore, the sleep-promoting drugs include sedative-hypnotic drugs and novel sleep-inducing drugs such as orexin receptor antagonists.

[0012] Furthermore, the sedative-hypnotic drugs include benzodiazepines and novel non-benzodiazepine drugs.

[0013] Furthermore, the benzodiazepine drugs include, but are not limited to, one or more of diazepam, flurazepam, triazolam, and / or temazepam.

[0014] Furthermore, the novel non-benzodiazepine drugs include, but are not limited to, one or more of zolpidem, eszopiclone, and / or zaleplon.

[0015] Furthermore, the novel sleep aid orexin receptor antagonist includes, but is not limited to, sovresen and / or one or more of the following: targeted blockade of orexin.

[0016] Furthermore, the active substances that enhance the body's immunity include one or more of the trace elements, minerals, vitamins, coenzyme Q, oryzanol, and / or melatonin required by the human body.

[0017] Furthermore, the trace elements include one or more of iron (Fe), zinc (Zn), copper (Cu), manganese (Mn), iodine (I) and / or selenium (Se).

[0018] Furthermore, the minerals include one or more of calcium (Ca), phosphorus (P), potassium (K), sodium (Na), chlorine (Cl), and / or magnesium (Mg).

[0019] Furthermore, the vitamins include one or more of vitamin A (VA), B vitamins (VB), vitamin C (VC), vitamin D (VD), vitamin E (VE), and / or vitamin K (VK).

[0020] Furthermore, the drug dosage forms include, but are not limited to, one or more of the following: tablets, capsules, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, injectable preparations, lozenges, oral films, transdermal preparations, and / or suppositories.

[0021] Furthermore, the formulation may be one or more of a conventional formulation, a sustained-release formulation, a controlled-release formulation, and / or a variety of microparticle delivery systems.

[0022] Furthermore, the drug can be introduced into the body through injection, permeation, absorption, or physical or chemical mediated methods.

[0023] Furthermore, the injection administration includes subcutaneous injection, intravenous injection, intramuscular injection, and intracavitary injection; the cavity administration includes rectal or vaginal administration; and the respiratory administration includes nasal administration.

[0024] In a second aspect, the present invention provides a pharmaceutical composition for improving sleep disorders, the pharmaceutical composition comprising Rapamycin and another (or more) active ingredients, said active ingredients being selected from drugs that promote sleep or active substances that enhance the body's immunity.

[0025] Furthermore, the sleep-promoting drugs include sedative-hypnotic drugs and novel sleep-inducing drugs such as orexin receptor antagonists.

[0026] Furthermore, the sedative-hypnotic drugs include benzodiazepines and novel non-benzodiazepine drugs.

[0027] Furthermore, the benzodiazepine drugs include, but are not limited to, one or more of diazepam, flurazepam, triazolam, and / or temazepam.

[0028] Furthermore, the novel non-benzodiazepine drugs include, but are not limited to, one or more of zolpidem, eszopiclone, and / or zaleplon.

[0029] Furthermore, the novel sleep aid orexin receptor antagonist includes, but is not limited to, sovresen and / or one or more of the following: targeted blockade of orexin.

[0030] Furthermore, the active substances that enhance the body's immunity include one or more of the trace elements, minerals, vitamins, coenzyme Q, oryzanol, and / or melatonin required by the human body.

[0031] Furthermore, the trace elements include one or more of iron (Fe), zinc (Zn), copper (Cu), manganese (Mn), iodine (I) and / or selenium (Se).

[0032] Furthermore, the minerals include one or more of calcium (Ca), phosphorus (P), potassium (K), sodium (Na), chlorine (Cl), and / or magnesium (Mg).

[0033] Furthermore, the vitamins include one or more of vitamin A (VA), B vitamins (VB), vitamin C (VC), vitamin D (VD), vitamin E (VE), and / or vitamin K (VK).

[0034] Furthermore, one or more pharmaceutically acceptable carriers may be added to the pharmaceutical composition.

[0035] Furthermore, the carrier material includes, but is not limited to, one or more of water-soluble carrier materials, poorly soluble carrier materials, and / or enteric carrier materials.

