Methods for improving sleep quality and / or subsequent behavioral outcome using flavonoids or phenolic acids

Abstract

The present invention relates generally to the use of compositions for improving sleep quality and / or subsequent behavioral outcomes, in particular all-day sustained cognitive performance. More particularly, the present disclosure relates to the administration of a composition comprising a flavonoid and / or phenolic acid compound at a predetermined time prior to eating a meal, at the same time as eating a meal, or at a predetermined time prior to sleep.

Description

[0001] The present invention relates generally to the use of compositions for improving sleep quality and / or subsequent behavioral outcomes, in particular, all-day sustained cognitive performance. More particularly, the present disclosure relates to the administration of a composition comprising flavonoid and / or phenolic acid compounds at a predetermined time prior to consuming a meal, at the time of consuming a meal, or at a predetermined time prior to sleep. BACKGROUND

[0002] Sleep is a vital biological function and is considered an important driver of health and happiness throughout life. Good sleep quality is associated with benefits for brain function, mood and mental performance, heart metabolic health, and immunity (Alvarez et al., 2004), while poor sleep quality can lead to negative consequences for health and happiness (Hublin et al., 2007).

[0003] The typical sleep architecture consists of two parts: non-rapid eye movement (NREM; slow wave sleep - SWS) and rapid eye movement (REM) sleep. Overall, sleep quality is considered to be driven by the total duration of SWS, while both SWS and REM have been found to contribute to next-day benefits, such as cognitive improvement. SWS and REM are associated with different physiological states, including different requirements for overnight energy metabolism, substrate oxidation, and glycemic management.

[0004] Sleep quality is closely related to next-day cognitive function, mood, and the feeling of vigor and energy. From a scientific perspective, sleep has been consistently linked to cognitive and mood benefits in humans (for reviews, see Palmer and Alfano, 2017; Rasch and Born, 2013; Walker, 2009). Among the different sleep stages, SWS duration has been suggested to be more closely associated with declarative memory, while REM sleep underlies the ability to synthesize abstract information, such as detection patterns in newly acquired information (non-declarative; Rasch and Born, 2013; Walker, 2009). More recent views on the role of each sleep stage have suggested that SWS and REM can have complementary roles in the consolidation of newly acquired information (for different theories, see Rasch and Born, 2013).

[0005] Moreover, sleep needs change throughout life as we age, and sleep quality decreases (Madrid-Valero JJ et al. (2017). Gac sanit, 31, 18-22.). Poor sleep throughout adulthood has been associated with effects on subjective health, quality of life (Magee CA et al. (2011). Sleep med., 12(4), 346-350) and progression of cognitive decline and dementia (Hudon C et al. (2020). Neuropsychol Rev, 30, 558-579).

[0006] Much of the evidence on the role of sleep on next-day performance comes from sleep deprivation studies, and evidence suggests that both sleep disruption and sleep deprivation can negatively affect aspects of cognition, including declarative memory, memory encoding and recall, and cognitive flexibility, the ability to use existing information to combine them in new ways (Walker, 2009). Among the cognitive domains most strongly affected by sleep, levels of daytime vigilance and subjective alertness are highly correlated with sleep duration (Jewett et al., 1999). In fact, vigilance tasks have been used as highly sensitive measures of sleep loss (Basner and Dinges, 2011). Moreover, sleep difficulties can have a significant negative impact on emotional regulation through a range of mechanisms, including reducing the ability to downregulate amygdala activation when receiving negative information. Specifically, studies have found that sleep deprivation can increase amygdala activity by nearly 60% when participants are presented with negative images (reviewed in Palmer and Alfano, 2017).

[0007] Overall, while knowledge of the direct effects of nutrients on the brain and the modes of action of nutrients to promote sleep are developing, there is still a need to identify dietary interventions for improving next-day benefits, and the mechanisms by which this dietary intervention can affect subjective and objective cognitive performance and mood. SUMMARY

[0008] It is therefore an object of the present application to provide a method for improving sleep quality and / or subsequent behavioral outcomes. There is also provided a method for treating, preventing and / or reducing at least one of the risk, incidence or severity of at least one condition for which improved sleep quality is beneficial. The method comprises orally administering to an individual in need thereof a composition comprising an effective amount of at least one compound selected from a flavonoid, a phenolic acid or a combination thereof.

