Sleep-improving composition and method of use

Abstract

Compositions comprising two or more sleep-inducing agonists and / or one sleep-inducing antagonist are disclosed herein. These compositions promote healthy sleep quality and treat, improve, prevent, or reduce one or more symptoms associated with menopause. Methods using the aforementioned compositions are also described herein.

Description

Background Art

[0001] Insomnia and a decline in sleep quality are conditions that affect 70 million Americans annually. Women have a 40% higher lifetime risk of insomnia and a decline in sleep quality than men. A decrease in estrogen concentration causes several symptoms associated with menopause such as night sweats, resulting in both a decrease in sleep duration and a decline in sleep quality, so a woman's condition worsens during menopause. Menopausal women report that their normal daily routines are disrupted more often at night than pre-menopausal women, and there are common reports of waking up earlier than planned, having difficulty falling asleep, and having difficulty staying asleep.

[0002] There are numerous prescription drug treatment options for insomnia and a decline in sleep quality, such as Valium, Xanax, Klonopin, Zopiclone, Zaleplon, Zolpidem, and Eszopiclon. These prescription drugs are associated with negative side effects such as headache, dizziness, dry mouth, nausea, cognitive impairment, and the risk of falls in the elderly population, all of which are particularly problematic in patient populations such as post-menopausal patients who tend to have these symptoms. There are also OTC (over-the-counter) pharmaceutical treatment options, among which melatonin is the most common option. However, melatonin also has side effects such as vivid dreams, nightmares, dizziness, daytime sleepiness, headache, stomach cramps, depression, and irritability.

[0003] Therefore, there is a need to develop safe and effective treatment options for improving sleep quality.

Summary of the Invention

[0004] Embodiments of the present disclosure relate to novel compositions and their use in promoting healthy sleep quality and treating, improving, preventing, or reducing one or more symptoms associated with menopause. These and other features, aspects, and advantages of embodiments of the present invention will be understood in connection with the following specification, appended claims, and appended drawings. [Brief explanation of the drawing]

[0005] [Figure 1A] The following are the combinations: (i) control; (ii) caffeine (7.5 mg / kg); (iii) combination of 7.5 mg / kg caffeine with 100 mg HED magnesium glycinate, 200 mg HED L-theanine, and 300 mg HED GABA (combo 1); (iv) combination of 7.5 mg / kg caffeine with 100 mg HED magnesium glycinate, 200 mg HED L-theanine, 300 mg HED GABA, and 412 mg HED of the total amount of S-adenosyl-L-methionine (SAMe) and propyl gallate (combo 2); (v) combination of 7.5 mg / kg caffeine with 100 mg HED magnesium glycinate, 200 mg HED L-theanine, and 412 mg HED of the total amount of SAMe and propyl gallate (combo 3); (vi) Caffeine 7.5 mg / kg combined with magnesium glycinate HED 100 mg, L-theanine HED 200 mg, SAMe and propyl gallate combined HED 412 mg, and phosphatidylserine HED 100 mg (combo 4); (vii) Caffeine 7.5 mg / kg combined with magnesium glycinate HED 100 mg, L-theanine HED 200 mg, GABA HED 300 mg, and phosphatidylserine HED 100 mg (combo 5); or (viii) Percentage of GABAA receptor 2 in mice treated with a combination of Combo 6: 100 mg HED of magnesium glycinate, 200 mg HED of L-theanine, 300 mg HED of GABA, 412 mg HED of SAMe and propyl gallate combined, and 100 mg HED of phosphatidylserine, along with caffeine 7.5 mg / kg. [Figure 1B]This shows the percentage of GABAB receptor 1 in mice treated with caffeine, caffeine with combo 1, caffeine with combo 2, caffeine with combo 3, caffeine with combo 4, caffeine with combo 5, or caffeine with combo 6. [Figure 1C] This shows the percentage of GABAB receptor 2 in mice treated with caffeine, caffeine with combo 1, caffeine with combo 2, caffeine with combo 3, caffeine with combo 4, caffeine with combo 5, or caffeine with combo 6. [Figure 1D] This shows the percentage of GluA1 in mice treated with caffeine, caffeine with combo 1, caffeine with combo 2, caffeine with combo 3, caffeine with combo 4, caffeine with combo 5, and caffeine with combo 6. [Figure 1E] This shows the percentage of GluN1 in mice treated with caffeine, caffeine with combo 1, caffeine with combo 2, caffeine with combo 3, caffeine with combo 4, caffeine with combo 5, or caffeine with combo 6. [Figure 1F] This shows the percentage of GluN2A in mice treated with caffeine, caffeine with combo 1, caffeine with combo 2, caffeine with combo 3, caffeine with combo 4, caffeine with combo 5, or caffeine with combo 6. [Figure 1G] This shows the percentage of 5-HT1A in mice treated with caffeine, caffeine with combo 1, caffeine with combo 2, caffeine with combo 3, caffeine with combo 4, caffeine with combo 5, or caffeine with combo 6. [Figure 1H] This shows the EEG amplitude in mice treated with caffeine, caffeine with combo 1, caffeine with combo 2, caffeine with combo 3, caffeine with combo 4, caffeine with combo 5, or caffeine with combo 6. [Figure 1I]This shows the EEG frequencies in mice treated with caffeine, caffeine with combo 1, caffeine with combo 2, caffeine with combo 3, caffeine with combo 4, caffeine with combo 5, or caffeine with combo 6. [Figure 1J] This shows the sleep duration in mice treated with pentobarbital (42 mg / kg) and caffeine in combo 1, combo 2, combo 3, combo 4, combo 5, or combo 6. [Figure 1K] This shows the sleep latency in mice treated with pentobarbital (42 mg / kg) and caffeine in combo 1, combo 2, combo 3, combo 4, combo 5, or combo 6. [Figure 2A] (i) Physiological saline (control), (ii) combination of caffeine (7.5 mg / kg) and physiological saline (caffeine control), (iii) combination of caffeine (7.5 mg / kg) and magnesium glycinate HED 100 mg, (iv) combination of caffeine (7.5 mg / kg) and L-theanine HED 200 mg, (v) combination of caffeine (7.5 mg / kg) and GABA HED 300 mg, (vi) caffeine (7.5 mg / kg), SAMe HED 150 mg, and propyl gallate HED The following shows the EEG amplitudes in female ovariectomized (OVX) mice treated with the following combinations: (vii) caffeine (7.5 mg / kg), magnesium glycinate HED 100 mg, L-theanine HED 200 mg, and GABA HED 300 mg, or (viii) caffeine (7.5 mg / kg), magnesium glycinate HED 100 mg, L-theanine HED 200 mg, GABA HED 300 mg, SAMe HED 150 mg, and propyl gallate HED 9 mg. [Figure 2B](i) Physiological saline (control), (ii) combination of caffeine (7.5 mg / kg) and physiological saline (caffeine control), (iii) combination of caffeine (7.5 mg / kg) and magnesium glycinate HED 100 mg, (iv) combination of caffeine (7.5 mg / kg) and L-theanine HED 200 mg, (v) combination of caffeine (7.5 mg / kg) and GABA HED 300 mg, (vi) caffeine (7.5 mg / kg), SAMe HED 150 mg, and propyl gallate The following shows the EEG frequencies in female OVX mice treated with the following combinations: (vii) a combination of caffeine (7.5 mg / kg), magnesium glycinate HED 100 mg, L-theanine HED 200 mg, and GABA HED 300 mg, or (viii) a combination of caffeine (7.5 mg / kg), magnesium glycinate HED 100 mg, L-theanine HED 200 mg, GABA HED 300 mg, SAMe HED 150 mg, and propyl gallate HED 9 mg. [Figure 2C] (i) Physiological saline (control), (ii) combination of caffeine (7.5 mg / kg) and physiological saline (caffeine control), (iii) combination of caffeine (7.5 mg / kg) and magnesium glycinate HED 100 mg, (iv) combination of caffeine (7.5 mg / kg) and L-theanine HED 200 mg, (v) combination of caffeine (7.5 mg / kg) and GABA HED 300 mg, (vi) caffeine (7.5 mg / kg), SAMe HED 150 mg, and propyl gallate The following shows the sleep duration in female OVX mice treated with a combination of (vii) caffeine (7.5 mg / kg), magnesium glycinate HED 100 mg, L-theanine HED 200 mg, and GABA HED 300 mg, or (viii) caffeine (7.5 mg / kg), magnesium glycinate HED 100 mg, L-theanine HED 200 mg, GABA HED 300 mg, SAMe HED 150 mg, and propyl gallate HED 9 mg. [Figure 2D](i) Physiological saline (control), (ii) combination of caffeine (7.5 mg / kg) and physiological saline (caffeine control), (iii) combination of caffeine (7.5 mg / kg) and magnesium glycinate HED 100 mg, (iv) combination of caffeine (7.5 mg / kg) and L-theanine HED 200 mg, (v) combination of caffeine (7.5 mg / kg) and GABA HED 300 mg, (vi) caffeine (7.5 mg / kg), SAMe HED 150 mg, and propyl gallate The following shows the sleep latency in female OVX mice treated with (vii) a combination of (7.5 mg / kg) HED 9 mg of (vii) caffeine, 100 mg HED of magnesium glycinate, 200 mg HED of L-theanine, and 300 mg HED of GABA, or (viii) a combination of (7.5 mg / kg) HED 100 mg of magnesium glycinate, 200 mg HED of L-theanine, 300 mg HED of GABA, 150 mg HED of SAMe, and 9 mg HED of propyl gallate. [Figure 2E] (i) Physiological saline (control), (ii) combination of caffeine (7.5 mg / kg) and physiological saline (caffeine control), (iii) combination of caffeine (7.5 mg / kg) and magnesium glycinate HED 100 mg, (iv) combination of caffeine (7.5 mg / kg) and L-theanine HED 200 mg, (v) combination of caffeine (7.5 mg / kg) and GABA HED 300 mg, (vi) caffeine (7.5 mg / kg), SAMe HED 150 mg, and propyl gallate The following shows melatonin levels in female OVX mice treated with the following combinations: (vii) caffeine (7.5 mg / kg), magnesium glycinate HED 100 mg, L-theanine HED 200 mg, and GABA HED 300 mg, or (viii) caffeine (7.5 mg / kg), magnesium glycinate HED 100 mg, L-theanine HED 200 mg, GABA HED 300 mg, SAMe HED 150 mg, and propyl gallate HED 9 mg. [Figure 2F](i) Physiological saline (control), (ii) combination of caffeine (7.5 mg / kg) and physiological saline (caffeine control), (iii) combination of caffeine (7.5 mg / kg) and magnesium glycinate HED 100 mg, (iv) combination of caffeine (7.5 mg / kg) and L-theanine HED 200 mg, (v) combination of caffeine (7.5 mg / kg) and GABA HED 300 mg, (vi) caffeine (7.5 mg / kg), SAMe HED 150 mg, and propyl gallate HED 9 The percentage of GABAA receptor 2 in female OVX mice treated with the following combinations: (vii) a combination of caffeine (7.5 mg / kg), magnesium glycinate HED 100 mg, L-theanine HED 200 mg, and GABA HED 300 mg, or (viii) a combination of caffeine (7.5 mg / kg), magnesium glycinate HED 100 mg, L-theanine HED 200 mg, GABA HED 300 mg, SAMe HED 150 mg, and propyl gallate HED 9 mg. [Figure 2G] (i) Physiological saline (control), (ii) combination of caffeine (7.5 mg / kg) and physiological saline (caffeine control), (iii) combination of caffeine (7.5 mg / kg) and magnesium glycinate HED 100 mg, (iv) combination of caffeine (7.5 mg / kg) and L-theanine HED 200 mg, (v) combination of caffeine (7.5 mg / kg) and GABA HED 300 mg, (vi) caffeine (7.5 mg / kg), SAMe HED 150 mg, and propyl gallate HED 9 The percentage of GABAB receptor 1 in female OVX mice treated with the following combinations: (vii) a combination of caffeine (7.5 mg / kg), magnesium glycinate HED 100 mg, L-theanine HED 200 mg, and GABA HED 300 mg, or (viii) a combination of caffeine (7.5 mg / kg), magnesium glycinate HED 100 mg, L-theanine HED 200 mg, GABA HED 300 mg, SAMe HED 150 mg, and propyl gallate HED 9 mg. [Figure 2H] (i) Physiological saline (control), (ii) combination of caffeine (7.5 mg / kg) and physiological saline (caffeine control), (iii) combination of caffeine (7.5 mg / kg) and magnesium glycinate HED 100 mg, (iv) combination of caffeine (7.5 mg / kg) and L-theanine HED 200 mg, (v) combination of caffeine (7.5 mg / kg) and GABA HED 300 mg, (vi) caffeine (7.5 mg / kg), SAMe HED 150 mg, and propyl gallate HED 9 The percentage of GABAB receptor 2 in female OVX mice treated with the following combinations: (vii) a combination of caffeine (7.5 mg / kg), magnesium glycinate HED 100 mg, L-theanine HED 200 mg, and GABA HED 300 mg, or (viii) a combination of caffeine (7.5 mg / kg), magnesium glycinate HED 100 mg, L-theanine HED 200 mg, GABA HED 300 mg, SAMe HED 150 mg, and propyl gallate HED 9 mg. [Figure 2I] (i) Physiological saline (control), (ii) combination of caffeine (7.5 mg / kg) and physiological saline (caffeine control), (iii) combination of caffeine (7.5 mg / kg) and magnesium glycinate HED 100 mg, (iv) combination of caffeine (7.5 mg / kg) and L-theanine HED 200 mg, (v) combination of caffeine (7.5 mg / kg) and GABA HED 300 mg, (vi) caffeine (7.5 mg / kg), SAMe HED 150 mg, and propyl gallate HED The percentage of GluA1 in female OVX mice treated with the following combinations: (vii) caffeine (7.5 mg / kg), magnesium glycinate HED 100 mg, L-theanine HED 200 mg, and GABA HED 300 mg, or (viii) caffeine (7.5 mg / kg), magnesium glycinate HED 100 mg, L-theanine HED 200 mg, GABA HED 300 mg, SAMe HED 150 mg, and propyl gallate HED 9 mg. [Figure 2J] (i) Physiological saline (control), (ii) combination of caffeine (7.5 mg / kg) and physiological saline (caffeine control), (iii) combination of caffeine (7.5 mg / kg) and magnesium glycinate HED 100 mg, (iv) combination of caffeine (7.5 mg / kg) and L-theanine HED 200 mg, (v) combination of caffeine (7.5 mg / kg) and GABA HED 300 mg, (vi) caffeine (7.5 mg / kg), SAMe HED 150 mg, and propyl gallate HED The percentage of GluN1 in female OVX mice treated with the following combinations: (vii) caffeine (7.5 mg / kg), magnesium glycinate HED 100 mg, L-theanine HED 200 mg, and GABA HED 300 mg, or (viii) caffeine (7.5 mg / kg), magnesium glycinate HED 100 mg, L-theanine HED 200 mg, GABA HED 300 mg, SAMe HED 150 mg, and propyl gallate HED 9 mg. [Figure 2K](i) Physiological saline (control), (ii) combination of caffeine (7.5 mg / kg) and physiological saline (caffeine control), (iii) combination of caffeine (7.5 mg / kg) and magnesium glycinate HED 100 mg, (iv) combination of caffeine (7.5 mg / kg) and L-theanine HED 200 mg, (v) combination of caffeine (7.5 mg / kg) and GABA HED 300 mg, (vi) caffeine (7.5 mg / kg), SAMe HED 150 mg, and gallate The percentage of GluN2 A in female OVX mice treated with the following combinations: (vii) caffeine (7.5 mg / kg), magnesium glycinate HED 100 mg, L-theanine HED 200 mg, and GABA HED 300 mg, or (viii) caffeine (7.5 mg / kg), magnesium glycinate HED 100 mg, L-theanine HED 200 mg, GABA HED 300 mg, SAMe HED 150 mg, and propyl gallate HED 9 mg. [Figure 3] Melatonin levels in female OVX mice and male mice treated with physiological saline (control), a combination of caffeine (7.5 mg / kg) and physiological saline (caffeine control), or a combination of caffeine (7.5 mg / kg), 100 mg of magnesium glycinate HED, 200 mg of L-theanine HED, 300 mg of GABA HED, 150 mg of SAMe HED, and 9 mg of propyl gallate HED, respectively. [Figure 4A] The following shows the changes in sleep duration during weeks 1, 2, and 3 in women aged 40–65 years treated with the composition described herein, compared to women treated with a placebo. [Figure 4B] This shows the percentage change in irritability-related sleep deprivation from the PROMIS SRI Confirmation Questionnaire in women aged 40–65 years after 3 weeks of taking the composition described herein, compared to women who took a placebo. [Figure 4C]This report presents the results of product effectiveness based on questionnaires from menopausal women regarding whether the product helped them fall asleep faster and whether it helped them fall back asleep faster. [Modes for carrying out the invention]

