Combinations for use in increasing brain health and mental performance

Abstract

The present invention relates to a composition comprising taurine and at least one B vitamin, in particular vitamin B9, for increasing glutathione levels in the brain and / or improving mental performance such as motivation and / or the ability to stay focused and maintain attention and / or feelings of energy and vitality.

Description

[Technical Field]

[0001] The present invention relates to a composition comprising taurine and at least one B vitamin, in particular vitamin B9, for increasing glutathione levels in the brain and / or improving mental performance such as motivation and / or the ability to stay focused and maintain attention and / or feelings of energy and vitality. [Background technology]

[0002] Glutathione (GSH) is an essential antioxidant used by the body to prevent cell and tissue damage. Glutathione is involved in many fundamental metabolic processes, ranging from the nitric oxide cycle to dietary mineral uptake. Additionally, glutathione helps cells regulate cell division and differentiation from progenitor cells to mature somatic cells.

[0003] As one of the body's primary antioxidants, glutathione binds to circulating reactive oxygen species (ROS), which can cause cellular and DNA damage if left unchecked. Reactive oxygen species, also known as free radicals, are metabolic by-products that can be widely harmful to the body. To remove circulating ROS, glutathione binds to ROS, thereby subjecting them to oxidation. This means that glutathione prevents the oxidation of important cellular proteins or DNA, which can inhibit their function.

[0004] Mitochondria are known to be essential organelles that produce energy to drive cellular, physiological, and behavioral responses (Picard et al., 2018). The brain consumes approximately 20% of the body's total energy (Rettberg et al., 2014), and stress can amplify this need, resulting in increased mitochondrial activity to meet energy demands (reserve capacity) (Morava and Kozicz, 2013; Picard et al., 2018). Therefore, mitochondria have recently been identified as essential for stress adaptation and cognitive function (Fattal et al., 2006; Khacho M. et al., 2017; Picard et al., 2013).

[0005] Increased oxidative damage and decreased glutathione levels are observed under conditions of high energy demand in the brain, such as psychological stress.

[0006] High levels of oxidized glutathione in the brain are characteristic of brain injury, whereas high levels in plasma can be considered healthy and normal. This is because oxidized glutathione must be returned to the bloodstream from the brain to remove ROS, which it holds, for metabolic processes that can actively use them. Alternatively, the oxidized form of GSH can be locally returned to its reduced state by glutathione reductase or returned to the bloodstream from the brain to actively remove ROS. Therefore, high levels of oxidized glutathione in the brain can indicate insufficient glutathione to remove all circulating reactive oxygen species, suggesting severe levels of stress.

[0007] Measurement of plasma glutathione levels alone may lead to the erroneous assumption that circulating glutathione is normal, even in individuals with cognitive impairment. Although it has recently been recognized that individuals with cognitive impairment have reduced brain glutathione levels, the conditions under which brain glutathione levels may transiently change in relation to performance and motivation in various cognitive and motor tasks in healthy individuals remain unknown, as high glutathione levels in the nucleus accumbens have been shown to mediate motivated behavior in "Glutathione in the nucleus accumbens regulates motivation to exert reward-incentivized effort" (Zalachoras I et al., 2022).

[0008] Direct supplementation of GSH is a difficult approach, especially because GSH can be rapidly decomposed into its constituent amino acids in the liver and can be partially hydrolyzed and oxidized.As a result, the bioavailability of GSH is limited after oral administration.Therefore, it is necessary to find compositions and methods that increase glutathione in the brain and maintain antioxidants that support high energy demands in the brain. Summary of the Invention

[0009] The present invention provides compositions and methods for enhancing glutathione levels in the brain. In particular, the present invention provides a composition comprising taurine and vitamin B9 in a specific effective ratio. The composition is intended for use in increasing glutathione levels in the brain of an individual and / or improving mental performance, particularly motivation, concentration and / or sustained attention, and fatigue.

[0010] As mentioned above, direct oral administration of glutathione has limited effectiveness in terms of bioavailability.

[0011] In a preferred embodiment, the composition is in the form of a feed, drink, food supplement or dietary supplement.

[0012] In a preferred embodiment, the composition further comprises at least one B vitamin selected from vitamin B6 and / or vitamin B12. [Brief explanation of the drawings]

[0013] [Figure 1] FIG. 1 shows the comparative effects of taurine and various taurine to vitamin B9 ratios on intracellular GSH synthesis. [Figure 2]

[0023] Figure 1 presents a cross-sectional analysis of first period data from the Motivational Task across Visits (MIDT), mean ± standard error predicted. The time between baseline and post-intervention visits was 4 weeks. [Figure 3a] FIG. 1 shows that mitochondrial spare capacity (PC) decreases with oxidative stress. [Figure 3b] FIG. 1 shows that mitochondrial coupling efficiency (CE) decreases with oxidative stress. [Figure 4] FIG. 1 shows the effect of taurine, vitamin B9, and compositions containing various ratios of taurine and vitamin B9 on mitochondrial reserve capacity (SPC). [Figure 5] FIG. 1 shows the effect of taurine, vitamin B9, and compositions containing various ratios of taurine and vitamin B9 on mitochondrial coupling efficiency (CE). DETAILED DESCRIPTION OF THE INVENTION

[0014] definition All percentages are by weight, relative to the total weight of the composition, unless otherwise specified. Similarly, all amounts and ratios are by weight, unless otherwise specified. When reference is made to pH, the value corresponds to the pH measured at 25°C with standard equipment. As used herein, "about," "approximately," and "substantially" are understood to refer to a number within a range of numerical values, e.g., within -10% to +10% of the referenced numerical value, preferably within -5% to +5% of the referenced numerical value, more preferably within -1% to +1% of the referenced numerical value, and most preferably within -0.1% to +0.1% of the referenced numerical value.

