WO2021108855A1

WO2021108855A1 - Neurologically active flavonoid compositions and methods of use thereof

Info

Publication number: WO2021108855A1
Application number: PCT/AU2020/051313
Authority: WO
Inventors: Alistair Cumming
Original assignee: Gretals Australia Pty Ltd
Priority date: 2019-12-06
Filing date: 2020-12-03
Publication date: 2021-06-10
Also published as: AU2020395610A1

Abstract

The present invention relates to compositions comprising (i) a flavonoid capable of traversing the blood-brain barrier of a human to affect a cell, a tissue, a structure, or an organ of the human central nervous system, and (ii) one or more human compatible nutrient(s), solvent(s) or solute(s), and/or (iii) one or more pharmaceutically acceptable excipients. The invention further relates to the use of said composition for treating or preventing a condition associated with an impairment in any one or more of the following parameters: cognitive function, problem solving, alertness, attention span, memory, concentration, and mood. An exemplary flavonoid is the naturally derived flavanone (2S)-5,7-dihydroxy-2-phenyl-2,3-dihydrochromen-4-one (pinocembrin). The composition may optionally comprise an organic acid such as taurine.

Description

NEUROLOGICALLY ACTIVE FLAVONOID COMPOSITIONS AND METHODS OF USE THEREOF

FIELD OF THE INVENTION

[001]. The present invention relates generally to compositions having beneficial effects on the human neurological system. The invention further relates to methods of use of such compositions in humans by ingestion.

BACKGROUND TO THE INVENTION

[002]. For centuries, humankind has sought to improve mood, alertness, cognitive function and general feelings of wellbeing. A huge variety of compositions have been formulated for those purposes and used with varying degrees of success.

[003]. For example, compositions containing caffeine have proven useful in both solid form and in solution. It has been demonstrated in the prior art that consumption of moderate amounts of caffeine increase alertness and reduces fatigue (especially important in low arousal situations), performance on vigilance tasks and improved cognitive function. Whilst beneficial in some respects, a person may develop a dependence on caffeine and experience withdraw symptoms such as headache and depressed mood when consumption ceases. Other negative effects of caffeine use include insomnia, nervousness, irritability, gastric upset, diuresis, tachycardia and muscle tremors. Many users of caffeine are able to control intake so as to limit or obviate any negative effects, however some users are unable to do so.

[004]. Nicotine is used extensively for its anxiolytic effects, normally by smoking tobacco or inhalation via electronic cigarettes. Nicotine agonises the nicotinic acetylcholine receptor, resulting in a number of downstream effects including an increase in activity of dopaminergic neurons in the midbrain reward system, as well as the decreased expression of monoamine oxidase in the brain. Nicotine is reported to improve concentration and the ability to perform complex tasks quickly. Nicotine is addictive and dependence forming to a much greater extent than many other stimulants and relaxants.

[005]. Controlled substances have also been used extensively to confer beneficial neurological effects on humans. Compounds such as ephedrine and phenylpropanolamine may be used as concentration aids. Prescription-only medicines including amphetamine and methylphenidate may produce generally positive feelings in patients. Controlled and prescription only medicines may be difficult to access, and often for good reason given their toxicities and the potential for abuse and even overdosing.

[006]. Compositions may also be formulated to provide a depressant or a calmative effect. Compounds such as benzodiazepines are well known to produce such effects, but equally well known to be highly addictive. Furthermore use of these compounds may result in side -effects such as paranoia, hallucinations and constipation.

[007]. It is an aspect of the present invention to provide improved compositions having beneficial neurological effects in humans. It is a further aspect of the present invention to provide a useful alternative to prior art compositions.

[008]. The discussion of documents, acts, materials, devices, articles and the like is included in this specification solely for the purpose of providing a context for the present invention. It is not suggested or represented that any or all of these matters formed part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application.

SUMMARY OF THE INVENTION

[009]. In a first aspect, but not necessarily the broadest aspect, the present invention provides a composition comprising (i) a flavonoid capable of traversing the blood-brain barrier of a human to affect a cell, a tissue, a structure, or an organ of the human central nervous system, and/or (ii) one or more human compatible nutrient(s), solvent(s)s or solute(s), and/or (iii) one or more pharmaceutically acceptable excipients.

[010]. In one embodiment of the first aspect, the flavonoid is a dihydroxyflavanone and/or a (2S)-flavan-4-one.

[Oil]. In one embodiment of the first aspect, the flavonoid is of the type naturally synthesised in a plant cell, although is not necessarily obtained from a plant cell for use in the composition, and may be partially or completely synthesised.

[012]. In one embodiment of the first aspect, the flavonoid is a flavanone, and may be (2S)-5, 7 -dihydroxy-2 -phenyl-2,3-dihydrochromen-4-one, or a functional derivative thereof.

[013]. In one embodiment of the first aspect, the one or more human compatible nutrient(s) is any one or more of: a fat, an oil, a carbohydrate, a protein.