[0009] In some embodiments, the subsequent behavioral outcome is a subsequent behavioral outcome comprising one or more of: (a) less frequent and / or less severe drowsiness, stress, tension / anxiety, fatigue / lassitude or depression / discontent, anger / hostility, subjective frustration, and / or (b) more and / or better sleep onset, relaxation, sedation, alertness, vigor / activity, friendliness, cognition, memory, working memory, attention, vigilance, processing speed, fat utilization, weight management, immunity, subjective perception of mental, physical, time demands, subjective performance perception, or next-day mood.

[0010] In another embodiment, the subsequent behavioral outcome is sustained cognitive performance throughout the day.

[0011] In some embodiments, the flavonoid is one of rutin, quercetin, isoquercetin, luteolin, or combinations thereof.

[0012] In some embodiments, the phenolic acid is one of caffeic acid, vanillic acid, chlorogenic acid, syringic acid, or combinations thereof.

[0013] In some embodiments, the composition is administered to the individual at a predetermined time prior to consumption of a meal and / or concurrently with consumption of a meal.

[0014] In another embodiment, the composition is administered to the individual at a predetermined time in the evening, preferably prior to sleep.

[0015] Additional features and advantages are described in, and will be apparent from, the following DETAILED DESCRIPTION and the Figures. BRIEF DESCRIPTION OF DRAWINGS

[0016] Figure 1 (A, B, C, D) show the effect of active treatment on actigraphy measures of sleep latency (A), self-reported sleep latency (B), self-reported effects on drowsiness / alertness the next day (C) compared to placebo. Values represent least square means (± SE). p values indicate significant differences between control and treatment groups.

[0017] Figure 2 (A, B) show the effect of active treatment on mood assessments compared to placebo. A. Profile of mood states - vigor / activity domain; B. Brief Mood Inventory (BMIS) - negative relaxation dimension, respectively. Values represent least square means (± SE). p values indicate significant differences between control and treatment groups. DETAILED DESCRIPTION

[0018] DEFINITIONS

[0019] Some definitions are provided below. However, definitions can be located in the “EMBODIMENTS” section below, and the heading “DEFINITIONS” above does not indicate that such disclosure in the “EMBODIMENTS” section is not a definition.

[0020] All percentages are by weight of total composition unless otherwise indicated. Similarly, all ratios are by weight unless otherwise indicated. As used herein, “about,” “approximately,” and “substantially” are understood to refer to numbers within 10% of the referenced number, preferably within 5% of the referenced number, more preferably within 1% of the referenced number, most preferably within 0.1% of the referenced number, e.g., within 0.01% of the referenced number.

[0021] Furthermore, all numerical ranges herein should be understood to include all integers, whole or fraction, within that range. Additionally, these numerical ranges should be construed as providing support for a claim where any number or subset of numbers within the specified range is intended. For example, a disclosure of from 1 to 10 should be construed as supporting a range of from 1 to 8, from 3 to 7, from 1 to 9, from 3.6 to 4.6, from 3.5 to 9.9, etc. Ranges defined by “between” include the recited endpoints.

[0022] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an” or “the” component includes a plurality of such “components,” reference to “an” or “the” process includes reference to one or more “processes” and so forth. The term “and / or” as used in the context of “X and / or Y” should be interpreted as meaning “X,” or “Y,” or “X and Y.” Similarly, “at least one of X or Y” should be interpreted as meaning “X,” or “Y,” or “both X and Y.”

[0023] Similarly, the words “comprise / comprising” are to be interpreted inclusively rather than exclusively. Likewise, the terms “include,” “comprise,” and “comprising,” and the like, are specifically understood to be inclusive, unless explicitly indicated otherwise. However, embodiments provided by the disclosure can not have any element not specifically disclosed herein. Thus, disclosure of an embodiment using the term “comprising” is also a disclosure of multiple embodiments of “consisting essentially of’ and “consisting of” the disclosed components. “Consisting essentially of’ means that the embodiment or component thereof includes more than 50% by weight of the identified component, preferably at least 75% by weight of the identified component, more preferably at least 85% by weight of the identified component, most preferably at least 95% by weight of the identified component, such as at least 99% by weight of the identified component.

[0024] The term "example" as used herein, especially with respect to a list of terms, is merely an example for illustration and should not be deemed to be exclusive or exhaustive. Any embodiment disclosed herein can be combined with any other embodiment disclosed herein, unless explicitly indicated otherwise.