[0015] Furthermore, all numerical ranges herein should be understood to include all integers, whole numbers, or fractions within that range. Furthermore, these numerical ranges should be interpreted as supporting claims directed to any number or subset of numbers within that range. For example, a disclosure of 1 to 10 should be interpreted as supporting ranges of 1 to 8, 3 to 7, 1 to 9, 3.6 to 4.6, 3.5 to 9.9, etc.

[0016] As used in this specification and the appended claims, singular words include plurals unless the context clearly dictates otherwise. Thus, references to "a," "an," and "the" generally include the plurals of the respective terms.

[0017] Similarly, the words "comprise," "comprises," and "comprising" should be interpreted as inclusive rather than exclusive. Similarly, the terms "include," "including," and "or" should all be interpreted as inclusive unless such interpretation is clearly prevented by the context. However, embodiments provided by the present disclosure may not include any element not specifically disclosed herein. Thus, disclosure of embodiments defined using the term "comprising" is also a disclosure of embodiments "consisting essentially of" and "consisting of" the disclosed components.

[0018] As used herein, the term "example," particularly when followed by a list of terms, is merely exemplary and illustrative and should not be considered exclusive or comprehensive. All embodiments disclosed herein can be combined with any other embodiment disclosed herein, unless expressly stated otherwise.

[0019] A "subject" or "individual" of the present invention is a human adult subject, preferably a healthy adult, animal, or pet, who is in need of improving motivation and / or mental performance and ensuring adequate cellular energy through regulating glutathione levels in the brain and / or protecting mitochondria from oxidative stress. The compositions of the present invention can be beneficially used to increase brain glutathione levels and / or protect mitochondria from oxidative stress to prevent or treat conditions or diseases characterized by low brain glutathione levels or mitochondrial dysfunction, whether transient or chronic.

[0020] "Reactive oxygen species" play an important role in cellular signaling, a process called redox signaling. Therefore, a balance must be struck between the production and consumption of reactive oxygen species to maintain proper cellular homeostasis. One source of reactive oxygen species under normal conditions in humans is the leakage of reactive oxygen species from mitochondria during oxidative phosphorylation. Other enzymes that can produce superoxide (O2-) include xanthine oxidase, NADPH oxidase, and cytochrome P450. Another potent oxidant, hydrogen peroxide, is produced by a variety of enzymes, including several oxidases.

[0021] The terms "treatment" and "treating" include any effect that results in the improvement of a condition or disorder, for example, alleviating, alleviating, controlling, or eliminating the condition or disorder. The term does not necessarily imply that a subject is treated to the point of cure. Non-limiting examples of "treating" or "treatment of" a condition or disorder include: (1) inhibiting the condition or disorder, i.e., arresting the development of the condition or disorder or its clinical symptoms, and (2) alleviating the condition or disorder, i.e., causing temporary or permanent regression of the condition or disorder or its clinical symptoms. Treatment may be patient-related or physician-related.

[0022] The term "prevention" or "preventing" means preventing the development of clinical symptoms of the referenced condition or disorder in an individual who may be exposed to or predisposed to the condition or disorder, but who has not yet experienced or exhibited symptoms of the condition or disorder. The terms "condition" and "disorder" refer to any disease, condition, symptom, or manifestation.

[0023] Relative terms such as "improved," "increased," and "enhanced" refer to the effect of the composition to increase glutathione in the brain, which in turn improves cognitive and / or motor performance in an individual subject.

[0024] "Mental performance," conceptualized as the ability to continue to feel motivated, focused, energized, and less fatigued, is paramount for accomplishing daily tasks, meeting work responsibilities, and allowing people to actively engage in hobbies and leisure activities. Losses in any of these areas can result in a decline in mental performance, highlighting the individual's need to maintain high levels of motivation / energy and focus / sustained attention, as well as reduced levels of fatigue, to promote better overall performance. The link between concentration, motivation, and fatigue has been well documented and points to a bidirectional relationship between all of these components (emotion-cognition-motivation interactions) (Pessoa, L., How do emotion and motivation direct executive control? Trends Cogn Sci, 2009.13(4):pp.160-6).

[0025] "Motivation" or "motivation" is synonymous with the term "mental energy" and the related terms "will," "will-power," "time-on-task," "persistence," "self-control," "persistence," and "self-efficacy" and "perceived effort." These terms all relate to a person's motivation to initiate and perform things. Motivation is related to subjectively perceived self-efficacy and well-being.

[0026] Motivational capacity describes the subjective perception of available mental resources, the subjective perception of "sense of energy" and / or "sense of vitality", which in turn relates to cognitive function (Egan et al. (2015) Personality & Social Psychology Bulletin, 41(3), 336-350). For example, in states of depression and anxiety, motivational capacity is reduced (O'Connor et al. (2006) Nutrition Reviews, 64(7Pt2), S2-6).