[014]. In one embodiment of the first aspect, the one or more human compatible nutrient(s) is, or is a component of, a food product.

[015]. In one embodiment of the first aspect, the food product is a meat-based food product, a dairy -based food product, or a plant-based food product.

[016]. In one embodiment of the first aspect, the solvent(s) and/or solute(s) are provided by a carbonated drink product, an energy drink product, a sports drink product, a coffee drink product, a tea drink product, a fruit or a vegetable juice drink product, an alcoholic drink product, a smoothie drink product, a flavoured drink product, a functional drink product, a malt drink product, a seltzer water product, or a kombucha drink product,

[017]. In one embodiment of the first aspect, the organic acid is an amino sulfonic acid. [018]. In one embodiment of the first aspect, the amino sulfonic acid is 2-aminoethane-l- sulfonic acid or a functional derivative thereof.

[019]. In one embodiment of the first aspect, the organic acid is of the type naturally synthesised in an animal cell, although is not necessarily obtained from an animal cell for use in the composition.

[020]. In one embodiment of the first aspect, the flavone is capable of effecting a cell, a tissue, a structure, or an organ of the human central nervous system.

[021]. In one embodiment of the first aspect, the flavone and/or the organic acid (where present) is/are capable of effecting a cell, a tissue, a structure, or an organ of the human central nervous system in any one or more of the following parameters: modulation of inflammation, modulation of neural cell membrane permeability, inhibiting the receptor for advanced glycation end products (RAGE), modulating mitochondrion-mediated apoptosis, reduction in reactive oxygen species, modulation of neurotransmission, potentiation of the striatum/hippocampus, membrane stabilization, modulation of neural cell volume, and inhibition of glutamate -mediate neurotoxicity.

[022]. In one embodiment of the first aspect, the flavone and/or the organic acid (where present) is capable of effecting a human in any one or more of the following parameters: cognitive function, problem solving, alertness, attention span, memory, concentration, and mood.

[023]. In one embodiment of the first aspect, the composition further comprises caffeine.

[024]. In one embodiment of the first aspect, the composition is in the form of a solid, a solution, a suspension or a slurry.

[025]. In one embodiment of the first aspect, the composition is in the form of a beverage. [026]. In one embodiment of the first aspect, the composition is in the form of an energy drink.

[027]. In one embodiment of the first aspect, the composition is carbonated.

[028]. In one embodiment of the first aspect, the composition is in a pharmaceutical dosage form.

[029]. In one embodiment of the first aspect, the composition is in the form of a food.

[030]. In one embodiment of the first aspect, the flavonoid is present at a concentration of at least about 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 15.0 or 20.0 g/lOOOg, or between about any two of the aforementioned concentrations.

[031 ]. In one embodiment of the first aspect, the organic acid is present at a concentration of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0,

9.0, 10.0, 15.0 or 20.0 g/lOOOg, or between about any two of the aforementioned concentrations.

[032]. In a second aspect, the present invention provides a method for effecting a cell, a tissue, a stmcture, or an organ of the human central nervous system, the method comprising the steps of administering the composition of any embodiment of the first aspect to a mammalian subject in need or desirous thereof.

[033]. In one embodiment of the second aspect, the effecting of a cell, a tissue, a structure, or an organ of the human central nervous system is an effect in any one or more of the following parameters: modulation of inflammation, modulation of neural cell membrane permeability, inhibiting the receptor for advanced glycation end products (RAGE), modulating mitochondrion-mediated apoptosis, reduction in reactive oxygen species, modulation of neurotransmission, potentiation of the striatum/hippocampus, membrane stabilization, modulation of neural cell volume, and inhibition of glutamate -mediate neurotoxicity.

[034]. In one embodiment of the second aspect, the effecting is effecting a human in any one or more of the following parameters: cognitive function, problem solving, alertness, attention span, memory, concentration, and mood.

[035]. In a third aspect, the present invention provides a method of treating or preventing a condition associated with an impairment in any one or more of the following parameters: cognitive function, problem solving, alertness, attention span, memory, concentration, and mood, the method comprising the steps of administering to a mammalian subject in need thereof an effective amount of a composition according to any embodiment of the first aspect.

[036]. In a fourth aspect, the present invention provides for use of the composition of any embodiment of the first aspect in the treatment or prevention of a condition associated with an impairment in any one or more of the following parameters: cognitive function, problem solving, alertness, attention span, memory, concentration, and mood.

[037]. In a fifth aspect, the present invention provides for use of a composition of any embodiment of the first aspect in the manufacture of a medicament in the treatment or prevention of a condition associated with an impairment in any one or more of the following parameters: cognitive function, problem solving, alertness, attention span, memory, concentration, and mood.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS THEREOF

[038]. After considering this description it will be apparent to one skilled in the art how the invention is implemented in various alternative embodiments and alternative applications. However, although various embodiments of the present invention will be described herein, it is understood that these embodiments are presented by way of example only, and not limitation. As such, this description of various alternative embodiments should not be constmed to limit the scope or breadth of the present invention. Furthermore, statements of advantages or other aspects apply to specific exemplary embodiments, and not necessarily to all embodiments, or indeed any embodiment covered by the claims.