[0006] Novel compositions are described herein, each containing two or more sleep-inducing agonists. In certain embodiments, the composition may consist of a first sleep-inducing agonist and a second sleep-inducing agonist, wherein the first sleep-inducing agonist is different from the second sleep-inducing agonist. An example of the first sleep-inducing agonist is L-theanine, and an example of the second sleep-inducing agonist is a magnesium salt. In certain embodiments, the composition may consist of a first sleep-inducing agonist, a second sleep-inducing agonist, and a third sleep-inducing agonist, wherein the first, second, and third sleep-inducing agonists are different from each other. An example of the first sleep-inducing agonist is L-theanine, an example of the second sleep-inducing agonist is a magnesium salt, and an example of the third sleep-inducing agonist is gamma-aminobutyric acid (GABA). The number of sleep-inducing agonists in the composition is not particularly limited. For example, the composition may contain one, two, three, four, five, six or more different sleep-inducing agonists. Examples of salts, though not limited to them, include sulfates, citrates, maleates, acetates, oxalates, hydrochlorides, hydrobroms, hydroiodides, nitrates, sulfates, bisulfates, phosphates, acid phosphates, isonicotinates, acetates, lactates, salicylates, citrates, acid citrates, tartrates, oleates, tannates, pantothenates, hydrogen tartrates, ascorbic acid, succinates, maleates, gentisinates, fumarates, glucons, glucarons, glycines, saccharates, formates, benzoates, glutamates, methanesulfons, ethanesulfons, benzenesulfons, p-toluenesulfons, and pamoic acid (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid)) salts.

[0007] When provided in the compositions described herein, the amount of each sleep-inducing agonist in the composition is approximately 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, 250 μg, 275 μg, 300 μg, 325 μg, 350 μg, 375 μg, 400 μg, 425 μg, 450 μg, 4 75μg, 500μg, 525μg, 575μg, 600μg, 625μg, 650μg, 675μg, 700μg, 725μg, 750μg, 775μg, 800μg, 825μg, 850μg, 875μg, 900μg, 925μg, 950μg g, 975μg, 1000μg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 10 0mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 575mg , 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1000mg, 1.25g, 1 The amount may be 0.5g, 1.75g, 2.0g, 2.25g, 2.5g, 2.75g, 3.0g, 3.25g, 3.5g, 3.5g, 3.75g, 4.0g, 4.25g, 4.5g, 4.75g, 5.0g, 5.25g, 5.5g, 5.75g, 6.0g, 6.25g, 6.5g, 6.75g, 7.0g, 7.25g, 7.5g, 7.75g, 8.0g, 8.25g, 8.5g, 8.75g, 9.0g, 8.25g, 9.5g, 9.75g, 10g, or more, or any amount in between. The amounts of sleep-inducing agonists in the composition relative to each other may be in a synergistic effective ratio.

[0008] As used herein, “synergistic ratio” means a ratio that elicits an unexpectedly superior pharmacological, physiological, nutritional, or nutritional supplemental effect in a subject. While the synergistic ratio is not particularly limited, any combination of compounds or components capable of achieving the synergistic effect as defined herein will be readily apparent to those skilled in the art in light of the terms of the claims and their surrounding context.