[0025] "Animal" includes, but is not limited to, mammals, which include, but are not limited to, rodents; aquatic mammals; domestic animals such as dogs and cats; farm animals such as sheep, pigs, cows and horses; and humans. When the terms "animal," "mammal" or their plurals are used, these terms also apply to any animal that is capable of the effect exhibited or intended to be exhibited by the context of the passage, e.g., an animal that benefits from reduced postprandial glucose. While the terms "individual" or "subject" are often used herein to refer to humans, the disclosure is not so limited. Thus, the terms "individual" or "subject" refer to any animal, mammal or human that can benefit from the methods and compositions disclosed herein.

[0026] The relative terms "improve," "promote," "enhance," and the like refer to the effect of the methods disclosed herein on sleep quality, particularly relative to consumption of the same formulated meal but without the mulberry extract provided by the composition, administration of the composition comprising mulberry extract at a predetermined time prior to consumption of the evening meal and / or at the same time as consumption of the evening meal. In some embodiments, sleep quality can be quantified by one or both of (a) total duration of slow wave sleep (SWS) and / or (b) total duration of rapid eye movement (REM). For example, improved sleep quality can be established by one or both of a longer total duration of SWS and / or total duration of REM. In some embodiments, improvement in sleep quality is an improvement in one or more of: i) sleep efficiency (e.g., measured by actigraphy data); ii) change in sleep latency (e.g., actigraphy data); iii) change in wake after sleep onset (e.g., by actigraphy); iv) change in total sleep duration (minutes, actigraphy); v) time in bed; vi) minutes spent in bed after waking. In other embodiments, sleep quality can be assessed by self-report (e.g., Karolinska Sleepiness Scale (KSS) or Epworth Sleepiness Scale (ESS).

[0027] As used herein, the term "treatment" refers to administration of a composition disclosed herein to a subject having a disorder to alleviate, reduce, or improve at least one symptom associated with the disorder and / or to slow, decrease, or block progression of the disorder. The term "treatment" includes both prophylactic or preventative treatment (preventing and / or delaying the development of a target pathologic condition or disorder), as well as curative, therapeutic or disease-modifying treatment, including therapeutic measures that cure, slow down, lessen symptoms of, and / or halt progression of an already diagnosed pathologic condition or disorder; and treatment of patients at risk of contracting a disease or suspected to have contracted a disease, as well as patients who are ill or have been diagnosed with a disease or medical condition. The term "treatment" does not necessarily imply that a subject is treated until total recovery. The term "treatment" also refers to health maintenance and / or promotion in individuals who are not ill but who can be susceptible to developing an unhealthy condition. The term "treatment" is also intended to include fortification or otherwise enhancing one or more primary prophylactic or therapeutic measures. By way of non-limiting example, treatment can be performed by a patient, caregiver, physician, nurse, or another health care professional. The term "prevention" refers to administration of a composition disclosed herein to a subject who does not show any symptoms of the disorder to decrease or prevent development of at least one symptom associated with the disorder. Further, "prevention" includes reducing the risk, incidence, and / or severity of a disorder or a disease.

[0028] As used herein, "effective amount" is an amount that treats or prevents a deficiency, treats or prevents a disease or medical condition in an individual, or more generally alleviates symptoms, controls the progression of the disease, or provides a nutritional, physiological, or medical benefit to the individual. As used herein, "administering" includes the act of another person providing a reference composition to an individual such that the individual can consume the composition, and also includes the act of the individual himself or herself consuming the reference composition.

[0029] The terms "food," "food product," and "food composition" mean a composition intended for ingestion by individuals, such as humans, and that provides at least one nutrient to the individual. "Food" and related terms include any food, feed, snack, food supplement, treat, meal replacement, or meal substitute, whether intended for humans or animals. A food supplement can be an oral nutritional supplement (ONS), which can be in the form of a solid powder, a powder bar, a capsule, or a solution. Animal food includes food or feed for any domesticated species or wild species. In preferred embodiments, food for animals means kibbles, extruded, or dried food, for example, extruded pet food, such as food for dogs and cats.

[0030] In the context of the present disclosure, the terms "beverage," "beverage product," and "beverage composition" mean a drinkable liquid product or composition intended for ingestion by individuals, such as humans, and that provides water, and can also include one or more nutrients and other ingredients that are safe for human consumption by the individual.