[039]. Throughout the description and the claims of this specification the word "comprise " and variations of the word, such as "comprising" and "comprises" is not intended to exclude other additives, components, integers or steps.

[040]. Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment, but may.

[041]. The present invention is predicated at least in part on the inventors’ discovery that certain plant derived flavones may be used in a food or beverage product, or in a pharmaceutical dosage form so as to provide beneficial neurological effects in humans when ingested. Advantageously such foods, beverages and pharmaceutical dosage forms may be used without medical prescription or supervision given the safety profile of the plant derived flavones. Thus, the consumer is provided with a readily available source of neurologically active flavones which have effects at the cellular level which manifest in noted improvements in any one or more of cognitive function, problem solving, alertness, attention span, memory, concentration, and mood.

[042]. Some embodiments of the invention are directed to the combination of a neurologically active organic acid and a neurologically active flavonoid provides beneficial neurological effects in humans. Advantageously, such compositions may be provided in the form of a beverage, or a food. In some instances the compositions are provided in the form of a pharmaceutical or nutraceutical formulation. In any event, the compositions are adapted to be taken orally by a human.

[043]. The Examples provided herein propose that compositions comprising an organic acid and a flavonoid in combination provide beneficial neurological effects not noted when either the organic acid or flavonoid are administered alone. Based on these observations the organic acid and/or the flavonoid may be acting in a synergistic manner to provide a new and unexpected effect in humans.

[044]. Without wishing to be limited by theory in any way, the beneficial effect brought about by the administration of the organic acid and the flavonoid appears to be the result of effects at the cellular level which manifest in noted improvements in any one or more of cognitive function, problem solving, alertness, attention span, memory, concentration, and mood.

[045]. In some embodiments of the composition, the flavonoid and/or the organic acid is/are not controlled substances. In the context of the present invention, the term “uncontrolled substance” is intended to mean any substance that does not require the prescription or approval of a medical practitioner, or the approval of a pharmacist for supply to a consumer. The use of uncontrolled substances is advantageous given that a composition produced therefrom may be freely sold in a retail outlet such as an online store, supermarket, convenience store, health food store, restaurant, cafe or bar.

[046]. In the context of the present invention, the term “flavonoid” is intended to include flavanols, flavones, and flavanones. In some embodiments of the composition the flavonoid is a flavanone, and in some embodiments a chiral flavanone existing as optical isomers, and in which case the flavanone may be either the D- form or the S-form. In some embodiments of the compositions the S-isomer is used in the present compositions. [047]. There are three main methods of production of pinocembrin. Extraction of pinocembrin may use as a starting material, a plant material, honey or propolis, and fungi for example.

[048]. For reason of cost, efficiency or consumer acceptance, the compound may be preferably extracted from a natural source. The compound is present in a wide variety of plants but is more prevalent in some families. It does not uniformly occur in a particular part of the plant, but each family tends to concentrate it in the same area. It is thought to perform a protective function for the plant in case of pathogen attack. The majority of plants appear to contain (S)-pinocembrin, but some contain the (R)-enantiomer or racemic material.

[049]. Many Eucalyptus species contain pinocembrin, and some to very high levels. For example Eucalyptus torelliana may express the compound to a level of 3.7% in fruit resin. Fower levels are found in leaf material, although nevertheless sufficient to provide for practical and economical extraction.

[050]. Some of the highest yields of pinocembrin come from Alpinia species, in fact Alpinia katsumadai appears to be a prime commercial source. The yields reported for this species range from 613mg/kg to 2490mg/kg from the seeds. 32000mg/kg has been isolated from the rhizomes of Alpinia ojficinarium.

[051 ]. The leaves of Glycyrrhiza glabra (liquorice) are reported to have a particularly high level of pinocembrin, up to 24100mg/kg.

[052]. Pinocembrin has been detected in monofloral honey of Leptospermum polygalifolium and Leptospermum scoparium. This indicates that the nectar of these plants contain pinocembrin, and at a level of 60 to 260mg/kg. [053]. Pinocembrin has been isolated from the flowers of Syzygium jambos and the leaves and fruit of S. samarangense. The content in the fruit is not particularly high at 2.2mg/kg, although usable.

[054]. Preferably, pinocembrin is isolated from a plant source without using chromatography. If chromatography must be used, it should be as late as possible in the process to minimise the complexity of the extract and the volumes of solvent required.