[0036] Furthermore, the water-soluble carrier material includes, but is not limited to, one or more of polyethylene glycol, polyvinylpyrrolidone, and / or organic acids.

[0037] Furthermore, the poorly soluble carrier material includes, but is not limited to, one or more of ethyl cellulose and / or cholesterol stearate.

[0038] Furthermore, the enteric carrier material includes, but is not limited to, one or more of cellulose acetate phthalate and / or carboxymethyl ethyl cellulose.

[0039] Furthermore, the dosage forms of the pharmaceutical composition include, but are not limited to, one or more of the following: tablets, capsules, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, injectable preparations, lozenges, oral films, transdermal preparations, and / or suppositories.

[0040] Furthermore, the formulation may be one or more of a conventional formulation, a sustained-release formulation, a controlled-release formulation, and / or a variety of microparticle delivery systems.

[0041] Furthermore, the tablets can widely utilize a variety of carriers known in the art, including one or more of diluents and absorbents, humectants and binders, disintegrants, disintegration inhibitors, absorption promoters and / or lubricants.

[0042] 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.

[0043] Furthermore, the wetting agent and adhesive include, but are not limited to, one or more of water, glycerin, polyethylene glycol, ethanol, propanol, starch paste, dextrin, syrup, honey, glucose solution, gum arabic paste, gelatin paste, sodium carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate and / or polyvinylpyrrolidone.

[0044] Furthermore, the disintegrant includes, but is not limited to, one or more of the following: dried starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene, sorbitol fatty acid ester, sodium dodecyl sulfonate, methylcellulose and / or ethylcellulose.

[0045] Furthermore, the disintegration inhibitors include, but are not limited to, sucrose, tristearate, cocoa butter, and / or hydrogenated oils.

[0046] Furthermore, the absorption enhancer includes, but is not limited to, one or more of quaternary ammonium salts and / or sodium dodecyl sulfate.

[0047] Furthermore, the lubricant includes, but is not limited to, one or more of talc, silica, corn starch, stearate, boric acid, liquid paraffin, and / or polyethylene glycol.

[0048] Furthermore, the tablets can be further formulated into coated tablets, including sugar-coated tablets, film-coated tablets, enteric-coated tablets, bilayer tablets, and multilayer tablets.

[0049] Furthermore, the pills can utilize a wide range of carriers known in the art, including diluents and absorbents, binders and / or disintegrants.

[0050] Furthermore, the diluent and absorbent include, but are not limited to, one or more of glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin and / or talc.

[0051] Furthermore, the adhesive includes, but is not limited to, one or more of gum arabic, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste, and / or flour paste.

[0052] Furthermore, the disintegrant includes, but is not limited to, one or more of agar powder, dried starch, alginate, sodium dodecyl sulfonate, methylcellulose and / or ethylcellulose.

[0053] Furthermore, the suppository can widely use various 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.

[0054] Furthermore, the injectable formulation includes, but is not limited to, one or more of the following: solutions, emulsions, lyophilized powder for injection, and / or suspensions.

[0055] Furthermore, the injectable formulation may use all diluents commonly used in the art, including but not limited to one or more of water, ethanol, polyethylene glycol, 1,3-propanediol, ethoxylated isostearyl alcohol, polyoxyethylene isostearyl alcohol, and / or polyoxyethylene sorbitan fatty acid esters.

[0056] Furthermore, in order to prepare an isotonic injection solution, appropriate amounts of one or more of sodium chloride, glucose, glycerol, conventional solubilizers, buffers, and / or pH adjusters may be added to the injectable formulation.

[0057] Furthermore, colorants, preservatives, flavorings, tasters, sweeteners, or other materials may be added to the pharmaceutical preparations if necessary.

[0058] Furthermore, the pharmaceutical composition can be administered by injection, cavity administration, respiratory administration, or mucosal administration.

[0059] Furthermore, the injection administration includes subcutaneous injection, intravenous injection, intramuscular injection, and intracavitary injection; the cavity administration includes rectal or vaginal administration; and the respiratory administration includes nasal administration.