[0031] Embodiments

[0032] One aspect of the present disclosure is a method of improving sleep quality and / or subsequent behavioral outcomes. In another aspect, the present disclosure provides a method of treating, preventing, and / or reducing at least one of the risk, incidence, or severity of at least one condition for which improved sleep quality is beneficial. The method comprises orally administering a composition comprising an effective amount of at least one compound selected from a flavonoid, a phenolic acid, or a combination thereof.

[0033] In one embodiment, the composition is administered to the individual a predetermined time prior to consuming a meal and / or concurrently with consuming a meal. Alternatively, the composition is administered to the individual in the evening, preferably a predetermined time prior to sleep.

[0034] Preferably, the meal is a dinner, such as a balanced dinner.

[0035] If the composition is administered outside of a meal, the composition can be delivered in the form of a capsule, liquid, etc.

[0036] Subsequent behavioral outcomes enhanced by improved sleep quality include one or more of the following: (a) less frequent and / or less severe drowsiness, stress, tension / anxiety, fatigue / lassitude, or depression / disheartenment, anger / hostility, subjective frustration, and / or (b) more and / or better sleep onset, relaxation, calmness, alertness, vigor / activity, friendliness, cognition, memory, working memory, attention, vigilance, processing speed, fat utilization, weight management, immunity, subjective perception of mental, physical, time demands, subjective performance perception, or next-day mood.

[0037] In a preferred embodiment, the subsequent behavioral outcome is sustained cognitive performance throughout the day.

[0038] The individual can be a mammal, such as a human, a canine, a feline, an equine, a goat, a bovine, a sheep, a swine, a cervid, or a primate. Preferably, the individual is a human.

[0039] In some embodiments, the composition is administered to an adult with sleep complaints.

[0040] In some embodiments, the flavonoid is one of rutin, quercetin, isoquercetin, luteolin, or a combination thereof. The flavonoid can be from any suitable source and can be isolated and / or chemically synthesized. In a preferred embodiment, the rutin, quercetin, isoquercetin, and / or luteolin is obtained from a plant source.

[0041] Rutin can be obtained from onions, buckwheat, linden flowers, elderflowers, hawthorn, rue, St. John's wort, ginkgo (Ginkgo), apples and other fruits and vegetables. Quercetin is the aglycone form of many other flavonoid glycosides, such as rutin and quercitrin, and is found in citrus fruits, buckwheat and onions, green tea, apples, berries, ginkgo trees (Ginkgo biloba), St. John's wort, American elder, etc. Isoquercitrin is a 3-O-glucoside of quercetin. Isoquercitrin can be isolated from various plant species, including Mangifera indica (mango) and Rheum nobile (Noble Canola). It is also found in Annona squamosa, the leaves of Camellia sinensis (tea). Luteolin can be found in fruits and vegetables such as celery, chrysanthemum, colored bell peppers, carrots, onion leaves, cauliflower, and parsley.

[0042] In one embodiment, the flavonoid is from a mulberry extract. The mulberry extract can be from any Morus source, including but not limited to: Morus alba L., Morus nigra L., Morus celtidifolia Kunth, Morus rubra L., a hybrid form between Morus alba and Morus rubra, Morus australis, Morus laevigata, and combinations thereof.

[0043] Mulberry extracts suitable for use in the present application can be derived from different parts of the mulberry tree, including bark (trunk, branches, or roots), roots, sprouts, branches, shoots, leaves, fruit, or combinations thereof. The mulberry extract can be in the form of, for example, a dry powder, such as a dry powder ground from different parts of the tree. The starting plant material for the mulberry extract can be fresh, frozen, or dried mulberry material. The extract can be used as a liquid or a dried, concentrated solid. Typically, such extracts comprise at least about 1% w / v of 1-DNJ. In a preferred embodiment, the mulberry extract is a mulberry leaf extract.

[0044] Vegetable and plant extracts according to the present application can be prepared by procedures well known in the art.

[0045] The compositions of the present application can generally comprise from about 1% to about 50%, including from about 2% to about 30%, such as from about 5% to about 20%, and also including from about 10% to about 15% of such extracts, by weight of the composition.

[0046] The composition can comprise flavonoids in an amount effective to promote better sleep quality in the individual. The amount can range from 0.01 mg to about 1 g, preferably 0.1 mg to 1 g, even more preferably 1 mg to about 1 g of each component per serving of the composition.

[0047] In some embodiments, the phenolic acid is one of caffeic acid, vanillic acid, chlorogenic acid, syringic acid, or combinations thereof.