[055]. A crude mixture of only 3 flavanoids was isolated from Eucalyptus sieberi by the following steps. Extraction with methanol at room temperature followed by partial concentration, followed by pouring into water and filtering off the precipitate. Repeated re-dissolution of the precipitate in methanol and re -precipitation with water until no flavanoids remained in the precipitate. Concentration of the combined aqueous methanol solutions and extraction of chlorophyll and wax with petroleum spirit. Partial concentration of the petroleum spirit and liquid-liquid extraction with ether for several days. Partial concentration and precipitation in the cold followed by separation by chromatography.

[056]. An alternative process to the concentration of large volumes of aqueous methanol would be to pass it through a macroporous resin such as XAD, carry out gradient elution and collect and concentrate the target fractions. Chromatography is nevertheless required.

[057]. Crude extracts containing flavanoids have been obtained from dry leaves by room temperature extraction, and by soxhlet extraction with n-hexane60 or methanol. Soxhlet extraction uses less solvent than cold extraction and indicates that pinocembrin can survive up to 68°C for extended periods. Extraction with methanol was investigated using soxhlet extraction (64.7°C, 32h), ultrasonic assisted extraction (ultrasound, 40°C. 30min thrice) and accelerated solvent extraction at 60°C (lOObar, 20min, two cycles), 80°C (lOObar, 20min, two cycles), and 100°C (lOObar, 20min, two cycles) which gave 3.2g, 2.6g, 3.3g, 3.6g and 3.5g of extract respectively. [058]. Pinocembrin for the present compositions may be obtained by fermentation methods in Escherichia coli, Saccharomyces cerevisiae and Streptomyces venezuelae. The first two appear to produce (S)-pinocembrin but S. venezuelae produces a racemate.

[059]. . Cell culture is proposed as a means for production of plant-derived metabolites

(including pinocembrin) as it has the potential to accumulate higher quantities than an intact plant. Members of the family Zingiberaceae produce significant quantities of pinocembrin. Up to 9.2g/kg has been reported for Boesenbergia rotunda, a member of this family. Cell suspension cultures have been established using a meristem-derived callus using a medium of naphthyl acetic acid and 2,4-dichlorophenoxyacetic acid. Inoculation at l.OmL of settled cell volume led to the maximum accumulation of pinocembrin at 8.6mg/kg of dry weight.

[060]. There are a number of chemical syntheses of pinocembrin reported in the literature.

For example, pinocembrin can be biosynthesised from L-phenylalanine. Four catalytic steps are required for this conversion. First, L-phenylalanine is converted to cinnamic acid by phenylalanine ammonia lyase (PAL). Cinnamic acid is then converted into the corresponding coenzyme A (CoA) ester by 4-coumarate:CoA ligase (4CL). Three molecules of malonyl-CoA are then condensed stepwise with one molecule of the cinnamyl-CoA ester to give (2S)-pinocembrin chalcone, catalysed by chalcone synthase (CHS). Finally chalcone isomerase (CHI) converts chalcone to (2S)-pinocembrin.

[061]. In some embodiments of the composition the flavanone is pinocembrin and preferably (S)-pinocembrin as shown below.

[062]. Other dihydro xyflavanones may be used in place of pinocembrin for example, 4’, 7-

Dihydroxyflavanone (liquiritigenin) may be used.

[063]. In some embodiments a monohydroxylflavanone such as pinostrobin (being a (2S)- flavanone substituted by a hydroxyl group at position 5 and a methoxy group at position 7.

[064]. Other potentially useful compounds include the flavanones chrysin, galangin and pinobanksin.

[065]. It will be understood that alternatives to pinocembrin may not necessarily confer the same level of benefit with respect to a neurological parameter when used in the present compositions, however may nevertheless be entirely useful in the context of the present invention.

[066]. The organic acid may be an organosulfonic acid, an amino acid, or an amino sulfonic acid. Preferably, the organic acid is taurine (2-Aminoethane-l -sulfonic acid).

[067]. The weight ratio of the flavonoid to the organic acid may range from about 1 :2000 to about 100:1, from about 1:1900 to about 95:1, for example from about 1:1800 to about 90 : 1 , for example from about 1 : 1700 to about 85:1, for example from about 1 : 1600 to about 80:1, for example from about 1:1500 to about 75:1, for example from about 1:1400 to about 70 : 1 , for example from about 1 : 1300 to about 65 : 1 , for example from about 1 : 1200 to about 60 : 1 , for example from about 1 : 1100 to about 60 : 1 , for example from about 1 : 1000 to about 60:1, for example from about 16:1 to about 1:16.

[068]. The flavonoid or organic acid may be used in the present compositions in substantially purified form, or in a virtually pure form. However, it may not be necessary in all circumstances for these compounds to be used in purified form. For example, the flavonoid or organic acid may be used as a partially purified biological extract. [069]. The flavonoid and the organic acid are both capable of traversing the blood -brain barrier in a human. Practically, this means the compounds can be ingested and then contact cells of the central nervous system. The blood-brain barrier is impermeable to many compounds given the presence of tight junctions between adjacent endothelial cells, the limited level of pinocytosis, and expression of multidmg transporters.