[0009] For example, in a composition comprising a first sleep-inducing agonist, a second sleep-inducing agonist, and a third sleep-inducing agonist, the synergistic effective ratio of the first sleep-inducing agonist:second sleep-inducing agonist:third sleep-inducing agonist is approximately 1:1:1, 1:1:2, 1:1:3, 1:1:4, 1:1:5, 1:1:6, 1:1:7, 1:1:8, 1:1:9, 1:1:10, 1:2:1, 1:2:2, 1:2:3, 1:2:4, 1:2:5, 1:2:6, 1:2:7, 1:2:8, 1:2:9, 1:2:10, 1:3:1, 1:3:2, 1:3:3, 1:3:4, 1:3:5, 1:3:6, 1:3:7, 1:3:8, 1:3:9, 1:3:10, 1:4:1, 1:4:2, 1:4:3, 1:4:4, 1:4:5, 1:4:6, 1:4:7, 1:4:8, 1:4:9, 1:4:10, 1:5:1, 1:5:2, 1:5:3, 1:5:4, 1:5:5, 1: 5:6, 1:5:7, 1:5:8, 1:5:9, 1:5:10, 1:6:1, 1:6:2, 1:6:3, 1:6:4, 1:6:5, 1:6:6, 1:6:7, 1:6:8, 1:6:9, 1:6:10, 1:7:1, 1:7:2, 1:7:3, 1:7:4, 1:7:5, 1:7:6 ,1:7:7,1:7:8,1:7:9,1:7:10,1:8:1,1:8:2,1:8:3,1:8:4,1:8:5,1:8:6,1:8:7,1:8:8,1:8:9,1:8:10,1:9:1,1:9:2,1:9:3,1:9:4,1:9:5,1:9:6,1 :9:7, 1:9:8, 1:9:9, 1:9:10, 1:10:1, 1:10:2, 1:10:3, 1:10:4, 1:10:5, 1:10:6, 1:10:7, 1:10:8, 1:10:9, 1:10:10, 2:1:1, 2:1:2, 2:1:3, 2:1:4, 2:1:5, 2:1:6, 2:1:7, 2:1:8, 2:1:9, 2:1:10, 2:2:1, 2:2:2, 2:2:3, 2:2:4, 2:2:5, 2:2:6, 2:2:7, 2:2:8, 2:2:9, 2:2:10, 2:3:1, 2:3:2, 2:3:3, 2:3:4, 2:3:5, 2:3 :6, 2:3:7, 2:3:8, 2:3:9, 2:3:10, 2:4:1, 2:4:2, 2:4:3, 2:4:4, 2:4:5, 2:4:6, 2:4:7, 2:4:8, 2:4:9, 2:4:10, 2:5:1, 2:5:2, 2:5:3, 2:5:4, 2:5:5, 2:5:6,2:5:7、2:5:8、2:5:9、2:5:10、2:6:1、2:6:2、2:6:3、2:6:4、2:6:5、2:6:6、2:6:7、2:6:8、2:6:9、2:6:10、2:7:1、2:7:2、2:7:3、2:7:4、2:7:5、2:7:6、2:7:7、2:7:8、2:7:9、2:7:10、2:8:1、2:8:2、2:8:3、2:8:4、2:8:5、2:8:6、2:8:7、2:8:8、2:8:9、2:8:10、2:9:1、2:9:2、2:9:3、2:9:4、2:9:5、2:9:6、2:9:7、2:9:8、2:9:9、2:9:10、2:10:1、2:10:2、2:10:3、2:10:4、2:10:5、2:10:6、2:10:7、2:10:8、2:10:9、2:10:10、3:1:1、3:1:2、3:1:3、3:1:4、3:1:5、3:1:6、3:1:7、3:1:8、3:1:9、3:1:10、3:2:1、3:2:2、3:2:3、3:2:4、3:2:5、3:2:6、3:2:7、3:2:8、3:2:9、3:2:10、3:3:1、3:3:2、3:3:3、3:3:4、3:3:5、3:3:6、3:3:7、3:3:8、3:3:9、3:3:10、3:4:1、3:4:2、3:4:3、3:4:4、3:4:5、3:4:6、3:4:7、3:4:8、3:4:9、3:4:10、3:5:1、3:5:2、3:5:3、3:5:4、3:5:5、3:5:6、3:5:7、3:5:8、3:5:9、3:5:10、3:6:1、3:6:2、3:6:3、3:6:4、3:6:5、3:6:6、3:6:7、3:6:8、3:6:9、3:6:10、3:7:1、3:7:2、3:7:3、3:7:4、3:7:5、3:7:6、3:7:7、3:7:8、3:7:9、3:7:10、3:8:1、3:8:2、3:8:3、3:8:4、3:8:5、3:8:6、3:8:7、3:8:8、3:8:9、3:8:10、3:9:1、3:9:2、3:9:3、3:9:4、3:9:5、3:9:6、3:9:7、3:9:8、3:9:9、3:9:10、3:10:1、3:10:2、3:10:3、3:10:4、3:10:5、3:10:6、3:10:7、3:10:8、3:10:9、3:10:10、4:1:1、4:1:2、4:1:3、4:1:4、4:1:5、4:1:6、4:1:7、4:1:8、4:1:9、4:1:10、4:2:1、4:2:2、4:2:3、4:2:4、4:2:5、4:2:6、4:2:7、4:2:8、4:2:9、4:2:10、4:3:1、4:3:2、4:3:3、4:3:4、4:3:5、4:3:6、4:3:7、4:3:8、4:3:9、4:3:10、4:4:1、4:4:2、4:4:3、4:4:4、4:4:5、4:4:6、4:4:7、4:4:8、4:4:9、4:4:10、4:5:1、4:5:2、4:5:3、4:5:4、4:5:5、4:5:6、4:5:7、4:5:8、4:5:9、4:5:10、4:6:1、4:6:2、4:6:3、4:6:4、4:6:5、4:6:6、4:6:7、4:6:8、4:6:9、4:6:10、4:7:1、4:7:2、4:7:3、4:7:4、4:7:5、4:7:6、4:7:7、4:7:8、4:7:9、4:7:10、4:8:1、4:8:2、4:8:3、4:8:4、4:8:5、4:8:6、4:8:7、4:8:8、4:8:9、4:8:10、4:9:1、4:9:2、4:9:3、4:9:4、4:9:5、4:9:6、4:9:7、4:9:8、4:9:9、4:9:10、4:10:1、4:10:2、4:10:3、4:10:4、4:10:5、4:10:6、4:10:7、4:10:8、4:10:9、4:10:10、5:1:1、5:1:2、5:1:3、5:1:4、5:1:5、5:1:6、5:1:7、5:1:8、5:1:9、5:1:10、5:2:1、5:2:2、5:2:3、5:2:4、5:2:5、5:2:6、5:2:7、5:2:8、5:2:9、5:2:10、5:3:1、5:3:2、5:3:3、5:3:4、5:3:5、5:3:6、5:3:7、5:3:8、5:3:9、5:3:10、5:4:1、5:4:2、5:4:3、5:4:4、5:4:5、5:4:6、5:4:7、5:4:8、5:4:9、5:4:10、5:5:1、5:5:2、5:5:3、5:5:4、5:5:5、5:5:6、5:5:7、5:5:8、5:5:9、5:5:10、5:6:1、5:6:2、5:6:3、5:6:4、5:6:5、5:6:6、5:6:7、5:6:8、5:6:9、5:6:10、5:7:1、5:7:2、5:7:3、5:7:4、5:7:5、5:7:6、5:7:7、5:7:8、5:7:9、5:7:10、5:8:1、5:8:2、5:8:3、5:8:4、5:8:5、5:8:6、5:8:7、5:8:8、5:8:9、5:8:10、5:9:1、5:9:2、5:9:3、5:9:4、5:9:5、5:9:6、5:9:7、5:9:8、5:9:9、5:9:10、5:10:1、5:10:2、5:10:3、5:10:4、5:10:5、5:10:6、5:10:7、5:10:8、5:10:9、5:10:10、6:1:1、6:1:2、6:1:3、6:1:4、6:1:5、6:1:6、6:1:7、6:1:8、6:1:9、6:1:10、6:2:1、6:2:2、6:2:3、6:2:4、6:2:5、6:2:6、6:2:7、6:2:8、6:2:9、6:2:10、6:3:1、6:3:2、6:3:3、6:3:4、6:3:5、6:3:6、6:3:7、6:3:8、6:3:9、6:3:10、6:4:1、6:4:2、6:4:3、6:4:4、6:4:5、6:4:6、6:4:7、6:4:8、6:4:9、6:4:10、6:5:1、6:5:2、6:5:3、6:5:4、6:5:5、6:5:6、6:5:7、6:5:8、6:5:9、6:5:10、6:6:1、6:6:2、6:6:3、6:6:4、6:6:5、6:6:6、6:6:7、6:6:8、6:6:9、6:6:10、6:7:1、6:7:2、6:7:3、6:7:4、6:7:5、6:7:6、6:7:7、6:7:8、6:7:9、6:7:10、6:8:1、6:8:2、6:8:3、6:8:4、6:8:5、6:8:6、6:8:7、6:8:8、6:8:9、6:8:10、6:9:1、6:9:2、6:9:3、6:9:4、6:9:5、6:9:6、6:9:7、6:9:8、6:9:9、6:9:10、6:10:1、6:10:2、6:10:3、6:10:4、6:10:5、6:10:6、6:10:7、6:10:8、6:10:9、6:10:10、7:1:1、7:1:2、7:1:3、7:1:4、7:1:5、7:1:6、7:1:7、7:1:8、7:1:9、7:1:10、7:2:1、7:2:2、7:2:3、7:2:4、7:2:5、7:2:6、7:2:7、7:2:8、7:2:9、7:2:10、7:3:1、7:3:2、7:3:3、7:3:4、7:3:5、7:3:6、7:3:7、7:3:8、7:3:9、7:3:10、7:4:1、7:4:2、7:4:3、7:4:4、7:4:5、7:4:6、7:4:7、7:4:8、7:4:9、7:4:10、7:5:1、7:5:2、7:5:3、7:5:4、7:5:5、7:5:6、7:5:7、7:5:8、7:5:9、7:5:10、7:6:1、7:6:2、7:6:3、7:6:4、7:6:5、7:6:6、7:6:7、7:6:8、7:6:9、7:6:10、7:7:1、7:7:2、7:7:3、7:7:4、7:7:5、7:7:6、7:7:7、7:7:8、7:7:9、7:7:10、7:8:1、7:8:2、7:8:3、7:8:4、7:8:5、7:8:6、7:8:7、7:8:8、7:8:9、7:8:10、7:9:1、7:9:2、7:9:3、7:9:4、7:9:5、7:9:6、7:9:7、7:9:8、7:9:9、7:9:10、7:10:1、7:10:2、7:10:3、7:10:4、7:10:5、7:10:6、7:10:7、7:10:8、7:10:9、7:10:10、8:1:1、8:1:2、8:1:3、8:1:4、8:1:5、8:1:6、8:1:7、8:1:8、8:1:9、8:1:10、8:2:1、8:2:2、8:2:3、8:2:4、8:2:5、8:2:6、8:2:7、8:2:8、8:2:9、8:2:10、8:3:1、8:3:2、8:3:3、8:3:4、8:3:5、8:3:6、8:3:7、8:3:8、8:3:9、8:3:10、8:4:1、8:4:2、8:4:3、8:4:4、8:4:5、8:4:6、8:4:7、8:4:8、8:4:9、8:4:10、8:5:1、8:5:2、8:5:3、8:5:4、8:5:5、8:5:6、8:5:7、8:5:8、8:5:9、8:5:10、8:6:1、8:6:2、8:6:3、8:6:4、8:6:5、8:6:6、8:6:7、8:6:8、8:6:9、8:6:10、8:7:1、8:7:2、8:7:3、8:7:4、8:7:5、8:7:6、8:7:7、8:7:8、8:7:9、8:7:10、8:8:1、8:8:2、8:8:3、8:8:4、8:8:5、8:8:6、8:8:7、8:8:8、8:8:9、8:8:10、8:9:1、8:9:2、8:9:3、8:9:4、8:9:5、8:9:6、8:9:7、8:9:8、8:9:9、8:9:10、8:10:1、8:10:2、8:10:3、8:10:4、8:10:5、8:10:6、8:10:7、8:10:8、8:10:9、8:10:10、9:1:1、9:1:2、9:1:3、9:1:4、9:1:5、9:1:6、9:1:7、9:1:8、9:1:9、9:1:10、9:、 2:1、9:2:2、9:2:3、9:2:4、9:2:5、9:2:6、9:2:7、9:2:8、9:2:9、9:2:10、9:3:1、9:3:2、9:3:3、9:3:4、9:3:5、9:3:6、9:3:7、9:3:8、9:3:9、9:3:10、9:4:1、9:4:2、9:4:3、9:4:4、9:4:5、9:4:6、9:4:7、9:4:8、9:4:9、9:4:10、9:5:1、9:5:2、9:5:3、9:5:4、9:5:5、9:5:6、9:5:7、9:5:8、9:5:9、9:5:10、9:6:1、9:6:2、9:6:3、9:6:4、9:6:5、9:6:6、9:6:7、9:6:8、9:6:9、9:6:10、9:7:1、9:7:2、9:7:3、9:7:4、9:7:5、9:7:6、9:7:7、9:7:8、9:7:9、9:7:10、9:8:1、9:8:2、9:8:3、9:8:4、9:8:5、9:8:6、9:8:7、9:8:8、9:8:9、9:8:10、9:9:1、9:9:2、9:9:3、9:9:4、9:9:5、9:9:6、9:9:7、9:9:8、9:9:9、9:9:10、9:10:1、9:10:2、9:10:3、9:10:4、9:10:5、9:10:6、9:10:7、9:10:8、9:10:9、9:10:10、10:1:1、10:1:2、10:1:3、10:1:4、10:1:5、10:1:6、10:1:7、10:1:8、10:1:9、10:1:10、10:2:1、10:2:2、10:2:3、10:2:4、10:2:5、10:2:6、10:2:7、10:2:8、10:2:9、10:2:10、10:3:1、10:3:2、10:3:3、10:3:4、10:3:5、10:3:6、10:3:7、10:3:8、10:3:9、10:3:10、10:4:1、10:4:2、10:4:3、10:4:4、10:4:5、10:4:6、10:4:7、10:4:8、10:4:9、10:4:10、10:5:1、10:5:2、10:5:3、10:5:4、10:5:5、10:5:6、10:5:7、10:5:8、10:5:9、10:5:10、10:6:1、10:6:2、10:6:3、10:6:4、10:6:5、10:6:6、10:6:7、10:6:8、10:6:9、10:6:10、10:7:1、10:7:2、10:7:3, 10:7:4, 10:7:5, 10:7:6, 10:7:7, 10:7:8, 10:7:9, 10:7:10, 10:8:1, 10:8:2, 10:8:3, 10:8:4, 10:8:5, 10:8:6, 10:8:7, 10:8:8, 10:8:9, 10:8:10, 10:9:1, 10:9:2, 10:9:3, 10:9:4, 10:9:5, 10:9:6, 10:9:7, 10:9:8, 10:9:9, 10:9:10, 10:10:1, 10:10:2, 10:10:3, 10:10:4, 10:10:5, 10:10:6, 10:10:7, 10:10:8, 10:10:9, or any ratio therebetween. In view of the results and discussions included herein, one of ordinary skill in the art would understand how to formulate a composition comprising two or more sleep-inducing agonists described herein to achieve the results described herein.,