[0048] Caffeic acid can be found in the bark of Eucalyptus globulus, Hordeum vulgare and the herb Dipsacus asperoides, Salvinia molesta, a fast-growing fern, and in mushrooms. Vanillic acid is found in some forms of vanilla and many other plant extracts such as the root of Angelica sinensis. Chlorogenic acid (CGA) is produced by certain plant species and is a major component of coffee. Syringic acid is a naturally occurring phenolic compound and dimethoxybenzene, which is often present as a plant metabolite. Syringic acid can be found in several plants, including Ardisia elliptica and Schumannianthus dichotomus.

[0049] Preferably, the total amount of phenolic acid in the composition is effective to promote better sleep quality in the individual.

[0050] In one embodiment, the composition further comprises an ingredient that reduces the glycemic response of the individual. In some embodiments, the ingredient that reduces the glycemic response is one or more of tryptophan (e.g., as a free amino acid and / or in a protein such as whey protein), a glucosidase inhibitor such as 1-deoxynojirimycin (DNJ) (e.g., isolated or in mulberry leaf or mora extract) or phlorizin (e.g., isolated or in apple extract), arginine-proline (AP) dipeptide (e.g., isolated or in milk protein hydrolysate), fiber, resistant starch, beta-glucan, A-cyclodextrin, a glucosidase (e.g., isolated and / or as part of a composition such as mulberry leaf extract), or an amylase inhibitor (e.g., isolated and / or in a composition such as white kidney bean or wheat albumin).

[0051] In some embodiments, the composition is administered once per day (e.g., with dinner, preferably not with other meals and / or not at other times of the day) for a total duration of at least 3 days, preferably at least one week, more preferably at least two weeks.

[0052] In some embodiments, the composition is administered at a predetermined time before sleep. The composition can be administered from immediately before sleep to 3 hours before sleep, preferably 2 hours before sleep, 1 hour before sleep, 30 minutes before sleep.

[0053] In some embodiments, the composition is a cereal snack, a cereal-containing beverage (e.g., an RTD beverage), a soup, a porridge, a bouillon or a flan, and is administered to an adult. In some embodiments, the composition is administered to a human toddler.

[0054] The composition according to the present application can be added to or mixed in a meal or can be consumed with a meal. In a preferred embodiment, the composition comprising ME according to the present application is in the form of a powder or granulate intended to be added to or mixed in a meal, preferably sprinkled on a meal.

[0055] As used herein, "meal" means one or more food products that are intended to be consumed at substantially the same time as each other; preferably such that one or more proteins, one or more carbohydrates, one or more fats and at least one micronutrient are provided by consumption of the meal; more preferably such that one or more proteins, one or more carbohydrates, one or more fats, one or more vitamins and one or more minerals are provided by consumption of the meal. Preferably, the meal comprises a plurality of food products. As used herein, "balanced meal" means a meal that provides all proteins, carbohydrates, fats, vitamins and minerals in amounts and proportions suitable for maintaining the health or growth of the individual. The amounts and proportions of proteins, carbohydrates, fats, vitamins and minerals suitable for maintaining the health or growth can be determined in accordance with current food and nutrition regulations and any specific requirements for the individual, e.g. based on age, physical activity and / or gender.

[0056] The Food and Nutrition Board, e.g. the Institute of Medicine (IOM), current energy, macronutrient and fluid recommendations, recommend an acceptable macronutrient distribution range of carbohydrates (45% to 65% of energy), proteins (10% to 35% of energy) and fats (20% to 35% of energy) for active individuals. In one embodiment, the balanced meal provides 45% to 65% of the total calories from carbohydrates, 20% to 35% of the total calories from fats and 10% to 35% of the total calories from proteins. In one embodiment, the meal provides 200 kcal to 1,000 kcal, preferably 250 kcal to 900 kcal, more preferably 300 kcal to 850 kcal, and most preferably 350 kcal to 800 kcal to the individual.

[0057] In some embodiments, "dinner" means a meal consumed about 1.0 hour to about 6.0 hours before sleep onset, preferably a meal consumed about 2.0 hours to about 5.0 hours before sleep onset, more preferably a meal consumed about 2.5 hours to about 4.5 hours before sleep onset, most preferably a meal consumed about 3.0 hours to about 4.0 hours before sleep onset.