[070]. Blood-brain barrier permeability may be predicted to some extent by a consideration of polarity, and hydrophobicity/hydrophilicity. However, many lipophilic species are impermeable because of multidmg transporters at the luminal and abluminal membranes. Conversely, many polar species traverse the barrier more readily than predicted by their oil/water partition coefficients due to the presence of specific nutrient transporters. In vitro models of the blood-brain barrier are useful in selecting components of the present compositions. For example, isolated brain micro vessels and cell culture models may be used. Isolated brain micro vessels from mammalian brains may be used to measure multidmg dmg transporters and tight junction integrity. Cell culture models allow for measurement of directional transport.

[071 ]. As will be appreciated, all of the organic acid or flavonoid does not need to traverse the blood-brain barrier. All that is required is for sufficient compound to traverse the barrier so as to achieve a desired neurological effect. In that regard, the compound may partition across the blood brain barrier at a ratio of at least about 0.01:10, 0.1:10, 1:10, 2:10, 3:10, 4:10, 5:10, 6:10, 7:10, 8:10, or 9:10 (semm side:CNS side).

[072]. In some circumstances, the ability of the compounds to traverse the blood-brain barrier may be assessed by measuring (qualitatively or quantitatively) a positive neurological parameter, as described in the illustrative examples infra. Such assessments should be made against suitable controls (such as sham compositions) to minimise any placebo effect.

[073]. The amount of flavonoid and organic acid in the composition may be according to the effect desired, the type of composition (beverage, food, or pharmaceutical), and the like. The composition may be formulated to contain at least about 0.0 lg, O.lg, l.Og, 2g, 3g, 4g, 5g, 6g, 7g, 8g, 9g or lOg of the flavonoid per serving or dose. The composition may be formulated to contain at least about O.Olg, O.lg, l.Og, 2g, 3g, 4g, 5g, 6g, 7g, 8g, 9g or lOg of the organic acid per serving or dose. Where the composition is a beverage, the serving may be between about 100 ml and about 500 ml. Where the composition is a food, the serving may be between about 100 g and about 500 g. Where the composition is solid pharmaceutical dosage form, the serving may be between about 1 g and about 10 g. Where the composition is liquid pharmaceutical dosage form, the serving may be between about 1 ml and about 10 ml. Where the composition is configured for sublingual administration, relatively low amounts such as from about 0.1 micrograms to about 0.5 mg of flavone may be efficacious.

[074]. Where the present compositions is formulated as a beverage, it may be a functional drink, a soft drink, an energy drink, a tea, a coffee, a kombucha, a diet drink, a nutritional drink, an alcoholic drink, or a milk-based drink. The beverage may be carbonated or still. Alternatively, the composition may be in powder or granular form suitable for dissolution in water to form a beverage.

[075]. The present compositions may be presented in solid form such as a functional food, a yoghurt, a biscuit, a slice, a cake, a sprinkle, or a chewing gum.

[076]. The composition or pharmaceutical composition may further comprise a nutrient ingredient selected from the group consisting of vitamins and minerals, and combinations thereof. The vitamin may be any one or more of vitamin A, vitamin D, vitamin E, vitamin K, thiamine, riboflavin, pyridoxine, cyanocobalamin, carotenoids (including beta-carotene, zeaxanthin, lutein and lycopene), niacin, folic acid, pantothenic acid, bergamot, a polyphenol compound, biotin, vitamin C, choline, inositol, and salts and derivatives thereof. The mineral may be any one or more of calcium, phosphorous, magnesium, iron, zinc, manganese, copper, cobalt, boron, iodine, sodium, potassium, molybdenum, selenium, chromium, fluorine and chloride. If present, the composition or pharmaceutical composition may comprise from about 0.0001 % to about 50 % by weight of vitamin(s) and/or mineral(s), based on the total weight of the composition, for example, from about 0.01 % to about 45% by weight, from about 0.1 % to about 40 % by weight, or from about 0.5 % to about 30 % by weight, or from about 0.5 % to about 20 % by weight, or from about 0.5 % to about 10 % by weight, or from about 0.5 % to about 5 %, or 20 from about 0.5 % to about 3 %, or from about 0.1 % to about 2 %, or from about 0.1 to about 1 % of vitamin(s) and/or mineral(s), based on the total weight of the composition or pharmaceutical composition. The composition may comprise from about 0.0001 % to about 5 wt. %, for example, from about 0.0001 % to about 2 wt. %, or from about 0.0001 % to about 1 wt. %, or from about 0.0001 % to about 0.5 wt. %, or from about 0.0001 % to about 0.1 wt. %, or from about 0.0001 % to about 0.01 wt. % by weight of vitamin(s) and/or mineral(s), based on the total weight of the composition.