[0010] In some embodiments, the compositions described herein may further comprise a sleep-inducing antagonist and / or a gallate ester. An example of a sleep-inducing antagonist is S-adenosyl L-methionine (SAMe), and an example of a gallate ester is propyl gallate. The amount of sleep-inducing antagonist in the composition is approximately 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, 250 μg, 275 μg, 300 μg, 325 μg, 350 μg, 375 μg, 400 μg, 425 μg, 450 μg, 475 μg, and 500 μg. , 525μg, 575μg, 600μg, 625μg, 650μg, 675μg, 700μg, 725μg, 750μg, 775μg, 800μg, 825μg, 850μg, 875μg, 900μg, 925μg, 950μg, 975 μg, 1000μg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100 mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 5 75mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1000m g, 1.25g, 1.5g, 1.75g, 2.0g, 2.25g, 2.5g, 2.75g, 3.0g, 3.25g, 3.5g, 3.5g, 3.75g, 4.0g, 4.25g, 4.5g, 4.75g, 5.0g, 5.25g, 5.5g, 5.75g, 6.0g, 6.25g, 6.5g, 6.75g, 7.0g, 7.25g, 7.5g, 7.75g, 8.0g, 8.25g, 8.5g, 8.75g, 9.0g, 8.25g, 9.5g, 9.75g, 10g or more,Or it may be any amount in between. The amount of gallic acid ester in the composition is approximately 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, 250 μg, 275 μg, 300 μg, 325 μg, 350 μg, 375 μg, 400 μg, 425 μg, 450 μg, 475 μg, 500 μg, 525 μg, 575 μg, 600 μg, 625 μg, 650 μg The amount may be g, 675 μg, 700 μg, 725 μg, 750 μg, 775 μg, 800 μg, 825 μg, 850 μg, 875 μg, 900 μg, 925 μg, 950 μg, 975 μg, 1000 μg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, or more, or any value in between. The amount of each sleep-inducing agonist relative to the combined amount of the sleep-inducing antagonist and gallate ester may be present in the composition described herein in a synergistic ratio. For example, in a composition comprising a combination of a first sleep-inducing agonist, a second sleep-inducing agonist, and a sleep-inducing antagonist and gallic acid ester, the synergistic effective ratio of the amount of the first sleep-inducing agonist: the amount of the second sleep-inducing agonist: the total amount of the sleep-inducing antagonist and gallic acid ester is approximately 1:1:1, 1:1:2, 1:1:3, 1:1:4, 1:1:5, 1:1:6, 1:1:7, 1:1:8, 1:1:9, 1:1:10, 1:2:1, 1:2:1.5, 1:2:1.59, 1:2: 2, 1:2:3, 1:2:4, 1:2:4.12, 1:2:5, 1:2:6, 1:2:7, 1:2:8, 1:2:9, 1:2:10, 1:3:1, 1:3:2, 1:3:3, 1:3:4, 1:3:5, 1:3:6, 1:3:7, 1:3:8, 1:3:9, 1:3:10, 1:4:1, 1:4:2, 1:4:3, 1:4:4, 1:4:5, 1:4:6, 1:4:7, 1:4:8, 1:4:9, 1:4:10, 1:5:1, 1:5:2, 1:5:3, 1:5:4, 1:5:5, 1:5:6,1:5:7、1:5:8、1:5:9、1:5:10、1:6:1、1:6:2、1:6:3、1:6:4、1:6:5、1:6:6、1:6:7、1:6:8、1:6:9、1:6:10、1:7:1、1:7:2、1:7:3、1:7:4、1:7:5、1:7:6、1:7:7、1:7:8、1:7:9、1:7:10、1:8:1、1:8:2、1:8:3、1:8:4、1:8:5、1:8:6、1:8:7、1:8:8、1:8:9、1:8:10、1:9:1、1:9:2、1:9:3、1:9:4、1:9:5、1:9:6、1:9:7、1:9:8、1:9:9、1:9:10、1:10:1、1:10:2、1:10:3、1:10:4、1:10:5、1:10:6、1:10:7、1:10:8、1:10:9、1:10:10、2:1:1、2:1:2、2:1:3、2:1:4、2:1:5、2:1:6、2:1:7、2:1:8、2:1:9、2:1:10、2:2:1、2:2:2、2:2:3、2:2:4、2:2:5、2:2:6、2:2:7、2:2:8、2:2:9、2:2:10、2:3:1、2:3:2、2:3:3、2:3:4、2:3:5、2:3:6、2:3:7、2:3:8、2:3:9、2:3:10、2:4:1、2:4:2、2:4:3、2:4:4、2:4:5、2:4:6、2:4:7、2:4:8、2:4:9、2:4:10、2:5:1、2:5:2、2:5:3、2:5:4、2:5:5、2:5:6、2:5:7、2:5:8、2:5:9、2:5:10、2:6:1、2:6:2、2:6:3、2:6:4、2:6:5、2:6:6、2:6:7、2:6:8、2:6:9、2:6:10、2:7:1、2:7:2、2:7:3、2:7:4、2:7:5、2:7:6、2:7:7、2:7:8、2:7:9、2:7:10、2:8:1、2:8:2、2:8:3、2:8:4、2:8:5、2:8:6、2:8:7、2:8:8、2:8:9、2:8:10、2:9:1、2:9:2、2:9:3、2:9:4、2:9:5、2:9:6、2:9:7、2:9:8、2:9:9、2:9:10、2:10:1、2:10:2、2:10:3、2:10:4、2:10:5、2:10:6、2:10:7、2:10:8、2:10:9、2:10:10、3:1:1、3:1:2、3:1:3、3:1:4、3:1:5、3:1:6、3:1:7、3:1:8、3:1:9、3:1:10、3:2:1、3:2:2、3:2:3、3:2:4、3:2:5、3:2:6、3:2:7、3:2:8、3:2:9、3:2:10、3:3:1、3:3:2、3:3:3、3:3:4、3:3:5、3:3:6、3:3:7、3:3:8、3:3:9、3:3:10、3:4:1、3:4:2、3:4:3、3:4:4、3:4:5、3:4:6、3:4:7、3:4:8、3:4:9、3:4:10、3:5:1、3:5:2、3:5:3、3:5:4、3:5:5、3:5:6、3:5:7、3:5:8、3:5:9、3:5:10、3:6:1、3:6:2、3:6:3、3:6:4、3:6:5、3:6:6、3:6:7、3:6:8、3:6:9、3:6:10、3:7:1、3:7:2、3:7:3、3:7:4、3:7:5、3:7:6、3:7:7、3:7:8、3:7:9、3:7:10、3:8:1、3:8:2、3:8:3、3:8:4、3:8:5、3:8:6、3:8:7、3:8:8、3:8:9、3:8:10、3:9:1、3:9:2、3:9:3、3:9:4、3:9:5、3:9:6、3:9:7、3:9:8、3:9:9、3:9:10、3:10:1、3:10:2、3:10:3、3:10:4、3:10:5、3:10:6、3:10:7、3:10:8、3:10:9、3:10:10、4:1:1、4:1:2、4:1:3、4:1:4、4:1:5、4:1:6、4:1:7、4:1:8、4:1:9、4:1:10、4:2:1、4:2:2、4:2:3、4:2:4、4:2:5、4:2:6、4:2:7、4:2:8、4:2:9、4:2:10、4:3:1、4:3:2、4:3:3、4:3:4、4:3:5、4:3:6、4:3:7、4:3:8、4:3:9、4:3:10、4:4:1、4:4:2、4:4:3、4:4:4、4:4:5、4:4:6、4:4:7、4:4:8、4:4:9、4:4:10、4:5:1、4:5:2、4:5:3、4:5:4、4:5:5、4:5:6、4:5:7、4:5:8、4:5:9、4:5:10、4:6:1、4:6:2、4:6:3、4:6:4、4:6:5、4:6:6、4:6:7、4:6:8、4:6:9、4:6:10、4:7:1、4:7:2、4:7:3、4:7:4、4:7:5、4:7:6、4:7:7、4:7:8、4:7:9、4:7:10、4:8:1、4:8:2、4:8:3、4:8:4、4:8:5、4:8:6、4:8:7、4:8:8、4:8:9、4:8:10、4:9:1、4:9:2、4:9:3、4:9:4、4:9:5、4:9:6、4:9:7、4:9:8、4:9:9、4:9:10、4:10:1、4:10:2、4:10:3、4:10:4、4:10:5、4:10:6、4:10:7、4:10:8、4:10:9、4:10:10、5:1:1、5:1:2、5:1:3、5:1:4、5:1:5、5:1:6、5:1:7、5:1:8、5:1:9、5:1:10、5:2:1、5:2:2、5:2:3、5:2:4、5:2:5、5:2:6、5:2:7、5:2:8、5:2:9、5:2:10、5:3:1、5:3:2、5:3:3、5:3:4、5:3:5、5:3:6、5:3:7、5:3:8、5:3:9、5:3:10、5:4:1、5:4:2、5:4:3、5:4:4、5:4:5、5:4:6、5:4:7、5:4:8、5:4:9、5:4:10、5:5:1、5:5:2、5:5:3、5:5:4、5:5:5、5:5:6、5:5:7、5:5:8、5:5:9、5:5:10、5:6:1、5:6:2、5:6:3、5:6:4、5:6:5、5:6:6、5:6:7、5:6:8、5:6:9、5:6:10、5:7:1、5:7:2、5:7:3、5:7:4、5:7:5、5:7:6、5:7:7、5:7:8、5:7:9、5:7:10、5:8:1、5:8:2、5:8:3、5:8:4、5:8:5、5:8:6、5:8:7、5:8:8、5:8:9、5:8:10、5:9:1、5:9:2、5:9:3、5:9:4、5:9:5、5:9:6、5:9:7、5:9:8、5:9:9、5:9:10、5:10:1、5:10:2、5:10:3、5:10:4、5:10:5、5:10:6、5:10:7、5:10:8、5:10:9、5:10:10、6:1:1、6:1:2、6:1:3、6:1:4、6:1:5、6:1:6、6:1:7、6:1:8、6:1:9、6:1:10、6:2:1、6:2:2、6:2:3、6:2:4、6:2:5、6:2:6、6:2:7、6:2:8、6:2:9、6:2:10、6:3:1、6:3:2、6:3:3、6:3:4、6:3:5、6:3:6、6:3:7、6:3:8、6:3:9、6:3:10、6:4:1、6:4:2、6:4:3、6:4:4、6:4:5、6:4:6、6:4:7、6:4:8、6:4:9、6:4:10、6:5:1、6:5:2、6:5:3、6:5:4、6:5:5、6:5:6、6:5:7、6:5:8、6:5:9、6:5:10、6:6:1、6:6:2、6:6:3、6:6:4、6、 :6:5、6:6:6、6:6:7、6:6:8、6:6:9、6:6:10、6:7:1、6:7:2、6:7:3、6:7:4、6:7:5、6:7:6、6:7:7、6:7:8、6:7:9、6:7:10、6:8:1、6:8:2、6:8:3、6:8:4、6:8:5、6:8:6、6:8:7、6:8:8、6:8:9、6:8:10、6:9:1、6:9:2、6:9:3、6:9:4、6:9:5、6:9:6、6:9:7、6:9:8、6:9:9、6:9:10、6:10:1、6:10:2、6:10:3、6:10:4、6:10:5、6:10:6、6:10:7、6:10:8、6:10:9、6:10:10、7:1:1、7:1:2、7:1:3、7:1:4、7:1:5、7:1:6、7:1:7、7:1:8、7:1:9、7:1:10、7:2:1、7:2:2、7:2:3、7:2:4、7:2:5、7:2:6、7:2:7、7:2:8、7:2:9、7:2:10、7:3:1、7:3:2、7:3:3、7:3:4、7:3:5、7:3:6、7:3:7、7:3:8、7:3:9、7:3:10、7:4:1、7:4:2、7:4:3、7:4:4、7:4:5、7:4:6、7:4:7、7:4:8、7:4:9、7:4:10、7:5:1、7:5:2、7:5:3、7:5:4、7:5:5、7:5:6、7:5:7、7:5:8、7:5:9、7:5:10、7:6:1、7:6:2、7:6:3、7:6:4、7:6:5、7:6:6、7:6:7、7:6:8、7:6:9、7:6:10、7:7:1、7:7:2、7:7:3、7:7:4、7:7:5、7:7:6、7:7:7、7:7:8、7:7:9、7:7:10、7:8:1、7:8:2、7:8:3、7:8:4、7:8:5、7:8:6、7:8:7、7:8:8、7:8:9、7:8:10、7:9:1、7:9:2、7:9:3、7:9:4、7:9:5、7:9:6、7:9:7、7:9:8、7:9:9、7:9:10、7:10:1、7:10:2、7:10:3、7:10:4、7:10:5、7:10:6、7:10:7、7:10:8、7:10:9、7:10:10、8:1:1、8:1:2、8:1:3、8:1:4、8:1:5、8:1:6、8:1:7、8:1:8、8:1:9、8:1:10、8:2:1、8:2:2、8:2:3、8:2:4、8:2:5、8:2:6、8:2:7、8:2:8、8:2:9、8:2:10、8:3:1、8:3:2、8:3:3、8:3:4、8:3:5、8:3:6、8:3:7、8:3:8、8:3:9、8:3:10、8:4:1、8:4:2、8:4:3、8:4:4、8:4:5、8:4:6、8:4:7、8:4:8、8:4:9、8:4:10、8:5:1、8:5:2、8:5:3、8:5:4、8:5:5、8:5:6、8:5:7、8:5:8、8:5:9、8:5:10、8:6:1、8:6:2、8:6:3、8:6:4、8:6:5、8:6:6、8:6:7、8:6:8、8:6:9、8:6:10、8:7:1、8:7:2、8:7:3、8:7:4、8:7:5、8:7:6、8:7:7、8:7:8、8:7:9、8:7:10、8:8:1、8:8:2、8:8:3、8:8:4、8:8:5、8:8:6、8:8:7、8:8:8、8:8:9、8:8:10、8:9:1、8:9:2、8:9:3、8:9:4、8:9:5、8:9:6、8:9:7、8:9:8、8:9:9、8:9:10、8:10:1、8:10:2、8:10:3、8:10:4、8:10:5、8:10:6、8:10:7、8:10:8、8:10:9、8:10:10、9:1:1、9:1:2、9:1:3、9:1:4、9:1:5、9:1:6、9:1:7、9:1:8、9:1:9、9:1:10、9:2:1、9:2:2、9:2:3、9:2:4、9:2:5、9:2:6、9:2:7、9:2:8、9:2:9、9:2:10、9:3:1、9:3:2、9:3:3、9:3:4、9:3:5、9:3:6、9:3:7、9:3:8、9:3:9、9:3:10、9:4:1、9:4:2、9:4:3、9:4:4、9:4:5、9:4:6、9:4:7、9:4:8、9:4:9、9:4:10、9:5:1、9:5:2、9:5:3、9:5:4、9:5:5、9:5:6、9:5:7、9:5:8、9:5:9、9:5:10、9:6:1、9:6:2、9:6:3、9:6:4、9:6:5、9:6:6、9:6:7、9:6:8、9:6:9、9:6:10、9:7:1、9:7:2、9:7:3、9:7:4、9:7:5、9:7:6、9:7:7、9:7:8、9:7:9、9:7:10、9:8:1、9:8:2、9:8:3、9:8:4、9:8:5、9:8:6、9:8:7、9:8:8, 9:8:9, 9:8:10, 9:9:1, 9:9:2, 9:9:3, 9:9:4, 9:9:5, 9:9:6, 9:9:7, 9:9:8, 9:9:9, 9:9:10, 9:10:1, 9:10:2, 9:10:3, 9:10:4, 9:10:5, 9:10:6, 9:10:7, 9:10:8, 9:10:9, 9:10:10, 10:1:1, 10:1:2, 10:1:3, 10:1:4, 10:1:5, 10:1:6, 10:1:7, 10:1:8, 10:1:9, 10:1:1 0, 10:2:1, 10:2:2, 10:2:3, 10:2:4, 10:2:5, 10:2:6, 10:2:7, 10:2:8, 10:2:9, 10:2:10, 10:3:1, 10:3:2, 10:3:3, 10:3:4, 10:3:5, 10:3:6, 10:3:7, 10:3:8, 10:3:9, 10:3:10, 10:4:1, 10:4:2, 10:4:3, 10:4:4, 10:4:5, 10:4:6, 10:4:7, 10:4:8, 10:4:9, 10:4:10, 10:5: 1, 10:5:2, 10:5:3, 10:5:4, 10:5:5, 10:5:6, 10:5:7, 10:5:8, 10:5:9, 10:5:10, 10:6:1, 10:6:2, 10:6:3, 10:6:4, 10:6:5, 10:6:6, 10:6:7, 10:6:8, 10:6:9, 10:6:10, 10:7:1, 10:7:2, 10:7:3, 10:7:4, 10:7:5, 10:7:6, 10:7:7, 10:7:8, 10:7:9, 10:7:10, 10:8:1, 10:8: The ratios may be 2, 10:8:3, 10:8:4, 10:8:5, 10:8:6, 10:8:7, 10:8:8, 10:8:9, 10:8:10, 10:9:1, 10:9:2, 10:9:3, 10:9:4, 10:9:5, 10:9:6, 10:9:7, 10:9:8, 10:9:9, 10:9:10, 10:10:1, 10:10:2, 10:10:3, 10:10:4, 10:10:5, 10:10:6, 10:10:7, 10:10:8, 10:10:9, or any of the ratios in between. In a composition comprising a combination of a first sleep-inducing agonist, a second sleep-inducing agonist, a third sleep-inducing agonist, and a sleep-inducing antagonist and a gallic acid ester,The synergistic effective ratio of the total amount of the sleep-inducing antagonist and gallate ester is approximately 1:1:1:1, 1:1:1:2, 1:1:1:3, 1:1:1:4, 1:1:1:5, 1:1:1:6, 1:1:1:7, 1:1:1:8, 1:1:1:9, 1:1:1:10, 1:2:1:1, 1:2:1:2, 1:2:2:1, 1:2:3:1, 1:2:3:1.59, 1:2:3:2, 1:2:3:3, 1:2:3:4, 1:2:3:4.125, 1:2:3:5, 1:2: The ratios may be 3:6, 1:2:3:7, 1:2:3:8, 1:2:3:9, 1:2:3:10, 1:3:1:1, 1:3:2:1, 1:3:3:1, 1:3:4:1, 1:3:5:1, 1:3:6:1, 1:3:7:1, 1:3:8:1, 1:3:9:1, 1:3:10:1, 1:2:4:1, 1:2:4:2, 1:2:4:3, 1:2:4:4, 1:2:4:5, 1:2:4:6, 1:2:4:7, 1:2:4:8, 1:2:4:9, 1:2:4:10, 1:3:1:1, 1:3:2:1, 1:3:3:1, 1:3:3:2, or any of the ratios in between. The synergistic ratio is not particularly limited. In light of the results and discussions contained herein, those skilled in the art will understand how to formulate the compositions described herein to achieve the results described herein.