[0060] Beneficial effects 1. Rapamycin of this invention is a non-addictive hypnotic drug that can induce natural sleep behavior, and all assessment indicators are effective and show significant improvement.

[0061] 2. Compared with existing hypnotic drugs that lead to a significant increase in mortality, the Rapamycin administration of this invention can prolong the lifespan of animals.

[0062] 3. After administration of Rapamycin of the present invention, sleep behavior indicators of normal and humanized Parkinson's disease nematode models at different stages were improved, indicating that Rapamycin helps improve sleep quality of normal and Parkinson's patients at different stages.

[0063] 4. This invention reveals the significant effect of Rapamycin in improving sleep disorders. This discovery is of great significance for improving patients' sleep quality and preventing disease, thus having broad medical prospects and significant economic value. Attached Figure Description

[0064] Figure 1 The changes in muscle movement count and arousal response delay time, sleep indicators of nematodes, after treatment with different concentrations of Rapamycin, and the dose-response relationship curves.

[0065] Figure 2 Changes in sleep parameters muscle movement count and arousal response delay at different time points after adulthood in wild-type nematodes (WT) and nematodes (PD), a model of Parkinson's disease, after treatment with Rapamycin. Detailed Implementation

[0066] The specific embodiments of the present invention will be further described below. It should be noted that these descriptions are for the purpose of aiding understanding the present invention, but do not constitute a limitation thereof. Furthermore, 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.

[0067] Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods, and the experimental materials used in the following embodiments are all available through conventional commercial channels.

[0068] Terminology Explanation Insomnia refers to persistent difficulty sleeping, with adequate sleep opportunities and associated daytime dysfunction. It is the most common type of sleep disorder. ICSD-3 classifies insomnia into three categories: chronic insomnia, short-term insomnia, and other insomnia disorders.

[0069] Central hypersomnia disorders include those presenting with excessive daytime sleepiness as the primary complaint, after ruling out other sleep disturbances as causes. ICSD-3 classifies them into narcolepsy type 1, narcolepsy type 2, idiopathic hypersomnia, Kleine-Levin syndrome, disease-related hypersomnia, drug or substance abuse-related hypersomnia, mental disorder-related hypersomnia, and sleep deprivation syndrome.

[0070] Circadian rhythm sleep-wake disorders are chronic or recurrent sleep disorders caused by changes in physiological rhythms or environmental factors that disrupt an individual's sleep-wake cycle. The ICSD-3 classifies them into delayed sleep-wake phase disorders, advanced / delayed sleep-wake phase disorders, non-24-hour sleep-wake rhythm disorders, irregular sleep-wake rhythm disorders, shift work sleep-wake disorders, and jet lag sleep disorders.

[0071] Sleep-related movement disorders: ICSD-3 classifies them into restless legs syndrome, periodic limb movement disorder, sleep-related leg cramps, sleep-related bruxism, sleep-related rhythmic movement disorder, benign infantile sleep myoclonus, and hypnagogic myoclonus.

[0072] Parasomnia refers to unpleasant physical events (complex movements, behaviors) or experiences (emotions, perceptions, dreams) that occur when falling asleep, during sleep, or upon waking. The ICSD-3 classifies it into three categories: non-rapid eye movement (NREM) parasomnia, rapid eye movement (REM) parasomnia, and other parasomnias.

[0073] The structural formula for Rapamycin is as follows: Example 1: Sleep-promoting effect of Rapamycin on nematodes In terms of behavior, the natural sleep state can be characterized by five indicators: (i) prolonged behavioral stillness, (ii) reversibility to stimulation (to distinguish it from numbness 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 exhibits sleep characteristics such as behavioral stillness, increased arousal threshold, and sleep homeostasis; therefore, behavioral changes in the nematode can be used to assess sleep quality.

[0074] 1.1 Materials and Methods wild-type nematodes Rapamycin compound 1.2 Steps Preparation from 10 -2 μM -10 3 After causative nematodes were induced to sleep by Rapamycin solutions of different concentration gradients at μM, various behavioral indicators of nematode sleep were evaluated.

[0075] Number of muscle activities: The number of muscle movements observed under a stereoscope within 20 seconds.