[077]. The present compositions may comprise further compounds functioning to improve a neurological parameter in a subject. Compounds such as caffeine, sugar, vitamins, minerals, and the like may be added to the flavonoid and organic acid to provide further benefit in neurological functioning.

[078]. The composition may, for example, be a pharmaceutical composition (medicament), suitable for oral, sublingual, buccal, nasal, topical, suppository, intravenous or intradermal administration. The composition may alternatively be a nutraceutical composition, for example, a foodstuff, food supplement, dietary supplement, health supplement, meal replacement product, beverage, beverage supplement, or food additive.

[079]. The term “pharmaceutical composition” or “medicament” in the context of this invention means a composition comprising (a pharmaceutically effective amount of) flavonoid and organic acid and additionally one or more pharmaceutically acceptable carriers and/or excipients and/or diluents. The pharmaceutical composition may further contain ingredients selected from, for example, diluents, adjuvants, excipients, vehicles, preserving agents, fillers, binders, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavouring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents, coating agents, encapsulating agents and dispersing agents, depending on the nature of the mode of administration and dosage forms. The pharmaceutical compositions may take the form, for example, of solid preparations including tablets, capsules, caplets, dragees, lozenges, granules, powders, pellets, beads and cachets; and liquid preparations including elixirs, symps, suspensions, sprays, emulsions, lotions, creams and solutions. Techniques and formulations generally may be found in Remington, The Science and Practice of Pharmacy, Mack Publishing Co., Easton, PA, latest edition.

[080]. In solid dosage forms of the invention for oral administration, the active flavonoid and organic acid may be mixed with one or more pharmaceutically acceptable carriers, such as dicalcium phosphate, and/or any of the following: diluents, fillers or extenders, such as starches, lactose, sucrose, glucose, dextrates, mannitol, microcrystalline cellulose and/or silicic acid; binders, such as, for example, hydroxypropylcellulose, hypromellose, hydroxypropyl methylcellulose, polyglycol such as polyethylene glycol, carboxymethylcellulose, gelatine, polyvinyl pyrrolidone’s, polyvinyl acetate, sucrose and/or acacia; disintegrating agents, such as starch, for example, potato or tapioca starch, starch derivatives such as sodium starch glycolate, crospolyvinylpyrollidone, calcium carbonate, croscarmellose sodium, alginic acid, silicone dioxide, and certain silicates; lubricants, such as talc, calcium stearate, magnesium stearate, stearic acid, sodium sulfate stearyl fumarate, solid polyethylene glycols, solubiliser such as sodium lauryl sulfate, flavouring and colouring agents and mixtures thereof.

[081]. Tablets, and other solid dosage forms of the pharmaceutical compositions of the invention, may optionally be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulation art. They may also be formulated so as to provide slow or controlled release of the active ingredient(s) therein using, for example, natural and synthetic polymers such as hydro xypropylmethyl cellulose methacrylates, methacrylic acid copolymers (e.g. methyl acrylate -methacrylic acid copolymers and methyl methacrylate -methacrylic acid copolymers), shellac, ethylcellulose, cellulose acetate phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, cellulose acetate succinate, hydroxyl propyl methyl cellulose acetate succinate, sodium alginate, waxes, fatty acids, zein, respectively, in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres may also be used. These compositions may also optionally contain colourants and/or opacifying agents and may be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.

[082]. The compositions may comprise no more than about 70 % w/w of a food-acceptable carrier (including a beverage acceptable carrier) or a pharmaceutically acceptable carrier and/or excipient and/or diluent, for example, no more than about 65 % w/w of carrier and/or excipients and/or diluent, or no more than about 60 % w/w of carrier and/or excipients and/or diluent, or no more than about 55 % carrier and/or excipients and/or diluent, or no more than about 50 % w/w of carrier and/or excipients and/or diluent, or no more than about 45 % w/w of carrier and/or excipients and/or diluent, or no more than about 40 % of w/w carrier and/or excipients and/or diluent, or no more than about 35 % w/w of carrier and/or excipients and/or diluent. For example, the composition may comprise at least about 1 % w/w, or at least about 10 % w/w, or at least about 15 % w/w, or at least about 20 % w/w, or at least about 25 % w/w, or at least about 30 % w/w of food acceptable carrier or pharmaceutically acceptable carrier and/or excipients and/or diluent.

[083]. Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions for oral ingestion. Liquid preparations can also be formulated in aqueous solution. In certain embodiments, the flavonoid and the organic acid may be mixed with one or more food acceptable or pharmaceutically acceptable carriers and/or excipients and/or diluents, such as water and/or any of the following: solvent such as propylene glycol, alcohol; humectant such as glycerol; sweeteners such as liquid glucose, com symp and sucrose; artificial sweeteners such as aspartame, stevia and sucralose; preservatives such as benzoates and parabens; viscosity modifiers/thickeners such as gums and alginates; buffering agents; flavouring agents and colouring agents. [084]. Also included are solid form food and pharmaceutical preparations, for example, tablets, capsules, granules and powder, which are intended to be converted, shortly before use, to liquid form preparations for oral ingestion. These particular solid form preparations may be provided in unit dose form and as such are used to provide a single dosage unit. Alternatively, sufficient solid may be provided so that multiple individual liquid doses may be reconstituted when required, by measuring predetermined volumes of the solid form preparation as with a spoon, or other measuring device. The solid form preparations intended to be converted to liquid form may contain, in addition to the active material, flavourings, colourants, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilising agents, and the like. The liquid utilized for preparing the liquid form preparation may be water, isotonic water, juices, milk, ethanol, and the like as well as mixtures thereof.