[0011] In certain embodiments, the composition may also include a brain health support agent. An example of a brain health support agent is phosphatidylserine. The amount of the brain health support agent is approximately 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, 250 μg, 275 μg, 300 μg, 325 μg, 350 μg, 375 μg, 400 μg, 425 μg, 450 μg, 475 μg, 500 μg, 525 μg, 575 μg g, 600μg, 625μg, 650μg, 675μg, 700μg, 725μg, 750μg, 775μg, 800μg, 825μg, 850μg, 875μg, 900μg, 925μg, 950μg, 975μg, 1000μg, 5m g, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150m g, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 575mg, 600mg, 625 mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1000mg, 1.25g, 1.5g, 1.7 The amounts may be 5g, 2.0g, 2.25g, 2.5g, 2.75g, 3.0g, 3.25g, 3.5g, 3.5g, 3.75g, 4.0g, 4.25g, 4.5g, 4.75g, 5.0g, 5.25g, 5.5g, 5.75g, 6.0g, 6.25g, 6.5g, 6.75g, 7.0g, 7.25g, 7.5g, 7.75g, 8.0g, 8.25g, 8.5g, 8.75g, 9.0g, 8.25g, 9.5g, 9.75g, 10g, or more, or any amount in between. The amounts of each sleep-inducing agonist and brain health support agent exist in synergistic ratios.For example, the composition may include a first sleep induction agonist: a second sleep induction agonist: a third agonist: a brain health support agent in a synergistic ratio of 1:2:3:1. The amounts of each sleep induction agonist, the total amount of the sleep induction antagonist and the gallic acid ester, and the amount of the brain health support agent are also present in a synergistic ratio. For example, in a composition comprising a first sleep induction agonist, a second sleep induction agonist, a combination of a sleep induction antagonist and a gallic acid ester, and a brain health support agent, the synergistic ratio may be about 1:2:4.12:1 for the first sleep induction agonist: the second sleep induction agonist: the combination of the sleep induction antagonist and the gallic acid ester: the brain health support agent. In view of the results and discussions included herein, one of ordinary skill in the art will understand how to formulate the compositions of the present disclosure to achieve the results described herein.

[0012] In some embodiments, the compositions described herein may include a pharmaceutically acceptable excipient, carrier, or diluent. The compositions described herein can be used to improve and / or maintain the quality of healthy sleep. In some embodiments, the compositions described herein can be used to reduce sleep latency and support and / or maintain a healthy sleep cycle. In some embodiments, the composition can be used to promote deep sleep. In some embodiments, the composition can be used to enhance memory consolidation and muscle recovery.

[0013] In some embodiments, the compositions described herein are administered to a subject to promote the quality of healthy sleep. In some embodiments, the composition is administered to a subject to improve cognitive function the next day. In certain embodiments, the compositions described herein are administered to a subject to treat, improve, prevent, or reduce one or more symptoms associated with menopause. Examples of such one or more symptoms are sleep difficulties and a decrease in memory and / or concentration.

[0014] In certain embodiments, the compositions described herein are administered to subjects who have difficulty falling asleep due to caffeine in order to promote sleep. For example, the compositions described herein are administered to subjects who take a high-concentration caffeine pre-workout supplement in the evening before bedtime to induce sleep and thus maintain a healthy sleep cycle. The compositions described herein can be administered to subjects before, at the same time as, or after the ingestion of caffeine-containing beverages, foods, and / or supplements.

[0015] In certain embodiments, compositions may be formulated as single-dose dosage forms administered orally, buccally, sublingually, or otherwise to a subject. With respect to oral administration, each composition disclosed herein may be provided as a tablet, aqueous or oily suspension, dispersible powder or granule, emulsion, hard or soft capsule, syrup, elixir, or beverage. Solid dosage forms, such as tablets or capsules, may include enteric coatings. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmacoagulable compositions, such compositions may contain one or more of the following agents: sweeteners, flavorings, colorings, coatings, and preservatives. Sweeteners and flavorings enhance the palatability of the formulation. Tablets containing a complex in a miscible material with a pharmacoagulable non-toxic excipient suitable for tablet manufacture are acceptable. Pharmacoagulable vehicles, such as excipients, are compatible with other components of the formulation (and are harmless to the patient). Examples of such excipients include inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. The tablets may be uncoated or coated to slow their disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a long period. For example, delaying agents such as glyceryl monostearate or glyceryl distearate can be used alone or in combination with wax.

[0016] In certain embodiments, the compositions described herein can be formulated as separate dosage forms intended to deliver one or more components of the composition separately. For example, (i) each sleep-inducing agonist can be formulated as a separate dosage form; (ii) two types of sleep-inducing agonists can be formulated as single-dose dosage forms, and the other sleep-inducing agonist in the composition can be formulated as a single-dose dosage form separated from the two types of sleep-inducing agonist dosage forms; (iii) each sleep-inducing agonist and sleep-inducing antagonist can be formulated as a separate dosage form; (iv) a sleep-inducing agonist can be formulated as a single-dose dosage form, and the sleep-inducing antagonist and gallate ester can be formulated as a single-dose dosage form separated from the sleep-inducing agonist dosage form.

[0017] A planned delivery scheme may be employed by formulating separate dosage forms. In certain embodiments, the planned delivery scheme may deliver each sleep-inducing agonist to the subject simultaneously. In some embodiments, the planned delivery scheme may deliver each sleep-inducing agonist and sleep-inducing antagonist to the subject simultaneously. In certain embodiments, the planned delivery scheme may deliver each sleep-inducing agonist, sleep-inducing antagonist, and gallate ester to the subject simultaneously. In certain embodiments, the planned delivery scheme may deliver each component of the composition at different times, at different frequencies, and / or by different delivery routes or forms. The delivery routes and specific dosage forms used to achieve this are not particularly limited and may be any of the delivery routes or dosage forms intended herein.

[0018] Oral formulations may also be provided as hard gelatin-containing capsules or non-gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil. Aqueous suspensions may contain the complex described herein, which is mixed with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents, dispersing agents, or wetting agents, one or more preservatives, one or more colorants, one or more flavoring agents, and one or more sweeteners, such as sucrose or saccharin.

[0019] Oil suspensions can be formulated by suspending them in vegetable oils such as Aratis oil, olive oil, sesame oil, or coconut oil, or in mineral oils such as liquid paraffin. Oil suspensions may contain thickeners such as beeswax, solid paraffin, or acetyl alcohol. Sweeteners and flavorings as described above can be added to provide palatable oral formulations. These compositions can be preserved by adding antioxidants such as ascorbic acid. Dispersible powders and granules suitable for preparing aqueous suspensions by adding water can provide active ingredients in admixtures of dispersants, wetting agents, suspending agents, and one or more preservatives. Additional excipients, such as sweeteners, flavorings, and colorants, may also be present.

[0020] Syrups and elixirs may be combined with sweeteners such as glycerol, sorbitol, or sucrose. Such combinations may also contain lubricants, preservatives, flavorings, or colorings.

[0021] The use of controlled-release excipients will be readily apparent to those skilled in the pharmaceutical art in light of the disclosures contained herein, and these embodiments can be applied to nutritional foods and dietary supplements. The technologies and products of this art are variably referred to as controlled-release, sustained-release, prolonged-acting, depot, repository, delayed-acting, delayed-release, and prolonged-release; the term “controlled-release” as used herein is intended to incorporate each of the aforementioned technologies.

[0022] Many controlled-release vehicles can be used, such as biodegradable or biodegradable polymers, e.g., polylactic acid, polyglycolic acid, and regenerated collagen. Controlled-release drug delivery devices include creams, lotions, tablets, capsules, gels, microspheres, liposomes, intraocular inserts, minipumps, and other infusion devices such as pumps and syringes. Implantable or injectable polymer matrices and transdermal formulations from which the active ingredient is slowly released can be used in the manner disclosed.

[0023] Release-controlled formulations are realized by the use of polymers that can form complexes with the compositions described herein or absorb the compositions described herein. Delivery control can be achieved by selecting appropriate macromolecules such as polyesters, polyamino acids, polyvinylpyrrolidone, ethylene vinyl acetate, methylcellulose, carboxymethylcellulose, and protamine sulfate, where the concentration and method of incorporation of these macromolecules are selected to control the release of the active complex.

[0024] The release control of the active complex may be interpreted as meaning any of the sustained-release dosage forms. The following terms: continuous release, release control, delayed release, depot, sustained release, long-term release, programmed release, proportional release, delayed release, sustained, delayed, slow-acting, spaced release, sustained release, time-coat, time-release, delayed action, long-term action, laminar time action, long-acting, sustained-release drugs and long-term release, release in terms of gastric and intestinal pH levels, molecular degradation, and release based on absorption and bioavailability may be considered substantially equivalent to release control for the purposes of the disclosure of this invention.

[0025] Hydrogels dissolved in aqueous components can be prepared by copolymerization of hydrophilic monoolefin monomers such as ethylene glycol methacrylate, so that the compositions disclosed herein are gradually released over time. Matrix devices can be used in which the compositions are dispersed in a matrix of a carrier material. The carrier can be porous, nonporous, solid, semi-solid, permeable, or impermeable. Alternatively, the release of the complex can be controlled using a device comprising a central reservoir of the compositions disclosed herein, surrounded by a rate-limiting membrane. Examples of rate-limiting membranes include ethylene vinyl acetate copolymer or polybutylene terephthalate / polytetramethylene ether terephthalate. The use of silicone rubber or ethylene vinyl alcohol depots is also conceivable.