[0076] Response latency: The time taken from the moment the nematode is stimulated until it exhibits a retreating evasive behavior is the reaction time, measured in seconds.

[0077] 1.3 Experimental Results like Figure 1 As shown, 10 are given respectively. -2 μM -10 3 After treatment with μM rapamycin, the sleep indices of muscle movement count and arousal response delay in nematodes were assessed. A dose-response curve was plotted, and the EC50 of rapamycin on arousal response delay in nematodes was calculated. 50 The concentration was 45.21 μM, and the IC50 value affected the number of muscle movements. 50 The concentration was 5.21 μM.

[0078] Example 2: Rapamycin improved sleep disorder symptoms in a Parkinson's nematode model. 2.1 Materials and Methods Wild-type nematode (WT) and humanized Parkinson's disease model nematode (PD) Rapamycin 2.2 Steps Preparation 10 -2 μM -10 3 Rapamycin solutions with gradient concentrations in the μM range were used to induce sleep in nematodes, and various behavioral indicators of nematode sleep were evaluated.

[0079] Number of muscle activities: The number of muscle activities observed under a stereoscope within 20 seconds.

[0080] Response latency: The time taken from the moment the nematode is stimulated until it exhibits a retreating evasive behavior is the reaction time, measured in seconds.

[0081] 2.3 Experimental Results like Figure 2 As shown, after treatment with Rapamycin, the sleep behavior indicators of muscle movement frequency and arousal response delay were improved in wild-type nematodes (WT) and nematode models of humanized Parkinson's disease (PD), indicating that Rapamycin helps improve sleep quality.

Claims

1. Application of Rapamycin in the preparation of drugs to improve sleep-related diseases.

2. The application as described in claim 1, wherein the sleep disorder-related diseases include, but are not limited to, depression, anxiety, schizophrenia, Parkinson's disease, Alzheimer's disease, periodic limb movement, diabetes, hypertension, and cardiovascular disease; and the sleep disorder includes insomnia, central hypersomnia, circadian rhythm sleep-wake disorder, sleep-related motor disorder, parasomnia, and other sleep disorders.

3. In the application described in claim 1, the drug may further comprise another active ingredient selected from sleep-promoting drugs or active substances that enhance the body's immunity.

4. The application as described in claim 1, wherein the pharmaceutical dosage form includes, but is not limited to, one or more of the following: tablets, capsules, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, injectable preparations, lozenges, oral films, transdermal preparations, and / or suppositories.

5. The application as described in claim 1, wherein the injection administration includes subcutaneous injection, intravenous injection, intramuscular injection, and intracavitary injection; the cavity administration includes rectal or vaginal administration; and the respiratory administration includes nasal administration.

6. A pharmaceutical composition for improving sleep disorders, the pharmaceutical composition comprising Rapamycin and another (or more) active ingredients, said active ingredients being selected from sleep-promoting drugs or active substances that enhance the body's immunity.

7. The pharmaceutical composition of claim 6, wherein the other sleep-promoting and wakefulness-enhancing drug comprises a sedative-hypnotic drug and a novel sleep-inducing drug orexin receptor antagonist; and the active substance that enhances the body's immunity comprises one or more of the following: trace elements, minerals, vitamins, coenzyme Q, oryzanol, and / or melatonin.

8. The pharmaceutical composition of claim 7, wherein the sedative-hypnotic drug includes, but is not limited to, one or more of diazepam, flurazepam, triazolam, temazepam, zolpidem, eszopiclone, and / or zaleplon; and the novel hypnotic drug orexin receptor antagonist includes, but is not limited to, suvorexin, and / or one or more of targeted orexin blocking agents.

9. The pharmaceutical composition of claim 6, wherein the dosage form of the pharmaceutical composition includes, but is not limited to, one or more of the following: tablets, capsules, drops, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal preparations, injectable preparations, lozenges, oral films, suppositories, and / or lyophilized powder injections.

10. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition can be administered by injection, cavity administration, respiratory administration, or mucosal administration; the injection administration includes subcutaneous injection, intravenous injection, intramuscular injection, and intracavitary injection; the cavity administration includes rectal or vaginal administration; and the respiratory administration includes nasal administration.

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