[0027] "Motivational capacity" or "motivation" can be measured by performance in both motor and cognitive tasks, which are typically performed under motivational conditions, i.e., conditions in which the individual is motivated by their performance in the task.

[0028] For example, motor task under motivational conditions may be measured as an individual's ability to perform a strenuous motor task, such as grasping a handgrip to measure both strength and endurance, where performance is normalized to the individual's muscle strength (Zhu et al. (2019) NeuroImage. Clinical, 23, 101922; Berchio et al., 2019; Strasser et al., 2020).

[0029] For example, the cognitive task under motivational conditions may be an individual's ability to perform an effortful cognitive task such as sustained / sustained attention and working memory (e.g., Unsworth et al. (2019) Journal of Experimental Psychology. Learning, Memory, and Cognition), mental arithmetic, or spatial reasoning (e.g., Nagase et al. (2015) Journal of the Society for Neuroscience, 38(10), 2631-2651), where performance is normalized to the individual's ability to perform the task.

[0030] Motivation is a complex construct, influenced by both internal and external factors, such as personal interest (i.e., internal) and the prospect of reward or punishment (i.e., external). These different aspects of motivation can also be measured through validated self-report questionnaires. For example, the Global Motivation Scale (GMS) is a scale designed to assess aspects of intrinsic motivation, extrinsic motivation, and amotivation to perform an activity. As such, it can provide important insight into the motivation underlying a participant's decision to engage in an activity. Furthermore, the Vitality subscale of the Profile of Mood States (POMS) can provide important insight into the perceived level of "resources" participants have at their disposal to perform mentally or physically challenging activities.

[0031] In animals such as rodents, motivational ability can be measured by motor tasks such as the forced swim test, or cognitive tasks such as the social dominance test or operant conditioning. Motivational ability can also be measured in relation to anxiety in tests such as the elevated plus maze (e.g., Hollis et al. (2018) Neuropharmacology, 138, 245-256) and the open field and novel object exploration (e.g., Toledo-Rodriguez and Sandi, (2011) Frontiers in Behavioral Neuroscience, 5, 17).

[0032] "Concentration" and / or "sustained attention" are the ability to focus and maintain full attention on the task at hand. Across various cognitive domains, the ability to maintain focus and concentration when the task requires high levels of continuous attention is considered evidence of mental capacity. Specifically, performance impairments in vigilance tasks, conceptualized as missed / incorrect responses, are thought to be associated with mental fatigue and can provide a proxy for mental performance capacity. Among these vigilance tasks, the Psychomotor Vigilance Test (PVT) is often used to detect changes in sustained attention (focus / concentration).

[0033] "Fatigue," or the level of perceived fatigue, is a major predictor of a person's ability to perform demanding tasks. It is a tired state that reduces energy, motivation, and concentration. Fatigue at this level impacts emotional and psychological health. Among instruments measuring fatigue, the Profile of Mood States (POMS) has been consistently used to assess fatigue in the context of nutritional therapy. The POMS is a questionnaire consisting of 65 items (37 items for the short-form POMS) that incorporate six mood constructs: tension / anxiety, depression / despair, anger / hostility, fatigue / inertia, confusion / confusion, and energy / activity.

[0034] The "nucleus accumbens" is the most ventral part of the striatum and is primarily connected to the limbic system. As a functional central structure between the amygdala, basal ganglia, mesolimbic dopaminergic regions, the mediodorsal thalamus, and the prefrontal cortex, the nucleus accumbens appears to play a modulative role in modulating the flow of information from the amygdala to these regions. Together with the prefrontal cortex and amygdala, the nucleus accumbens is part of a brain circuit that controls functions related to effort or motivation. The nucleus accumbens is uniquely anatomically arranged to provide the emotional and behavioral components of sensation. The nucleus accumbens plays an important role in food intake, sexual behavior, reward-motivated behavior, stress-related behavior, and substance addiction, and is thought to be a neural interface between motivation and behavior (Mavridis, Psychiatriki. 2015 Oct-Dec;25(4):282-94).

[0035] Mitochondrial function within the nucleus accumbens and prefrontal cortex has a direct role in anxiety-like and social behaviors (Hollis et al., 2015, 2018), as well as other brain regions (Burtscher J et al., 2022) and "depressive-like" behaviors (Filipovic D. et al., 2017; Ciubuc-Batcu MT et al., 2023), and age-related cognitive decline (Glavis-Bloom C. et al., 2023).

[0036] Importantly, trait anxiety appears to negatively impact attentional control (Basten et al., 2011; Berggren et al., 2013) and distractibility (Fell J. et al., 2023), processing efficiency (Derakshan et al., 2009), and motivation through altered motivational processing when rewards require effort (Berchio et al., 2019). Depressive symptoms are characterized by low mood, lack of motivation, negative cognitive outlook, and sleep disturbances (Piao J. et al., 2023).

[0037] Furthermore, higher levels of glutathione measured in the nucleus accumbens significantly correlate with improved motivational performance (https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC9642999 / ).

[0038] The terms "food," "beverage," "food product," "beverage product," "food composition," and "beverage composition" refer to a product or composition intended for consumption by an individual, such as a human, and that provides at least one nutrient to the individual. The compositions of the present disclosure, including the many embodiments described herein, may include, consist of, or consist essentially of any additional or optional ingredients, components, or limitations described herein or otherwise useful in a diet, in addition to the essential elements and limitations described herein.