[085]. Also included are solid form preparations which are intended to be combined with a food or foodstuff before oral consumption. The solid form preparations may be mixed into the food or foodstuff or applied to the food or foodstuff, e.g., by sprinkling onto the food or foodstuff. Such solid forms include powders, granules, pellets and the like. Such food of foodstuffs include, without limitation, prepared meals (cooked or fresh), soup, dairy based products (e.g., yoghurt, cream, creme-fraiche), flour based products such as bread and pasta, snack or convenience items such as snack bars (e.g., chocolate bars), confectionary products, and the like.

[086]. In certain embodiments, the food or foodstuff, and the like, comprises from about 0.1 wt. % to about 50 wt. % of the composition of the invention described herein, based on the total weight of the food or foodstuff, for example, from about 0.1 wt. % to about 40 wt. %, or from about 0.1 wt. % to about 30 wt. %, or from about 0.1 wt. % to about 20 wt. %, or from about 0.1 wt. % to about 15 wt. %, or from about 0.1 wt. % to about 10 wt. %, or from about 0.1 wt. % to about 8 wt. %, or from about 0.1 wt. % to about 6 wt. %, or from about 0.1 wt. % to about 4 wt. %, or from about 0.1 wt. % to about 2 wt. % of the composition of the invention described herein. In certain embodiments, the food or foodstuff, and the like, comprise at least about 0.2 wt. % of the compositions of the invention described herein, based on the total weight of the food or foodstuff, for example, at least about 0.5 wt. %, or at least about 1 wt. %, or at least about 5 wt. % of the composition of the invention described herein.

[087]. In certain embodiments, the composition is ingested at least daily or weekly by the subject. In some circumstances, a single ingestion will provide a positive neurological effect. It is contemplated that regular ingestion will lead to long term improvement in neurological function, and possibly even positive remodelling of neurological function. For some subjects, only a transient effect is required (for example when studying or prior to an examination) in which case an isolated ingestion may be sufficient.

[088]. The amount of composition administered may be varied depending upon the requirements of the subject. For both therapeutic and non -therapeutic applications, the amount of composition administered may be varied depending upon the desired results, the requirements of the subject and the level of improvement in neurological function required. Determination of the proper serving/dosage for a particular situation is within the skill of the art. The total daily serving/dosage may be divided and administered in portions during the day if desired.

[089]. In general, a suitable daily dose or serving of active agents in the composition according to the invention will be that amount which is the lowest dose or serving effective to produce the desired effect, for example, a therapeutic effect or a non-therapeutic effect (such as an improvement in an already acceptable neurological parameter). It is contemplated that a wide range of doses and servings may be used, due to the generally non-toxic nature of the composition. A person of ordinary skill in the art will understand that a suitable dosage or serving will typically vary from subject to subject, and will be dependent on factors such as the type and magnitude of effect required. For example, the dose or serving of composition (whether liquid or solid) may be at least about 100 g, 200 b, 300 g, 400 g, 500 b, 600 g, 700 g, 800 g, 900 g or 1000 g per day. [090]. Conveniently, where in the form of a beverage the composition may be presented in a beverage can or bottle or the type well known in the field of single server consumer beverages. Such can or bottle may have a capacity of between about 250 ml and 500 ml. Smaller “shot” size servings may be provided in bottles having a capacity of between 50 mL to 250 ml, or between about 50 ml and 100 ml.

[091 ]. The compositions of the present invention (whether food, beverage, pharmaceutical or other) may be used in various therapeutic and non-therapeutic applications. Modulation of a neurological parameter in a recipient may occur after immediately or shortly after a single serving or dose. In some instances, multiple administrations may be required over a time period in order to provide a desired outcome.

EXAMPLE 1: Preparation of food compositions comprising pinocembrin, and optionally taurine

[092]. .A first bread loaf product is prepared according to industry standard methods and using industry standard ingredients, except that pincocembrin (in purified powdered form) is well mixed with flour at a rate of 0.1% to 10% (w/w) before combining with other ingredients.

[093]. A second bread loaf product is prepared according to industry standard methods and using industry standard ingredients, except that pincocembrin (in purified powdered form) is well mixed with flour at a rate of 0.1 % to 10% (w/w of flour). T aurine (in purified powered form) is added at a rate of 0.1% to 10% (w/w of flour) before combining with other ingredients.