[0026] Controlled-release oral formulations can also be used. In one embodiment, the compositions described herein are incorporated into a soluble or biodegradable matrix such as a pill or lozenge. In another example, the oral formulation may be a liquid used for sublingual administration. These liquid compositions may also be in the form of a gel or paste. Hydrophilic gums such as hydroxymethylcellulose are commonly used. To assist in the tableting process, lubricants such as magnesium stearate, stearic acid, or calcium stearate may be used.

[0027] In some embodiments, a composition comprising two or more sleep-inducing agonists described herein, or a combination of a sleep-inducing antagonist and two or more sleep-inducing agonists, is administered orally 15 minutes to 2 hours before bedtime. For example, the composition may be administered 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours before bedtime, or at any time in between. The total amount of agonists or combinations of agonists and antagonists may be about 10 μg to about 10 g. For example, the amounts are approximately 10μg, 15μg, 20μg, 25μg, 30μg, 35μg, 40μg, 45μg, 50μg, 55μg, 60μg, 65μg, 70μg, 75μg, 80μg, 85μg, 90μg, 95μg, 100μg, 125μg, 150μg, 175μg, 200μg, 225μg, 2 50μg, 275μg, 300μg, 325μg, 350μg, 375μg, 400μg, 410μg, 425μg, 450μg, 475μg, 500μg g, 525μg, 575μg, 600μg, 625μg, 650μg, 675μg, 700μg, 725μg, 750μg, 775μg, 800μg, 8 25μg, 850μg, 875μg, 900μg, 925μg, 950μg, 975μg, 1000μg, 1.25g, 1.5g, 1.75g, 2.0 g, 2.25g, 2.5g, 2.75g, 3.0g, 3.25g, 3.5g, 3.5g, 3.75g, 4.0g, 4.25g, 4.5g, 4.75g, 5 It can be 0g, 5.25g, 5.5g, 5.75g, 6.0g, 6.25g, 6.5g, 6.75g, 7.0g, 7.25g, 7.5g, 7.75g, 8.0g, 8.25g, 8.5g, 8.75g, 9.0g, 8.25g, 9.5g, 9.75g, 10g, or more, or in any of those amounts.

[0028] In some embodiments, a morning blend containing a sleep-inducing antagonist is first administered orally to the subject in the morning, followed by the oral administration of a composition containing two or more sleep-inducing agonists as described herein, 15 minutes to 2 hours before bedtime. For example, the two or more sleep-inducing agonists may be administered at 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours before bedtime, or at any time in between. The morning blend may contain caffeine and herbs / substances associated with mental alertness, such as taurine, ginseng root extract, L-carnitine, L-tartrate, guarana seed extract, quercetin, branched-chain amino acids, ginkgo biloba, milk thistle, inositol, acai berry, yerba mate, glucuronolactone, vitamin A, vitamin B, vitamin C, vitamin E, selenium, or any combination thereof. The morning blend not only promotes daytime concentration and cognitive function, but also enhances the effects of sleep-inducing agonists, thus promoting deep sleep.

[0029] The amount of sleep-inducing antagonist in the morning blend may preferably be about 10 μg to 10 g once a day. For example, the amounts may be 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, 25 μg 0μg, 275μg, 300μg, 325μg, 350μg, 375μg, 400μg, 410μg, 425μg, 450μg, 475μg, 500μg g, 525μg, 575μg, 600μg, 625μg, 650μg, 675μg, 700μg, 725μg, 750μg, 775μg, 800μg, 8 25μg, 850μg, 875μg, 900μg, 925μg, 950μg, 975μg, 1000μg, 1.25g, 1.5g, 1.75g, 2.0 g, 2.25g, 2.5g, 2.75g, 3.0g, 3.25g, 3.5g, 3.5g, 3.75g, 4.0g, 4.25g, 4.5g, 4.75g, 5 The amount can be 0.0g, 5.25g, 5.5g, 5.75g, 6.0g, 6.25g, 6.5g, 6.75g, 7.0g, 7.25g, 7.5g, 7.75g, 8.0g, 8.25g, 8.5g, 8.75g, 9.0g, 8.25g, 9.5g, 9.75g, 10g, or more, or in between. The total amount of sleep-inducing agonist taken before bedtime can be approximately 10μg to 10g.For example, the amounts are 10μg, 15μg, 20μg, 25μg, 30μg, 35μg, 40μg, 45μg, 50μg, 55μg, 60μg, 65μg, 70μg, 75μg, 80μg, 85μg, 90μg, 95μg, 100μg, 125μg, 150μg, 175μg, 200μg, 225μg, 25 0μg, 275μg, 300μg, 325μg, 350μg, 375μg, 400μg, 410μg, 425μg, 450μg, 475μg, 500μg g, 525μg, 575μg, 600μg, 625μg, 650μg, 675μg, 700μg, 725μg, 750μg, 775μg, 800μg, 8 25μg, 850μg, 875μg, 900μg, 925μg, 950μg, 975μg, 1000μg, 1.25g, 1.5g, 1.75g, 2.0 g, 2.25g, 2.5g, 2.75g, 3.0g, 3.25g, 3.5g, 3.5g, 3.75g, 4.0g, 4.25g, 4.5g, 4.75g, 5 It can be 0g, 5.25g, 5.5g, 5.75g, 6.0g, 6.25g, 6.5g, 6.75g, 7.0g, 7.25g, 7.5g, 7.75g, 8.0g, 8.25g, 8.5g, 8.75g, 9.0g, 8.25g, 9.5g, 9.75g, 10g, or more, or in any of those amounts.

[0030] In certain embodiments, the composition may be administered daily, every two days, every three days, every four days, every five days, every six days, weekly, every eight days, every nine days, every ten days, every two weeks, monthly, or more or less frequently, as necessary to achieve the desired therapeutic effect.

[0031] The composition may be administered to the subject in a single dose or over a series of treatments, and may be administered to the subject at any point in time after diagnosis. The composition may be administered as a single treatment or in combination with drugs or therapies useful for treating the condition.

[0032] As used herein, the terms “prevent” and “prevent” may mean treating an object that is susceptible to or at risk of developing a particular disease or condition, even though it does not yet exhibit symptoms of the disease or condition, thereby reducing the likelihood that the patient will develop the disease or condition. As used herein, the terms “treatment,” “treatment,” etc., are used herein to generally mean obtaining a desired pharmacological and physiological effect, and may also mean the effect of a nutritional agent or nutritional supplement, the scope and meaning of which will be apparent to those skilled in the art based on the context in which these terms are used. The effect may be preventive in that it prevents or partially prevents the disease, symptoms, or condition, and / or therapeutic in that it may partially or completely cure the disease, condition, symptoms, or adverse effects resulting from the disease. As used herein, the term “treatment” encompasses the treatment of any disease in mammals, particularly humans, and includes (a) preventing the disease from occurring in a subject susceptible to the disease but not yet diagnosed with it; (b) suppressing the disease or preventing its onset; or (c) reducing the disease, causing regression of the disease and / or its symptoms, pathology, and comorbidities. In some embodiments, the compositions described herein may be administered to maintain healthy levels of a particular condition or biomarker in a subject, for example, to maintain healthy levels of sleep duration and / or sleep quality. Any composition administered for the prevention, treatment, reduction, or improvement of any pathology as described herein may be administered to maintain healthy levels of a physiological or biological condition. In certain embodiments, a composition is administered to maintain healthy levels of one or more of the conditions disclosed herein. The scope and meaning of “prevent,” “treat,” “treat,” “reduce,” “improve,” and “maintain healthy levels of” will be immediately apparent to those skilled in the art, given the context of this disclosure and the terms in the claims."Pharmaceutical preparation," "preparation," "composition," etc., may mean a preparation that takes such a form in order to enable the biological activity of an active ingredient, and therefore may be administered to a subject for therapeutic use in conjunction with the use of dietary supplements and / or nutritional supplements. The meanings of these terms will be obvious to those skilled in the art based on the context in which they are used.

[0033] The disclosure of “ratios” of compounds and compositions provided herein corresponds to the ratio provided with respect to the mass of the components present in that ratio. As used herein, the term “excipient material” means any compound that is not an active ingredient, i.e., a part of a formulation that does not have relevant biological activity, and is added to the formulation to provide specific properties to the dosage form, such as, for example, providing protection for the active ingredient from chemical degradation, or facilitating the release of tablets or capsules from the apparatus in which they are formed.

[0034] As used herein, the term “subject” means an organism that can be treated with the compositions described herein, including human children and human adults having attention-deficit / hyperactivity disorder (ADHD).

[0035] As used herein, the terms “ingredient” and “ingredients” mean, but are not limited to, each active ingredient such as sleep-inducing agonists, sleep-inducing antagonists, gallates, and brain support agents as described herein.

[0036] To provide a more concise explanation, some of the quantitative expressions given herein are not modified by the term “approximately.” Whether explicitly used or not, all quantities given herein refer to an actual given value and are understood to also refer to an approximation of such given value that would be reasonably inferred on the basis of those skilled in the art, for example, an approximation of such given value due to experimental and / or measurement conditions. [Examples]

[0037] Deep sleep provides specific physical and mental benefits and is an indicator of healthy sleep quality. Agonists of GABAA receptors, GABAB receptor 1, GABAB receptor 2, GluA1 receptor, GluN1 receptor, GluN2A receptor, and / or 5-HTA1 induce deep sleep. Deep sleep can be represented by long sleep duration, short sleep latency, high electroencephalogram (EEG) amplitude, and low EEG frequency.

[0038] Example 1 Preclinical studies were conducted to evaluate the efficacy of six exemplary compositions by measuring GABAA receptor 2, GABAB receptor 1, GABAB receptor 2, GluA1, GluN1, GluN2A, 5-HTA1, EEG amplitude, EEG frequency, sleep duration, and sleep latency (see Table 1 below).

[0039] Five male BALB / c mice (age: 8 weeks; weight: 180±20g) were housed in a controlled environment with a 12:12 light-dark cycle at 22°C, and the mice were given free access to solid feed and water. The mice were fasted for 24 hours prior to the study, which was conducted between 1 PM and 5 PM, under the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals, as approved by the Ethics Committee of Medipol University. The mice were divided into eight groups, anesthetized with urethane (1.25 g / kg, intraperitoneal; Sigma U2500), and carefully fixed to a stereotactic frame. Rectal temperature was maintained at 36.5–37.0°C using a feedback-controlled heating device (507221F, Harvard Apparatus, ABD). Lidocaine (2.0%) was applied to the incision site to prevent pain. The skin was incised along the midline, following the sagittal suture of the skull. A portion of the skull above the left parietal cortex was removed using a dental drill. An Ag-AgCl ball electrode was placed in the left somatomotor cortex (1 mm anterior to the bregma / 1.5 mm lateral to the bregma; 3 mm posterior to the bregma / 1.5 mm lateral to the bregma), and a reference electrode was attached to the left foot for ECoG recording. Group 1 was treated with saline. To induce sleep disturbance, groups 2-8 were intraperitoneally injected with 7.5 mg / kg of caffeine at 15 minutes after recording, and at 30 minutes, groups 2-8 were injected with saline and each of the six compositions, respectively. The compositions were dissolved in distilled water, and the concentration of each resulting solution was adjusted so that the injection volume remained constant at 1.0 ml / kg body weight.

[0040] After administration, mice were placed in individual cages and subjected to measurements of sleep latency and sleep duration. Brain electrical activity was monitored and recorded for a total of 2 hours. A Power Lab system (16 / 30, AD Instruments, Castle Hill, Australia) was used to sample the signal at 1000 Hz with a bandpass filter set to 0.5–500 Hz. EEG frequency and amplitude were determined using LabChart 8.1.17 software (AD Instruments, New South Wales, Australia).

[0041] Two hours later, the mice were sacrificed under deep anesthesia. The brains were removed, and protein concentrations were determined using Western blotting. 50 μg of protein was electrophoresed on a 4–15% tris-glycine polyacrylamide gel, transferred to an Immobilon-P PVDF membrane, blocked in 5% skim milk for 1 hour, and incubated overnight at 4°C with GABAA receptor 2, GABAB receptor 1, GABAB receptor 2, GluA1, GluN1, GluN2A, or 5-HTA1. The membrane was then incubated with horseradish peroxidase (HRP)-conjugated IgG secondary antibody. Bands were quantified using imaging software and normalized to actin as a loading control. Data were analyzed using the GLM procedure in SAS and presented as mean ± SEM. Five sample sizes / treatment were calculated based on a power of 85% and a p-value of 0.05. Treatments were compared using ANOVA and Student's unpaired t-test, and a P<0.05 was considered statistically significant.

[0042] The results are shown in Figures 1A to 1K.

[0043] [Table 1]

[0044] Figure 1A shows that in mice treated with caffeine, the percentage of GABAA receptor 2 was significantly reduced from 100% to approximately 25%, and in mice treated with combo 1, combo 2, combo 3, combo 4, combo 5, and combo 6, the percentage of GABAA receptor 2 was reduced from 100% to approximately 55%, from 100% to approximately 75%, from 100% to approximately 35%, from 100% to approximately 40%, from 100% to approximately 60%, and from 100% to approximately 78%, respectively.