[0039] The composition may be any type of composition suitable for human and / or animal consumption. For example, the composition may be selected from the group consisting of food compositions, dietary supplements, nutritional compositions, dietary supplements, powdered nutritional formulations to be reconstituted with water or milk before consumption, food additives, pharmaceuticals, beverages and drinks including coffee-based products (e.g., coffee RTDs, coffee capsules, etc.). In one embodiment, the composition is an oral nutritional supplement (ONS), a complete nutritional formula, a pharmaceutical product, a medical product, or a food product. In a preferred embodiment, the composition is administered to an individual as a beverage. The composition may be stored as a powder in a sachet and then suspended in a liquid such as water for use.

[0040] As used herein, "complete nutrition" refers to a composition containing sufficient variety and levels of macronutrients (protein, lipids, and carbohydrates) and micronutrients to be the sole source of nutrition for the individual to whom the composition is administered, such that the individual can receive 100% of their nutritional needs from such a complete nutritional composition.

[0041] Administration of the compositions of the present invention is preferably oral, but encompasses all forms of "enteral administration."

[0042] Each of the compounds can be administered simultaneously with the other compounds (ie, as a single unit) or separated by some time interval (ie, in separate units).

[0043] All modes of administration may be considered in combination with glutathione itself.

[0044] Embodiment The composition comprises taurine:vitamin B9 in a ratio of about 1:2500. The composition is for use in increasing brain glutathione levels and / or improving mental performance, motivation, focus, sustained attention and / or fatigue in an individual.

[0045] Such compositions increase glutathione in the nucleus accumbens region of the brain, providing benefit to the subject.

[0046] Glutathione Glutathione (GSH) is the most abundant intracellular component of the overall antioxidant defense. GSH is a tripeptide synthesized de novo within cells from the precursor amino acids glycine, cysteine, and glutamate in two steps catalyzed by glutamate cysteine ​​ligase (GCL, also known as γ-glutamylcysteine ​​synthetase, EC 6.3.2.2) and γ-L-glutamyl-L-cysteine:glycine ligase (glutathione synthetase, EC 6.3.2.3).

[0047] Glutathione is also known as γ-glutamylcysteinylglycine, γ-L-glutamyl-L-cysteinylglycine, γ-L-glutamyl-L-cysteinylglycine, glutathione, glutathione, L-γ-glutamyl-L-cysteinyl-glycine, L-γ-glutamyl-L-cysteinyl-glycine, L-glutathione, L-glutathione, GSH, N-(NL-γ-glutamyl-L-cysteinyl)glycine. Glutathione is typically administered as S-acetylglutathione or reduced L-glutathione.

[0048] Foods rich in glutathione include cruciferous vegetables, such as broccoli, cauliflower, Brussels sprouts, and bok choy; allium vegetables, such as garlic and onion; eggs, nuts, legumes, lean proteins, such as fish and chicken, and whey protein.Herbs rich in glutathione include milk thistle, flaxseed, and Eucheuma algae.The compositions and methods of the present invention can also be used in combination with dietary recommendations for glutathione-rich foods to complement diet.

[0049] Lifestyle parameters can affect glutathione levels in the brain. For example, glutathione is also negatively affected by insomnia. Therefore, the compositions and methods of the present invention also include recommendations for getting enough sleep.

[0050] Psychogenic stress is defined as an imminent or perceived threat to homeostasis, and the brain and body undergo various physiological responses to adapt, and glutathione levels in the brain can be affected by such stress.

[0051] Taurine Taurine, also known as 2-aminoethanesulfonic acid, is an organic acid that occurs naturally in foods, especially shellfish (e.g., scallops, mussels, clams), and dark meat from turkey and chicken, as well as other meats and eggs.

[0052] In a preferred embodiment, the daily dose of taurine is administered to a human in an amount of at least about 500 mg.

[0053] In a specific, non-limiting example, the daily dose for a 60 kg human subject is from about 500 mg to about 3000 mg / day of taurine or a functional derivative thereof.

[0054] In another embodiment, the daily dose of taurine is administered to an animal or pet in an amount equivalent to a human dose converted to an animal dose based on body surface area in accordance with FDA guidelines (Nair AB, Jacob SA simple practice guide for dose conversion between animals and humans. J Basic Clin Pharm. 2016 Mar;7(2):27-31. doi:10.4103 / 0976-0105.177703. PMID:27057123; PMCID:PMC4804402).

[0055] In one embodiment, the daily dose of taurine is administered to the dog in an amount of at least about 15 mg per kg of body weight.

[0056] In one embodiment, the taurine and vitamin B9 are present in a ratio such that the respective amounts of taurine and B9 in the composition are, for example, about 100 mg and 0.04 mg, or 120 mg and 0.05 mg, or 150 mg and 0.06 mg, or 200 mg and 0.08 mg, or 300 mg and 0.12 mg, or 400 mg and 0.16 mg, or 500 mg and 0.2 mg, or 600 mg and 0.24 mg, or 800 mg and 0.32 mg, or 1000 mg and 0.4 mg, or 2000 mg and 0.8 mg, or 3000 mg and 1.2 mg.

[0057] Vitamin B9, also known as folate or folic acid, is an essential nutrient that the body cannot produce. Folate occurs naturally in vegetables (especially dark green leafy vegetables), fruits and fruit juices, nuts, beans, peas, seafood, eggs, dairy products, meat, poultry, and grains.