[0058] In some embodiments, "dinner" means a meal consumed about 4:30 pm to about 11:30 pm in the geographical region in which the individual is located, preferably a meal consumed about 5:00 pm to about 11:00 pm in the geographical region in which the individual is located, more preferably a meal consumed about 5:30 pm to about 10:30 pm in the geographical region in which the individual is located, most preferably a meal consumed about 6:00 pm to about 10:00 pm in the geographical region in which the individual is located.

[0059] Preferably, the food or supplement according to the present application is orally administered to the individual in a form selected from the group consisting of a dairy beverage and a non-dairy beverage, and the unit dosage form is a pre-determined amount of the beverage.

[0060] In some embodiments, the composition can be a ready-to-drink (RTD) beverage in a container, and the unit dosage form is a pre-determined amount of the RTD beverage sealed in the container, which is opened for oral administration.

[0061] In other embodiments, the method comprises forming the composition by reconstituting a unit dosage form of a powder in water or milk, thereby forming the composition for subsequent oral administration to the individual (e.g., within about ten minutes after reconstitution, within about five minutes after reconstitution, or within about one minute after reconstitution). The unit dosage form of the powder can be sealed in a sachet or other packaging, which can be opened for reconstitution and subsequent oral administration.

[0062] In some embodiments, the unit dosage form of the composition can further comprise one or more of the following: melatonin (e.g., as a light greenish-yellow powder (e.g., about 0.1 mg to about 0.3 mg melatonin)), vitamin B3 and B6 (e.g., about 15% NRV to about 2 mg), magnesium (e.g., about 40 mg magnesium), and / or zinc (e.g., about 15% NRV to about 15 mg). In some embodiments, the composition can further comprise one or more of the following: gamma-aminobutyric acid (GABA), alpha-casozepine, or theanine.

[0063] The unit dosage form of the composition can additionally contain excipients, emulsifiers, stabilizers, and mixtures thereof. The composition can comprise any nutritional or non-nutritional ingredient that increases volume and will in most cases be substantially inert and not significantly negate the blood glucose benefit of the composition. The filler material most typically includes fiber and / or carbohydrate having a low glycemic index.

[0064] Carbohydrate sources suitable for inclusion in the compositions disclosed herein include those having a low glycemic index, such as fructose and low-DE maltodextrin, as such ingredients do not introduce a high glycemic load into the composition. Other suitable components of the composition include any dietary fiber suitable for human or animal consumption, including soluble and insoluble fiber, with soluble fiber being especially preferred. The beneficial effects of soluble fiber on glucose response have been widely reported. Non-limiting examples of suitable soluble fiber include FOS, GOS, inulin, resistant maltodextrin, partially hydrolyzed guar gum, polydextrose, and combinations thereof.

[0065] Non-limiting examples of commercially available fibers for use in the composition include Sunfiber® (Taiyo International, Inc.,), which is a water-soluble dietary fiber produced by enzymatic hydrolysis of guar beans; Fibersol 2™ (Archer Daniels Midland Company), which is a digestion-resistant maltodextrin; and polydextrose.

[0066] In one embodiment, the composition can further comprise tryptophan. In a preferred embodiment, the composition comprises a protein that comprises at least a portion of the tryptophan in the composition, preferably whey protein, such as whey protein isolate; a mixture of whey protein and casein; or soy protein. In some embodiments, the supplement is administered in a unit dosage form comprising about 120 mg to about 5 g of tryptophan.

[0067] In one embodiment, the composition can comprise tryptophan, an extract as a source of flavonoids and / or phenolic acids, and soluble fiber. In a preferred embodiment, the composition comprises soluble fiber selected from the group consisting of polydextrose, resistant maltodextrin (such as soluble corn fiber Fibersol-2), and combinations thereof.

[0068] The composition can further comprise other fillers, stabilizers, anti-caking agents, antioxidants, or combinations thereof.

[0069] The composition can also include one or more additional components, such as minerals; vitamins; salts; or functional additives, including, for example, palatants, colorants, emulsifiers, antimicrobials, or other preservatives. Non-limiting examples of minerals suitable for use in the compositions disclosed herein include calcium, phosphorus, potassium, sodium, iron, chloride, boron, copper, zinc, magnesium, manganese, iodine, selenium, chromium, molybdenum, fluoride, and any combination thereof. Non-limiting examples of vitamins suitable for use in the compositions disclosed herein include water-soluble vitamins (such as thiamine (vitamin Bl), riboflavin (vitamin B2), niacin (vitamin B3), pantothenic acid (vitamin B5), pyridoxine (vitamin B6), biotin (vitamin B7), inositol (vitamin B8), folic acid (vitamin B9), cobalamin (vitamin B12), and vitamin C) and fat-soluble vitamins (such as vitamins A, D, E, and K) including salts, esters, or derivatives thereof.