[0045] Figure 1B shows that, compared to mice treated with combo 1, combo 2, combo 3, combo 4, combo 5, and combo 6, in which the percentage of GABAB receptor 1 was reduced from 100% to approximately 50%, 100% to approximately 78%, 100% to approximately 35%, 100% to approximately 42%, 100% to approximately 58%, and 100% to approximately 80%, respectively, caffeine-treated mice showed a significant reduction in the percentage of GABAB receptor 1 from 100% to approximately 18%. Figure 1C shows that in mice treated with caffeine, the percentage of GABAA receptor 2 was significantly reduced from 100% to approximately 28%, while in mice treated with combo 1, combo 2, combo 3, combo 4, combo 5, and combo 6, the percentage of GABAA receptor 2 was reduced from 100% to approximately 56%, 100% to approximately 75%, 100% to approximately 40%, 100% to approximately 45%, 100% to approximately 58%, and 100% to approximately 78%, respectively.

[0046] Figure 1D shows that in mice treated with caffeine, the percentage of GluA1 receptors was significantly reduced from 100% to approximately 26%, and in mice treated with combo 1, combo 2, combo 3, combo 4, combo 5, and combo 6, the percentage of GluA1 receptors was reduced from 100% to approximately 70%, 100% to approximately 82%, 100% to approximately 40%, 100% to approximately 50%, 100% to approximately 65%, and 100% to approximately 90%, respectively.

[0047] Figure 1E shows that in mice treated with caffeine, the percentage of GluN1 receptors was significantly reduced from 100% to approximately 35%, and in mice treated with combo 1, combo 2, combo 3, combo 4, combo 5, and combo 6, the percentage of GluN1 receptors was reduced from 100% to approximately 55%, from 100% to approximately 70%, from 100% to approximately 38%, from 100% to approximately 45%, from 100% to approximately 58%, and from 100% to approximately 78%, respectively.

[0048] Figure 1F shows that, compared to mice treated with combo 1, combo 2, combo 3, combo 4, combo 5, and combo 6, in which the percentage of GluA1 receptors was reduced from 100% to approximately 45%, 100% to approximately 78%, 100% to approximately 30%, 100% to approximately 42%, 100% to approximately 50%, and 100% to approximately 80%, respectively, the percentage of GluN2A receptors was significantly reduced from 100% to approximately 20% in mice treated with caffeine.

[0049] Figure 1G shows that, compared to mice treated with combo 1, combo 2, combo 3, combo 4, combo 5, and combo 6, in which the percentage of 5-HT1A receptors was reduced from 100% to approximately 50%, 100% to approximately 75%, 100% to approximately 35%, 100% to approximately 40%, 100% to approximately 55%, and 100% to approximately 90%, respectively, caffeine-treated mice showed a significant reduction in the percentage of 5-HT1A receptors from 100% to approximately 20%.

[0050] In short, the data shown in Figures 1A-1G demonstrate that the compositions described herein can beneficially counteract / reverse the effects of caffeine and thus induce deep sleep. The compositions described herein offer unexpectedly superior benefits, inducing deep sleep even when the subject has ingested or used stimulants such as caffeine.

[0051] Figure 1H shows that the EEG amplitude in caffeine-treated mice decreased dramatically from approximately 100 mV to approximately 70 mV within 75 minutes, while in mice treated with a combination of caffeine and any one of the six exemplary compositions, the EEG amplitude increased from 100 mV to at least 110 mV. Figure 1I shows that the EEG frequency in caffeine-treated mice increased significantly from approximately 100 spikes to approximately 200 spikes in 90 minutes, and that the EEG frequency in mice treated with a combination of caffeine and any one of the six exemplary compositions not only did not show the increase that would be expected for caffeine administration, but its spikes were actually significantly different from the EEG frequency that decreased from approximately 100 spikes to at least approximately 90 spikes. These unexpectedly superior results further demonstrate that the compositions described herein counteract the effects of caffeine and thus promote deep sleep.

[0052] Figure 1J shows that the sleep duration in mice treated with any one of the six exemplary compositions ranged from approximately 70 to 85 minutes, which was unexpectedly significantly longer than the sleep duration of approximately 50 minutes in mice treated with pentobarbital. Figure 1K shows that the sleep latency in mice treated with any one of the six exemplary compositions ranged from 1.4 to 1.6 minutes, which was considerably shorter than the sleep latency of approximately 2 minutes in mice treated with pentobarbital. These results demonstrate that the compositions described herein are unexpectedly superior in increasing sleep duration compared to pentobarbital, a known drug for treating insomnia.

[0053] Example 2 In a separate preclinical study, the two exemplary compositions described herein were evaluated for their effects on deep sleep, compared to a combination of magnesium glycinate (a magnesium salt that reduces nervous system excitability), L-theanine (an amino acid that improves sleep quality), GABA (a substance that promotes relaxation), and SAMe (a substance that increases energy) with propyl gallate (an antioxidant).

[0054] Female ovariectomized mice were divided into 8 groups and treated for 1 to 3 weeks. Daily, Group 1 was treated with physiological saline as a control; Group 2 was treated with caffeine 7.5 mg / kg and physiological saline; Group 3 was treated with caffeine 7.5 mg / kg and magnesium glycinate HED 100 mg; Group 4 was treated with caffeine 7.5 mg / kg and L-theanine HED 200 mg; Group 5 was treated with caffeine 7.5 mg / kg and GABA HED 300 mg; and caffeine 7.5 mg / kg, SAMe HED 150 mg, and Group 6 was treated with 9 mg of propyl gallate HED; Group 7 was treated with 7.5 mg / kg of caffeine, 100 mg of magnesium glycinate HED, 200 mg of L-theanine HED, and 300 mg of GABA HED; and Group 8 was treated with 7.5 mg / kg of caffeine, 100 mg of magnesium glycinate HED, 200 mg of L-theanine HED, 300 mg of GABA HED, 150 mg of SAMe HED, and 9 mg of propyl gallate HED. EEG amplitude, EEG frequency, sleep duration, sleep latency, and percentage of GABAA receptor 2, percentage of GABAB receptor 1, percentage of GABAB receptor 2, percentage of GluA1, percentage of GluN1, and percentage of GluN2A were measured according to the procedures described in Examples 1 and 2. Melatonin levels were measured using an ELISA kit. The results are shown in Figures 2A to 2K.

[0055] Figure 2A shows that between 45 and 90 minutes, the EEG amplitude in group 8 was approximately 180 mV, which was unexpectedly significantly higher than that of groups 1-6, which had EEG amplitudes in the range of approximately 90-130 mV. Furthermore, the EEG amplitude of group 7 was approximately 135 mV, which was still higher than that of groups 1-6.

[0056] Figure 2B shows that between 45 and 90 minutes, the EEG frequencies in Group 7 and Group 8 were approximately 80 and 50 spikes, respectively, which were unexpectedly much lower than the range of 100 to 250 spikes for Groups 1-6.

[0057] Figure 2C shows that the sleep durations for Group 7 and Group 8 were approximately 72 minutes and 80 minutes, respectively, which were unexpectedly much longer than the sleep durations for Groups 1-6, which ranged from 40 to 69 minutes.

[0058] Figure 2D shows that the sleep latency for Group 7 and Group 8 was approximately 2.6 minutes and 2.5 minutes, respectively, which was unexpectedly much shorter than the sleep latency for Groups 1-6, which ranged from 2.8 to 4.2 minutes.

[0059] Figure 2E shows that melatonin levels in Group 7 and Group 8 were approximately 16 pg / ml and 19 pg / ml, respectively, which were unexpectedly much higher than the melatonin levels in Groups 1-6, which ranged from approximately 7 to 14 pg / ml.

[0060] Figure 2F shows that the percentage of GABAA receptor 2 in group 8 was approximately 275%, which was unexpectedly much higher than the percentages in groups 1-6, which ranged from approximately 100-225%.

[0061] Figure 2G shows that the percentages of GABAB receptor 1 in groups 7 and 8 were approximately 240% and 300%, respectively, which were unexpectedly much higher than the percentages in groups 1-6, which ranged from approximately 60% to 210%.

[0062] Figure 2H shows that the percentages of GABAB receptor 2 in groups 7 and 8 were approximately 200% and 260%, respectively, which were unexpectedly much higher than the percentages in groups 1-6, which ranged from approximately 55% to 180%.

[0063] Figure 2I shows that the percentages of GluA1 receptors in Group 7 and Group 8 were approximately 210% and 240%, respectively, which were unexpectedly much higher than the percentages in Groups 1-6, which ranged from approximately 60% to 180%.

[0064] Figure 2J shows that the percentage of GluN1 receptors in group 8 was approximately 220%, which was unexpectedly much higher than the percentages in groups 1-6, which ranged from approximately 70% to 155%.

[0065] Figure 2K shows that the percentage of GluN2A receptors in group 8 was approximately 180%, which was unexpectedly much higher than the percentages in groups 1-6, which ranged from approximately 60% to 150%.

[0066] In short, the results shown in Figures 2A-2K demonstrate that the compositions described herein are unexpectedly superior to magnesium, L-theanine, GABA, and SAMe alone in inducing deep sleep.

[0067] Example 3 A comparative study was conducted to evaluate the effects of exemplary compositions containing 100 mg of magnesium glycinate HED, 200 mg of L-theanine HED, 300 mg of GABA HED, 150 mg of SAMe HED, and 9 mg of propyl gallate HED on female OVX mice and male mice.

[0068] Both female and male OVX mice were divided into three groups: one group treated with physiological saline, one group treated with 7.5 mg / kg of caffeine, and one group treated with a combination of 7.5 mg / kg of caffeine and a composition of magnesium glycinate, L-theanine, GABA, SAMe, and propyl gallate. After 2 hours, the mice were sacrificed under deep anesthesia and their brains were removed. Serum melatonin levels were measured using an ELISA kit. The results are shown in Figure 3.

[0069] Figure 3 shows that (i) melatonin levels in OVX mice treated with caffeine decreased from approximately 11 pg / ml to approximately 8 pg / ml, while melatonin levels in OVX mice treated with caffeine and a composition of magnesium glycinate, L-theanine, GABA, SAMe, and propyl gallate increased from approximately 11 pg / ml to approximately 19 pg / ml, and (ii) melatonin levels in male mice treated with caffeine dramatically decreased from approximately 33 pg / ml to approximately 12 pg / ml, while melatonin levels in these mice treated with caffeine and a composition of magnesium glycinate, L-theanine, GABA, SAMe, and propyl gallate decreased from approximately 33 pg / ml to approximately 18 pg / ml.

[0070] Data demonstrate that the components of magnesium glycinate, L-theanine, GABA, SAMe, and propyl gallate are effective in inducing sleep in men and menopausal women, and are more effective in menopausal women. As mentioned above, women are generally at a considerably higher risk of insomnia and poor sleep quality than men, and menopausal women have worse sleep quality than pre-menopausal and post-menopausal women. Therefore, based on the results obtained from the administration of the composition of the present invention, it can be easily concluded that this composition is also very effective in inducing deep sleep in pre-menopausal and post-menopausal women.

[0071] Example 4 A randomized, double-blind, placebo-controlled, parallel-group trial was conducted to evaluate the efficacy of the composition described herein in terms of its effect on sleep compared to placebo. The composition contains 150 mg of SAMe, 9.0 mg of propyl gallate, 300 mg of GABA, 200 mg of theanine, and 100 mg of magnesium glycinate, while the placebo contains plant-derived raw materials of microcrystalline cellulose, stearic acid, sodium starch glycolate, and magnesium stearate coated with Plasacryl T20.

[0072] A total of 112 menopausal and pre-menopausal women aged 40–65 years were enrolled in the study. Prior to enrollment, participants were screened for eligibility ("De Facto Visit 1"); that is, participants were otherwise essentially healthy but had difficulty sleeping (e.g., difficulty falling asleep, sleeping through the night, and falling back asleep). During screening, each participant's medical information was verified for accuracy. If deemed eligible, the study procedure was explained to the participants, they completed all questionnaires, and a final study visit ("De Facto Visit 2") was scheduled. Participants were then randomly divided into two groups: an active treatment group and a control group. From day 9 after De Facto Visit 1, the active treatment group received the composition orally daily about 60 minutes before bedtime for three weeks, while the control group received a placebo orally. From day 1 to day 9 of De Facto Visit 1, participants completed the initial set of questionnaires, which were used as baseline and then every seven days thereafter. On the day of the de facto visit 2, participants completed the final questionnaire, and medical information was reviewed to confirm that there had been no significant changes during the study period. The questionnaire included sleep duration, as well as whether the supplement (composition or placebo) helped to speed up falling asleep and falling back asleep. Episodes of irritable sleep deprivation were assessed using the questionnaire described in the Patient Reported Outcome Measurement Information System Sleep-Related Disorders Reduced Version (PROMIS SRI SF). The results are shown in 4A–4C.