[0058] The present inventors have surprisingly found the most effective amount of taurine and its ratio to vitamin B9 in a composition for increasing intracellular GSH.

[0059] Thus, in a first embodiment of the invention, the composition comprises vitamin B9 and taurine in a ratio of about 1:2500, which means that the amount of taurine is 2500 times the amount of vitamin B9 in the composition.

[0060] In one embodiment, vitamin B9 is in an amount of about 0.2 mg to about 1.2 mg.

[0061] In one embodiment, the composition further comprises at least one B vitamin, preferably selected from vitamin B6 and / or vitamin B12.

[0062] Other B vitamins One or more B vitamins are used in the composition. Non-limiting examples of suitable B vitamins include vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin or niacinamide), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine, pyridoxal, or pyridoxamine, or pyridoxine hydrochloride), vitamin B7 (biotin), and vitamin B12 (various cobalamins, commonly cyanocobalamin in vitamin supplements), and combinations thereof. "Vitamins" include compounds naturally obtained from plant and animal foods or synthetically produced, provitamins, their derivatives, and their analogs.

[0063] In some embodiments, the composition is for use in increasing glutathione levels in the brain and / or improving mental performance, particularly motivation, concentration and / or sustained attention, and fatigue.

[0064] In one embodiment, the composition administered to a human comprises: Vitamin B9 in amounts of about 0.2 mg to about 1.2 mg Vitamin B6 in amounts of about 1.3 mg to about 7.8 mg, Vitamin B12 in amounts ranging from approximately 2.4mcg to approximately 14.4mcg The method further includes at least one of:

[0065] In one embodiment, the composition administered to an animal or pet further comprises at least one B vitamin in an amount equivalent to a human dose to an animal dose based on body surface area in accordance with FDA guidelines.

[0066] In one embodiment, the composition administered to the dog comprises: Vitamin B9 at approximately 0.006 mg per kg of body weight or the equivalent human dose to animal dose based on body surface area per FDA guidelines; Vitamin B6 at approximately 0.04 mg per kg of body weight or the equivalent human dose to animal dose based on body surface area per FDA guidelines; Approximately 0.072 mcg of vitamin B12 per kg of body weight, or the equivalent human dose to animal dose based on body surface area per FDA guidelines The method further includes at least one of:

[0067] In one embodiment, the composition is administered orally.

[0068] In one embodiment, the composition is a food, beverage, food supplement, or dietary supplement.

[0069] In one embodiment, the composition is in the form of an RTD, RTD coffee, coffee capsule, tablet, gummy or powder sachet.

[0070] In one embodiment, the present invention provides: i) improved motivation; ii) improved concentration and / or sustained attention; iii) reduced fatigue; The present invention relates to the use of the compositions disclosed herein in a healthy individual in need of at least one of the following:

[0071] In one embodiment, the composition is for use in cytoprotection and ameliorating oxidative stress.

[0072] Composition Formulation In one embodiment, the composition is a food composition, including human food compositions and pet food compositions, hi some embodiments, the food composition is a product comprising at least one nutrient for improving motivational performance or mental energy.

[0073] The pet food composition can provide the required dietary requirements for an animal, an animal treat (e.g., biscuit), or a dietary supplement. The composition can be a dry composition (e.g., kibble), a semi-moist composition, a wet composition, or any mixture thereof. In another embodiment, the composition is a dietary supplement such as a gravy, drinking water, drink, yogurt, powder, granules, paste, suspension, chew, morsel, treat, snack, pellet, pill, capsule, tablet, or any other suitable delivery form. The dietary supplement is administered to the animal in small amounts, or alternatively, can be diluted before administration to the animal. The dietary supplement may need to be or can be mixed with water or other diluent before administration to the animal.

[0074] In another embodiment, the composition is in the form of a food or dietary supplement, in particular in the form of a tablet, powder sachet or gummy.

[0075] In a preferred embodiment, the composition is in the form of an effervescent tablet.

[0076] Effervescent tablets can be manufactured and controlled similarly to conventional tablets. These controls include physicochemical properties such as hardness, weight variation, friability, dissolution time, pH, and content uniformity. Effervescent tablets can be manufactured by direct compression, fusion, wet or dry granulation, or any other suitable method. A low relative humidity (e.g., up to 25%) and a moderate to low temperature (e.g., about 25°C or 77°F) environment may be necessary to prevent granules or tablets from sticking to the tablet press.

[0077] In the direct compression method, effervescent tablets can be formed by compressing the powdered ingredients into a dense mass, for example, using a tablet press. Before tableting, the powdered ingredients may first be granulated to similar or equal sizes so that the powder mixture has good flowability without particle segregation. Granulation may not be necessary if the raw materials are selected to achieve a free-flowing, non-segregating, compressible powder blend. The tablets can then be dried by heating, for example, in an air-circulating oven at a suitable temperature for a suitable time, and after cooling, can be packed into suitable packaging.

[0078] In the fusion method, the ingredients can be mixed in a suitable mixer, such as a blender, for a suitable time. The resulting mixture can then be heated to a suitable temperature. The powders can be mixed regularly until the crystallization water of citric acid is released as a binder (e.g., approximately 30 minutes), resulting in a suitable paste-like mass. This wet mass can be passed through a sieve to obtain the desired granules, which can then be dried at a suitable temperature for a suitable time. After drying, the granules can be passed through a sieve again. Other ingredients can be added to the granule mass and mixed for a suitable time. The granule mixture can then be compressed into tablets using a tablet press. Finally, the tablets can be dried and packed into suitable packaging.