[0070] All references to treatment herein include curative, palliative and prophylactic treatment. Treatment can also include arresting progression of disease severity. Both human and veterinary treatment are within the scope of the present disclosure. Preferably, the composition is administered in an amount or unit dosage form comprising a therapeutically effective amount or a prophylactically effective amount of the blood glucose response-reducing ingredient.

[0071] Non-limiting embodiments:

[0072] Example 1

[0073] The following non-limiting examples present experimental data that develop and support the concepts underlying the embodiments provided by the present disclosure.

[0074] The objective of the current study was to evaluate the effectiveness of an active formulation containing 0.75 g mulberry leaf extract (containing 1% 1-deoxynojirimycin) and 120 mg tryptophan, mulberry leaf extract, tryptophan, and vitamins and minerals (MlT) to promote better sleep and next-day mood and cognitive performance in sleep- compromised healthy adults.

[0075] Methods

[0076] The clinical trial design was double-blind, controlled, randomized, 2-arm, continuous group crossover (Clinical Trial Government Identifier: NCT05372900). Adult (age 25 to 50 years) poor sleepers (Pittsburgh Sleep Quality Index SQI > 5 and sleep efficiency < 85% during a 14-day screening) received a standardized meal and concurrently ingested either the active formulation MlT or placebo consumed approximately 4 hours before sleep. The intervention phase lasted 14 days with a 28- to 42-day washout period. The primary outcomes were sleep efficiency (SE) and sleep onset latency (SOL) measured by actigraphy. Secondary outcomes included self-reported mood, sleep quality (measured 1 hour after waking), and objective daily average cognitive performance measures.

[0077] Results

[0078] Linear mixed model analyses were performed with the intent to treat, adjusting for baseline and order of treatment for sleep, mood, and cognitive outcomes. There was no significant effect of treatment on SE (p = 0.23). However, there were significant improvements in actigraphy SOL (p = 0.026) and self-reported SOL (p = 0.048) after comparing active treatment to control (see Figure 1 , A and B). Subjective self-reported measures (Karolinska Sleepiness Scale) also showed that participants felt less sleepy the next morning (p = 0.042) (see Figure 1 C).

[0079] There was a significant increase in the Vigor-Activity subscale (1 hour after waking) score assessed by the Profile of Mood States-Short Form questionnaire (p = 0.038) in the active treatment condition (6.63 ± 0.43) compared to the control condition (5.82 ± 0.40) (see Figure 2 A). There was also a significant difference in the negative / relaxed dimension of the Profile of Mood States-Short Form in the waking state in the treatment condition (11.65 ± 0.31) compared to the control condition (12.05 ± 0.31) (p = 0.003).

[0080] Active treatment resulted in participants objectively entering sleep faster, feeling less sleepy and more relaxed, and being more energetic (vigor) the next morning. In addition, these findings suggest that sleep onset, sleep quality, and mood outcomes can be improved via a nutritional intervention and can represent a simple and convenient strategy for supporting sleep and its related health outcomes in adult populations. A large body of observational research has shown an association between sleep duration and cognitive performance, including working memory and arithmetic tasks [1, 2]. In addition, other research has demonstrated a link between sleep quality and cognitive performance on tasks involving sustained attention, memory (emotional memory, working memory, memory recall, visual spatial memory), and verbal fluency [2-5]. Furthermore, sleep quality has also been found to be associated with academic performance [6, 7].

[0081] 1. Lo, J.C., et al., Self-reported sleep duration and cognitive performance in older adults: a systematic review and meta-analysis. Sleep Med, 2016. 17: p. 87-98.

[0082] 2. Sternberg, D.A., et al., The largest human cognitive performance dataset reveals insights into the effects of lifestyle factors and aging. Front Hum Neurosci, 2013. 7: p. 292.

[0083] 3. Steenari, M.R., et al., Working memory and sleep in 6- to 13-year-old schoolchildren. J Am Acad Child Adolesc Psychiatry, 2003. 42(1): p. 85-92.