[0073] Figure 4A shows that the group experienced a significant increase in sleep duration of approximately 33 minutes compared to baseline, which was unexpectedly longer than the group that took the composition for three weeks and then a placebo, resulting in only about a 13-minute increase in sleep duration compared to baseline. Figure 4B shows that after taking the composition for three weeks, the group experienced a significant reduction of approximately 41% in irritable sleep deprivation episodes compared to baseline, compared to the placebo group, which experienced only about a 27% reduction in irritable sleep deprivation episodes compared to baseline. The results shown in Figures 4A and 4B demonstrate that the composition described herein is effective in improving sleep quality in both menopausal and pre- and post-menopausal women.

[0074] Figure 4C shows the effectiveness of the product in menopausal women three weeks after taking the composition, compared to a placebo. When asked whether the supplement helped them fall asleep faster and, if they did not wake up, whether it helped them fall back asleep faster, the active treatment group agreed, while the placebo group reported no change or disagreed.

[0075] Example 5 Clinical trials will be conducted to evaluate the efficacy and safety of the compositions described herein in inducing deep sleep in women.

[0076] SAMe 150 mg and propyl gallate 4.7 mg are formulated into a single tablet containing microcrystalline cellulose, magnesium stearate, water, and titanium dioxide as inactive ingredients. GABA 150 mg, L-theanine 100 mg, and magnesium glycinate 100 mg are formulated into a single capsule containing magnesium stearate, silicon dioxide, microcrystalline cellulose, and gelatin as inactive ingredients.

[0077] A total of 60 women will be enrolled in three study groups. Group 1 will take one tablet with approximately 226g (8 ounces) of liquid at approximately the same time each day in the morning on an empty stomach, and two capsules with approximately 226g (8 ounces) of liquid 60 minutes before bedtime; Group 2 will take one capsule and two capsules with approximately 226g (8 ounces) of liquid 60 minutes before bedtime; Group 3 will take two capsules with approximately 226g (8 ounces) of liquid 60 minutes before bedtime. Each group will take their assigned study product from day 1 to day 29. Each participant will be provided with a heart rate and / or sleep monitor, such as a wearable device like WhooP® 4.0, to wear all day, every day.

[0078] Effectiveness is determined by sleep parameters, sleep quality, daytime sleepiness, and quality of life. Sleep parameters include total sleep time (TST), total wake time (TWT), sleep latency (SLO), light sleep (LS[N1+N2]), deep sleep (DL[N3]), rapid eye movement (REM), sleep efficiency (SE), wake time (WASO), sleep disturbances, and napping. These parameters are assessed by heart rate and / or sleep monitors, such as wearable devices like Whoop® 4.0, and by morning and evening sleep logs. Sleep quality is assessed by the change from baseline in scores on the Patient Reported Outcome Measurement Information System Sleep-Related Disorders Reduced Version (PROMIS SD SF) and the Visual Analog Scale (VAS) Sleep Quality Questionnaire. Daytime sleepiness is determined by the change from baseline in the Karolinska Sleepiness Scale (KSS) score, which is assessed daily upon waking, at 11:00 a.m., 3:00 p.m., and 7:00 p.m. Quality of life is determined by the change from baseline in the Menopausal Quality of Life (MENQOL) score.

[0079] The safety of the composition is evaluated based on reports of adverse events. Example 6 Further clinical trials will be conducted to evaluate the efficacy and safety of the compositions described herein in inducing deep sleep in women.

[0080] Magnesium stearate 100 mg, L-theanine 200 mg, GABA 300 mg, SAMe 400 mg, and propyl gallate 12.5 mg are formulated into a single tablet containing microcrystalline cellulose, magnesium stearate, water, and titanium dioxide as inactive ingredients. Magnesium stearate 100 mg, L-theanine 200 mg, GABA 300 mg, SAMe 400 mg, propyl gallate 12.5 mg, and phosphatidylserine 100 mg are formulated into a single capsule containing magnesium stearate, silicon dioxide, microcrystalline cellulose, and gelatin as inactive ingredients.

[0081] A total of 60 women will be enrolled in one of three research groups. Group 1 will take one tablet with approximately 226g (8 ounces) of liquid at approximately the same time each day in the morning on an empty stomach, and two capsules with approximately 226g (8 ounces) of liquid 60 minutes before bedtime; Group 2 will take one capsule and two capsules with approximately 226g (8 ounces) of liquid 60 minutes before bedtime; Group 3 will take two capsules with approximately 226g (8 ounces) of liquid 60 minutes before bedtime. Each group will take their assigned test product from day 1 to day 29. Each participant will be provided with a heart rate and / or sleep monitor, such as a wearable device like WhooP® 4.0, to wear all day, every day.

[0082] Effectiveness is determined by sleep parameters, sleep quality, daytime sleepiness, and quality of life. Sleep parameters include total sleep time (TST), total wake time (TWT), sleep latency (SLO), light sleep (LS[N1+N2]), deep sleep (DL[N3]), rapid eye movement (REM), sleep efficiency (SE), wake time (WASO), sleep disturbances, and napping. These parameters are assessed by heart rate and / or sleep monitors, such as wearable devices like WhooP® 4.0, and by morning and evening sleep logs. Sleep quality is assessed by the change from baseline in scores on the Patient Reported Outcome Measurement Information System Sleep-Related Disorders Reduced Version (PROMIS SD SF) and the Visual Analog Scale (VAS) Sleep Quality Questionnaire. Daytime sleepiness is determined by the change from baseline in the Karolinska Sleepiness Scale (KSS) score, which is assessed daily upon waking, at 11:00 a.m., 3:00 p.m., and 7:00 p.m. Quality of life is determined by the change from baseline in the Menopausal Quality of Life (MENQOL) score.

[0083] The safety of the composition is evaluated based on reports of adverse events. Although the present invention is described in some detail for the purposes of clarity and understanding, it will be understood that various modifications of form and detail can be made without departing from the true scope of the invention.

Claims

1. A composition for promoting healthy sleep quality, containing two or more sleep-inducing agonists.

2. The composition according to claim 1, further comprising a sleep-inducing antagonist.

3. The composition according to claim 1, wherein the two or more sleep-inducing agonists include a first sleep-inducing agonist and a second sleep-inducing agonist, and the first sleep-inducing agonist is different from the second sleep-inducing agonist.

4. The composition according to claim 3, wherein the first sleep-inducing agonist is L-theanine and the second sleep-inducing agonist is a magnesium salt.

5. The composition according to claim 4, wherein the magnesium salt is magnesium glycinate.

6. The composition according to claim 4, further comprising a third sleep-inducing agonist.

7. The composition according to claim 6, wherein the third sleep-inducing agonist is γ-aminobutyric acid (GABA).

8. The composition according to claim 7, further comprising a brain health support agent.

9. The composition according to claim 8, wherein the brain health support agent is phosphatidylserine.

10. The composition according to claim 7, further comprising a combination of a sleep-inducing antagonist and a gallic acid ester.

11. The composition according to claim 10, wherein the sleep-inducing antagonist is S-adenosyl L-methionine (SAMe), and the gallic acid ester is propyl gallate.

12. The composition according to claim 11, further comprising a brain health support agent.

13. The composition according to claim 12, wherein the brain health support agent is phosphatidylserine.

14. The composition according to claim 4, further comprising a combination of a sleep-inducing antagonist and a gallic acid ester.

15. The composition according to claim 14, wherein the sleep-inducing antagonist is SAMe and the gallic acid ester is propyl gallate.

16. The composition according to claim 15, further comprising a brain health support agent.

17. The composition according to claim 16, wherein the brain health support agent is phosphatidylserine.

18. The composition according to claim 2, wherein the sleep-inducing antagonist is SAMe.

19. The composition according to claim 18, further comprising a brain health support agent.

20. The composition according to claim 19, wherein the brain health support agent is phosphatidylserine.

21. The composition according to claim 7, wherein the amount of the magnesium salt, the amount of L-theanine, and the amount of GABA are present in a synergistic effective ratio.

22. The composition according to claim 21, wherein the synergistic effect ratio is approximately 1:2:3 of the magnesium salt:L-theanine:GABA, respectively.

23. The composition according to claim 9, wherein the amount of the magnesium salt, the amount of L-theanine, the amount of GABA, and the amount of phosphatidylserine are present in a synergistic ratio.

24. The composition according to claim 23, wherein the synergistic ratio is approximately 1:2:3:1 of the magnesium salt:L-theanine:GABA:phosphatidylserine, respectively.

25. The composition according to claim 11, wherein the amount of the magnesium salt, the amount of L-theanine, the amount of GABA, and the total amount of SAMe and propyl gallate are present in a synergistic effective ratio.

26. The composition according to claim 25, wherein the synergistic ratio is approximately 1:2:3:4.12 for each combination of magnesium salt:L-theanine:GABA:SAMe and propyl gallate.

27. The composition according to claim 13, wherein the amount of the magnesium salt, the amount of L-theanine, the amount of GABA, the total amount of SAMe and propyl gallate, and the amount of phosphatidylserine are present in a synergistic effective ratio.

28. The composition according to claim 27, wherein the synergistic ratio is approximately 1:2:3:4.125:1 of the magnesium salt:L-theanine:GABA:SAMe and propyl gallate combination:phosphatidylserine, respectively.

29. The composition according to claim 15, wherein the amount of the magnesium salt, the amount of L-theanine, and the total amount of SAMe and propyl gallate are present in a synergistic effective ratio.

30. The composition according to claim 29, wherein the synergistic ratio is approximately 1:2:4.125 for each combination of magnesium salt:L-theanine:SAMe and propyl gallate.

31. The composition according to claim 17, wherein the amount of the magnesium salt, the amount of L-theanine, the total amount of SAMe and propyl gallate, and the amount of phosphatidylserine are present in a synergistic effective ratio.

32. The composition according to claim 31, wherein the synergistic ratio is approximately 1:2:4.125:1 of the magnesium salt:L-theanine:combination of SAMe and propyl gallate:phosphatidylserine, respectively.

33. A composition that promotes healthy sleep quality, comprising a first sleep-inducing agonist, a second sleep-inducing agonist, and a third sleep-inducing agonist, wherein the first sleep-inducing agonist, the second sleep-inducing agonist, and the third sleep-inducing agonist are different from each other.

34. A method for promoting healthy sleep quality in a subject, comprising administering a sleep-inducing composition containing three types of sleep-inducing agonists to the subject before bedtime.

35. The method according to claim 34, wherein the three types of sleep-inducing agonists are GABA, L-theanine, and magnesium glycinate.

36. The method according to claim 35, wherein the amounts of GABA, L-theanine, and magnesium glycinate are 150 mg, 100 mg, and 10 mg, respectively.

37. A method for promoting healthy sleep quality in a subject, comprising administering to the subject a composition containing one type of sleep-inducing antagonist and three types of sleep-inducing agonists before bedtime.

38. The method according to claim 37, further comprising a gallic acid ester.

39. The method according to claim 38, wherein the sleep-inducing antagonist is SAMe, the gallate ester is propyl gallate, and the three types of sleep-inducing agonists are GABA, L-theanine, and magnesium glycinate.

40. The method according to claim 39, wherein the amounts of SAMe, propyl gallate, GABA, L-theanine, and magnesium glycinate are 150 mg, 4.7 mg, 150 mg, 100 mg, and 10 mg, respectively.

41. A method for promoting healthy sleep quality in the subject, Administering a morning blend composition containing a sleep-inducing antagonist to the subject in the morning when they are fasting; Administering a sleep-inducing composition to the same subject before bedtime; Methods that include...

42. The method according to claim 41, further comprising a gallic acid ester.

43. The method according to claim 42, wherein the sleep-inducing antagonist is SAMe, the gallate ester is propyl gallate, and the sleep-inducing composition comprises GABA, L-theanine, and magnesium glycinate.

44. The method according to claim 43, wherein the amounts of SAMe, GABA, L-theanine, and magnesium glycinate are 150 mg, 4.7 mg, 150 mg, 100 mg, and 10 mg, respectively.

45. A method for treating, improving, preventing, or reducing one or more symptoms associated with menopause in a subject: Identifying that the subject is experiencing or will experience one or more symptoms associated with menopause, wherein the one or more symptoms include difficulty sleeping and a decline in both memory and concentration; Administering a sleep-inducing composition containing two or more sleep-inducing agonists to the subject; Methods that include...

46. A method for treating, improving, preventing, or reducing one or more symptoms associated with menopause in a subject: Identifying that the subject is experiencing or is likely to experience one or more symptoms associated with menopause; Administering a sleep-inducing composition containing one type of sleep-inducing antagonist and two or more types of sleep-inducing agonists to the subject; Methods that include...

Images