[0079] In wet granulation, ingredients may be milled in a mill, either separately or as a mixture with ethanol, ethanol-water mixtures, isopropanol, etc., and the resulting powder may be passed through a sieve and then blended. A binder solution may be added to the mixture to form a paste-like mass. The paste-like mass may then be passed through a sieve to obtain the desired granules, which may then be dried. The dried mass may be passed through a sieve again, and other ingredients may be added and mixed. The resulting granulated mixture may then be compressed into tablets in a tablet press. Finally, the tablets may be dried and packaged in suitable packaging. Wet granulation can also be carried out by carefully adding 0.1 percent to 1.0 percent water (weight-to-weight basis) to a blend of raw materials that has the uniformity, compressibility, and flow properties required to produce quality tablets but lacks the necessary binding properties. Free water is typically added in the form of a fine spray to selected formulation components while mixing in a suitable blender, and acts as a binder. The granulation process must be precisely timed to thoroughly mix the ingredients and ensure the granulation fluid is evenly distributed throughout the blend. The mixture is then quickly discharged into a drying oven. After drying, the granules are sized and a final blend is performed. The granules are then compressed into tablets using tablet machines.

[0080] Dry granulation can use specialized processing equipment known as "roller compactors" or "chilsonators." These machines compress premixed powders between two counter-rotating rollers under extremely high pressure. Depending on the roller configuration, the feed material may be compressed into a dense ribbon-like material known as flakes (smooth rolls) or into dense briquettes (almond or stick shape) if the rollers have grooved or etched surfaces. The compressed material is reduced to a suitable size for tablet granulation purposes. Another dry granulation procedure is slugging, in which powder particles are compressed into large, flat tablets or pellets using a tablet press or, more commonly, heavy-duty tablet compression equipment. The resulting tablets or slugs are crushed to obtain the desired granule characteristics.

[0081] Effervescent tablets can be made in any shape and can have any suitable size. As a non-limiting example, the tablet can have a length, thickness, and / or diameter (if circular) of 5 mm to 20 mm. The size of the tablet can be 5 mm to 10 mm, 5 mm to 15 mm, 10 mm to 15 mm, 10 mm to 20 mm, or 15 mm to 20 mm.

[0082] The effervescent tablet may contain a binder such as polyvinylpyrolidone (PVP) or any other suitable binder. The binder is preferably water-soluble. The binder can be added as a dry powder or in wet form as an aqueous or hydroalcoholic solution. Small amounts of mannitol, PEG 6000, and water can also be used as binders. PEG 6000 at a 3% usage level can be used as a dry binder. The ideal amount of binder is one that ensures the tablet is hard enough to handle, yet soft enough to disintegrate, and dry enough to be stable. The effervescent tablet may also be formulated without a binder.

[0083] beverage composition In one embodiment, the composition is a beverage composition. Such a beverage composition is intended for consumption by humans or animals. In some embodiments, the beverage is a dairy-based beverage; a performance nutrition product, a medical nutrition product; a dairy product, such as a dairy drink, or a product containing at least one nutrient for improving motivation, performance, or mental energy.

[0084] Dairy products In one embodiment, the composition can be formulated as a "dairy product" with a milk protein, such as a milk protein concentrate or a milk protein isolate; a caseinate or casein, such as a casein micelle concentrate or a casein micelle isolate; or a whey protein, such as a whey protein concentrate or a whey protein isolate. Additionally or alternatively, at least a portion of the protein can be a vegetable protein, such as one or more of soy protein, pea protein, or canola protein.

[0085] nutritional supplements In one embodiment, the composition of the present invention can be formulated as a "nutritional supplement" together with the glutathione-enhancing compound of the present invention.The compound of the present invention can be used alone or in combination with suitable additives for producing tablets, gummies, powders, granules or capsules, for example, in combination with conventional additives such as lactose, mannitol, corn starch or potato starch; in combination with binders such as crystalline cellulose, functional cellulose derivatives, gum arabic, corn starch or gelatin; in combination with disintegrants such as corn starch, potato starch or sodium carboxymethylcellulose; in combination with lubricants such as talc or magnesium stearate; and, if desired, in combination with diluents, buffers, wetting agents, preservatives and flavoring agents.

[0086] Administration The compositions of the present invention may be administered at least one day per week, preferably at least two days per week, more preferably at least three or four days per week (e.g., every other day), and most preferably at least five days per week, six days per week, or seven days per week. The administration period may be at least one week, preferably at least one month, more preferably at least two months, and most preferably at least three months, e.g., at least four months. In one embodiment, administration is at least daily, e.g., the subject may receive one or more administrations per day. In some embodiments, administration continues for the remainder of the individual's life. In other embodiments, administration is administered until no detectable symptoms of the condition remain. In specific embodiments, administration is administered until a detectable improvement in at least one symptom occurs, and in further cases, is continued to maintain remission.

[0087] The ideal duration of administration of the composition can be determined by one skilled in the art.