[0084] 4. Yun, C.H., et al., Daytime sleepiness associated with poor sustained attention in middle and late adulthood. Sleep Med, 2015. 16(1): p. 143-51.

[0085] 5. Gobin, C.M., et al., Poor sleep quality is associated with a negative cognitive bias and decreased sustained attention. J Sleep Res, 2015. 24(5): p. 535-42.

[0086] 6. Gilbert, S.P. and C.C. Weaver, Sleep Quality and Academic Performance in University Students: A Wake-Up Call for College Psychologists. Journal of College Student Psychotherapy, 2010. 24(4): p. 295-306.

[0087] 7. Seun-Fadipe, C. and K. Mosaku, Sleep quality and academic performance among Nigerian undergraduate students. Journal of Systems and Integrative Neuroscience, 2017. 3.

[0088] It is to be understood that various alterations and modifications to the presently preferred embodiments described herein will become apparent to those of ordinary skill in the art and that the same are intended to be covered by the ensuing claims. Accordingly, it is intended that all such alterations and modifications be considered as falling within the true spirit and scope of the inventive subject matter. It is further understood that the use of relational terms such as first, second, and third, and the like, are used solely to distinguish one from another entity or action without necessarily implying a serial or chronological order in their use.

Claims

1. A method of improving sleep quality and / or subsequent behavioral outcomes, the method comprising orally administering to an individual a composition comprising an effective amount of at least one compound selected from a flavonoid, a phenolic acid, or a combination thereof.

2. A method of treating, preventing, and / or reducing at least one of the risk, incidence, or severity of at least one condition for which improved sleep quality is beneficial, the method comprising orally administering to an individual a composition comprising at least one compound selected from a flavonoid, a phenolic acid, or a combination thereof.

3. The method of any one of claims 1 or 2, wherein the flavonoid is one of rutin, quercetin, isoquercetin, luteolin, or a combination thereof.

4. The method of any one of claims 1 to 3, wherein the phenolic acid is one of caffeic acid, vanillic acid, chlorogenic acid, syringic acid, or a combination thereof.

5. The method of any one of claims 1 to 4, wherein subsequent behavioral outcomes comprise one or more of: (a) less frequent and / or less severe drowsiness, stress, tension / anxiety, fatigue / lassitude, or depression / discontent, anger / hostility, subjective frustration, and / or (b) more and / or better sleep onset, relaxation, calmness, alertness, vigor / activity, friendliness, cognition, memory, working memory, attention, vigilance, processing speed, fat utilization, weight management, immunity, subjective perception of mental, physical, time demands, subjective performance perception, or next-day mood.

6. The method of any one of claims 1 to 5, wherein the subsequent behavioral outcome is sustained cognitive performance throughout the day.

7. The method of any one of claims 1 to 5, wherein the total amount of the at least one flavonoid and / or phenolic acid compound in the composition is effective to promote better sleep quality in the individual.

8. The method of any one of claims 1 to 6, wherein the at least one flavonoid and / or phenolic acid is in the form of a vegetable or plant extract.

9. The method of any one of claims 1 to 8, wherein the composition further comprises one or more of melatonin, vitamin B3, vitamin B6, magnesium, zinc, gamma-aminobutyric acid (GABA), alpha-casozepine, or theacrine.

10. The method of any one of claims 1 to 7, wherein the composition further comprises a blood glucose response-reducing ingredient, wherein the blood glucose response-reducing ingredient is one or more of tryptophan, a glucosidase inhibitor, a polymeric piperidine, 1-deoxynojirimycin (DNJ), an arginine-proline (AP) dipeptide, fiber, resistant starch, beta-glucan, A-cyclodextrin, a glucosidase or amylase inhibitor.

11. The method of any one of claim 11, wherein the composition comprises a protein having at least a portion of tryptophan, preferably a whey protein such as whey protein isolate; a mixture of whey protein and casein; or a soy protein.

12. The method of any one of claims 1 to 10, wherein the composition is a liquid beverage, preferably a ready-to-drink beverage or a beverage formed by reconstituting a powder in a diluent.

13. The method according to any one of claims 1 to 11, wherein the individual is a mammal, preferably a companion animal or a human.

14. The method according to any one of claims 1 to 12, wherein the composition is administered to the individual at a predetermined time prior to consumption of a meal and / or concurrently with consumption of a meal.

15. The method according to any one of claims 1 to 14, wherein the composition is administered to the individual at a predetermined time in the evening, preferably prior to sleep.

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