[0088] It should be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present subject matter and without diminishing its intended advantages. Accordingly, such changes and modifications are intended to be covered by the appended claims. [Example]

[0089] Example 1 We investigated the effect of different taurine to vitamin B9 ratios on intracellular glutathione (GSH) synthesis (Figure 1). To measure GSH increases after supplementation with taurine and vitamin B9 at various ratios, rat primary astrocytes were cultured in medium depleted of vitamin B9, but still supplemented with 15% FBS to have a reduction in this vitamin rather than a complete depletion, as this is more physiologically relevant for human applications.

[0090] Standard DMEM is very high in vitamin B9 (approximately 9 μM), so to see the full dynamic range in response to supplementation, we used a reduction in such vitamins rather than a complete depletion, as this does not reflect the human condition. The following amounts and ratios of components of the composition were used (Table 1):

[0091] [Table 1]

[0092] Intracellular GSH was measured in cultured rat primary astrocytes using the GSH-Glo™ assay, a luminescent assay for the detection and quantification of total intracellular glutathione levels. The assay is based on the conversion of a luciferin derivative to luciferin in the presence of GSH. The reaction was catalyzed by the glutathione S-transferase (GST) enzyme provided in the kit. The formed luciferin was detected in a coupling reaction using Ultra-Glo™ Recombinant Luciferase, which produces a glow-type luminescence proportional to the amount of glutathione present in the cells. A standard curve was used for each biological replicate, and at least five technical replicates were run for each condition and each biological replicate (three biological replicates). Protein amounts were measured by BCA using 10% lysates from each technical and biological replicate, which was used to normalize the intracellular content of GSH to total protein. Buthionine-sulfoximine (BSO), a specific inhibitor of γ-glutamylcysteine ​​ligase (GCL), was added at 15 mM at the beginning of the treatment to confirm the specificity of the readout.

[0093] Measurements were taken 48 hours after treatment. Results were compared to the control condition (vehicle) for each biological replicate and for each condition.

[0094] The inventors have found the most effective ratio of taurine to vitamin B9 (1:2500) in the composition for increasing intracellular GSH.

[0095] FIG. 1 shows the greatest effect of the composition taurine on increasing GSH and its ratio to vitamin B9 in the composition of 1:2500.

[0096] Example 2 The effects of 4 weeks of oral supplementation with a combination of B vitamins (B6, B9, B12) and taurine versus placebo were evaluated on motivation in healthy adults.

[0097] investigational drug The investigational products (IPs) are Taurine: 500mg Vitamin B6: 1.3 mg Vitamin B9: 0.2 mg Vitamin B12: 2.4 mcg It was provided in a single capsule containing

[0098] Placebo: The placebo consisted of identically appearing capsules containing microcrystalline cellulose.

[0099] Both IP and placebo were administered orally once daily in capsule form to 44 participants (21 women and 23 men, ages 25-40 years) ideally during traditional meal times (i.e., breakfast, lunch, and dinner), approximately 30 minutes to 1 hour before behavioral testing, which was scheduled to begin.

[0100] The primary outcome was the monetary incentive delay task (MIDT). Improved motivation was assessed by the MIDT, measured as a change from baseline to day 28 of product intake, with an expected effect size of 0.08. Each MIDT trial began with participants seated facing a laptop screen and holding a hand dynamometer connected to a BIOPAC system, which recorded force and grip duration. The screen then displayed a fixation cross followed by an anticipatory signal indicating the trial's motivation (e.g., 50, 20, or 10 pesos). The start of the force exertion period was signaled by the appearance of a red circle around the fixation cross. Once the set force threshold was reached within a specific time frame, the red circle was replaced with a green circle. The green circle also indicated that the participant had to maintain the contractile force level for a specific period of time. If the participant did not reach the threshold in the first time frame or if the force level fell below the maintenance threshold during the maintenance period, the trial was deemed a failure, visualized by the display of a red cross on the screen. If force is maintained for the required time, a green check mark indicates successful task performance during a trial. The task is performed in blocks with a 3-minute rest period between blocks. Each block contains sessions, and each session has trials: an equal number of motivational reward trials, each with different motivational stimuli, in random order, and non-motivational rest trials interspersed with every 3 motivational trials. The motivational trial is expected to last approximately 15-18 minutes.

[0101] This trial had a crossover design in which the baseline and two follow-up measurements crossed, allowing for the estimation of period or carryover effects by comparing the two baselines. The time between the baseline and follow-up visits was 4 weeks. The washout period was also 4 weeks. We identified period and carryover effects, which motivated us to cross-sectionally analyze only the first period data. Furthermore, we hypothesized that incentives might modify the effects, and therefore only analyzed the conditions under incentives (10, 20, and 50 pesos).

[0102] As shown in Figure 2, the cross-sectional analysis showed a statistical trend of an increase from baseline in MIDT of 0.04 (p<0.1), indicating a trend of improved motivation in the study drug condition compared to control.

[0103] Example 3 The dose response of oxidative stress (induced by tert-butyl hydroperoxide (tBHP)) on astrocytes and mitochondrial function were investigated.

[0104] Primary astrocytes were cultured at a density of 15,000 cells per well on Seahorse XF-96 (Seahorse BioSciences-Bucher Biotec AG) plates coated with 0.1 mg / ml poly-D-lysine (catalog number A3890401_Gibco) diluted to 50 μg / ml in phosphate-buffered saline (PBS). Cells were cultured in the aforementioned medium and treated with a composition containing vitamin B9, taurine, and taurine:vitamin B9 at ratios of 1:2500 and 1:1700 for 48 hours prior to oxidative stress application and metabolic flux analysis. After performing a 1-hour dose-response of tBHP (7.8, 15.6, 31.2, 62.5, 125, and 250 micromolar) (see Figures 3a and 3b), 125 μM tBHP was selected to affect mitochondrial function and test the protective effects of the mentioned compounds.

[0105] As shown in Figure 3a, mitochondrial function, including reserve capacity, is reduced by oxidative stress.

[0106] Mitochondrial metabolism must continually adapt to stressful or harsh conditions in order to maintain bioenergetic levels relevant to cellular function. Metabolic adaptation requires mitochondrial reserve capacity to meet increasing demands.

[0107] As shown in Figure 3b, mitochondrial function, such as coupling efficiency, is decreased by oxidative stress.

[0108] Due to proton leak, tightly coupled mitochondria produce more ATP with less substrate and heat dispersion, whereas loosely coupled mitochondria produce less ATP with more substrate and heat dispersion.

[0109] Using a Seahorse XF metabolic analyzer, we performed a "mitochondrial stress test" according to a standard design (Gu X. et al., 2021). Three baseline measurements of oxygen consumption rate (OCR) were sampled before successive injections of mitochondrial inhibitors. Three metabolic determinations were sampled after each mitochondrial inhibitor addition and before subsequent inhibitor injections. The mitochondrial inhibitors used were oligomycin (1.5 μM), FCCP (carbonyl cyanide 4-(trifluoromethoxy)-phenylhydrazone) (3 μM), and antimycin (5 μM) and rotenone (0.5 μM). OCR was automatically calculated and recorded by the Seahorse software. After the assay, cells were stained with DAPI and nuclear counts were performed for normalization (OCR values / cell) using a Molecular Devices ImageXpress Micro Confocal High-content Imaging system. Spare respiratory capacity is calculated by Seahorse assay as (maximal respiration) / (basal respiration) x 100, and coupling efficiency is calculated as (ATP production rate) / (basal respiration rate) x 100. In treatment assays, values ​​are reported normalized to vehicle.

[0110] As shown in Figure 4, a taurine:vitamin B9 ratio of 1:2500 protects mitochondria from oxidative stress by improving mitochondrial reserve capacity. In fact, while other compounds alone or at different ratios (1:700) produce worse results than the vehicle, a ratio of 1:2500 shows better effects and outperforms the others up to the highest dose. Reserve capacity is an important characteristic of mitochondria adapting to cellular energy demands.

[0111] Figure 5 shows that a taurine:vitamin B9 ratio of approximately 1:2500 protects mitochondria from oxidative stress. In fact, it increases coupling efficiency in a dose-response manner, which in turn supports maximal ATP production with lower energy dissipation.

Claims

1. Taurine: A composition containing vitamin B9 in a ratio of approximately 1:2500 (where "approximately" refers to a value within the range of -10% to +10% of the reference value).

2. The composition according to claim 1, for use in increasing glutathione levels in the brain and / or improving mental abilities in an individual.

3. The composition according to claim 1 or 2, for use in improving motivation, concentration and / or sustained attention and fatigue in an individual.

4. The composition according to claim 1 or 2, further comprising at least one type of vitamin B.

5. The composition according to claim 1 or 2, wherein the at least one vitamin B is selected from vitamin B6 and / or vitamin B12.

6. The composition according to claim 1 or 2, wherein taurine and vitamin B9 are contained in the composition in a ratio such that the amounts of taurine and vitamin B9 in the composition are approximately 100 mg and 0.04 mg, or 120 mg and 0.05 mg, or 150 mg and 0.06 mg, or 200 mg and 0.08 mg, or 300 mg and 0.12 mg, or 400 mg and 0.16 mg, or 500 mg and 0.2 mg, or 600 mg and 0.24 mg, or 800 mg and 0.32 mg, or 1000 mg and 0.4 mg, or 2000 mg and 0.8 mg, or 3000 mg and 1.2 mg (where "approximately" refers to a value within the range of -10% to +10% of the reference value).

7. The composition according to claim 1 or 2, wherein taurine is administered to a human in an amount of at least about 500 mg (where "about" refers to a value within the range of -10% to +10% of the reference value).

8. Approximately 0.2 mg to 1.2 mg of vitamin B9, Vitamin B6 in amounts ranging from approximately 1.3 mg to approximately 7.8 mg. Vitamin B12 in amounts ranging from approximately 2.4 mcg to approximately 14.4 mcg The composition according to claim 5, further comprising at least one of the above (where "about" refers to a value within the range of -10% to +10% of the reference value).

9. The composition according to claim 1 or 2, wherein taurine and / or at least one of the vitamin B is administered to an animal or pet in an equivalent amount converted from a human dose to an animal dose based on body surface area, in accordance with FDA guidelines.

10. The composition according to claim 1 or 2, which is in the form of a food composition, dietary supplement, nutritional composition, nutritional supplement, powdered nutritional preparation that is reconstituted with water or milk before consumption, food additive, pharmaceutical, beverage and drink including coffee-based products, oral nutritional supplement (ONS), complete nutritional formulation, drug, medical product, or food product.

11. The composition according to claim 1 or 2, for use in cell protection and improvement of oxidative stress.

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