[094]. A first biscuit product is prepared according to industry standard methods and using industry standard ingredients, except that pincocembrin (in purified powdered form) is well mixed with flour at a rate of 0.1% to 10% (w/w of flour) before combining with other ingredients. [095]. A second biscuit product is prepared according to industry standard methods and using industry standard ingredients, except that pincocembrin (in purified powdered form) is well mixed with flour at a rate of 0.1% to 10% (w/w of flour). Taurine (in purified powered form) is added at a rate of 0.1% to 10% (w/w of flour) before combining with other ingredients.

[096]. A first yoghurt product is prepared according to industry standard methods and using industry standard ingredients, except that pincocembrin (in purified powdered form) is well mixed with the yoghurt before final packaging at a rate of 0.1% to 10% (w/w of yoghurt).

[097]. A second yoghurt product is prepared according to industry standard methods and using industry standard ingredients, except that pincocembrin (in purified powdered form) is well mixed with yoghurt at a rate of 0.1 % to 10% (w/w of yoghurt). Taurine (in purified powered form) is added at a rate of 0.1% to 10% (w/w of yoghurt) before combining with other ingredients.

[098]. A first breakfast cereal flake breakfast product is prepared according to industry standard methods and using industry standard ingredients, except that a pincocembrin solution is evenly sprayed onto the exterior surfaces of the flakes while being continuously tossed in a rotating bin. Air is blown through the coated flakes to evaporate solvent from the pinocembrin composition to leave a pinocembrin coating. In some cases, the pinocembrin solution comprises also a sugar or other substance that will positively adhere to the flake surface thereby trapping the pinocembrin to the flake. The pinocembrin solution is prepared to provide a 0.1% to 10% (w/w of flakes).

[099]. A second breakfast cereal flake breakfast product is prepared according to industry standard methods and using industry standard ingredients, except that a pincocembrin and taurine solution is evenly sprayed onto the exterior surfaces of the flakes while being continuously tossed in a rotating bin. Air is blown through the coated flakes to evaporate solvent from the pinocembrin and taurine solution to leave a pinocembrin/taurine coating. [100]. In some cases, the pinocembrin and taurine solution comprises also a sugar or other substance that will positively adhere to the flake surface thereby trapping the pinocembrin to the flake. The pinocembrin and taurine solution is prepared to provide a 0.1% to 10% (w/w of flakes).

EXAMPLE 2: Preparation of aqueous composition comprising pinocembrin and optionally taurine

Solid components were weighed and mixed with water at room temperature until all solid components were apparently dissolved.

EXAMPLE 3: Preparation of aqueous composition comprising pinocembrin, taurine and caffeine

Solid components were weighed and mixed with water at room temperature until all solid components were apparently dissolved. EXAMPLE 4: Preparation of aqueous composition comprising pinocembrin and taurine, caffeine and other ingredients for an energy drink

[101]. Solid components were weighed and mixed with water at room temperature until all solid components were apparently dissolved.

EXAMPLE 5 Administration of composition and effects on mood and cognitive function.

[102]. Four healthy adult subjects ingested 150 ml of a composition as prepared in

Example 1 , having the combination of pinocembrin and taurine. Control compositions were prepared as follows:

[103]. Test: Composition as for Example 1 (having 0.1 g pinocembrin)

[104]. Control #1 : Composition as for Example 1 , except devoid of pinocembrin

[105]. Control #2: Composition as for Example 1 , except devoid of taurine. [106]. Control #3 Composition as for Example 1, except devoid of taurine and pinocembrin

[107]. In each case, the composition was consumed in the morning, one hour after rising and in the absence of other gastric contents.

[108]. The presence of sugar tended to mask any unusual flavour of the pinocembrin and taurine (if any). In that regard, the study was blinded with no subject being aware whether a test, control or vehicle was being consumed.

[109]. On day 1, all subjects ingested the test composition.

[110]. On day 2, all subjects ingested control composition #1

[111]. On day 3, all subjects ingested control composition #2.

[112]. On day 4, all subjects ingested control composition #3.

[113]. These administrations were repeated the following week.

[114]. Subjects performed tests of neurological activity one hours after consumption of the relevant composition.

[115]. Subjects did not consume any food, drink or medication until after the test of neurological activity was completed.

[116]. Subjects complete the following tests online:

[117]. Attention Span Test:

[118]. https://www.psvchologvtodav.com/au/tests/personality/attention-span-test

[119]. Memory Test:

[120] https://www.psychologytoday.com/au/tests/iq/memory-test [121]. Concentration Test:

[122]. https://www.psvchologvtodav.com/au/tests/career/concentration-focus-ski11s-test

[123]. Mood Test:

[124]. https://www.nhs.uk/conditions/stress-anxiety-depression/mood-self-assessment/

[125]. For each subject, results of each test were compared and are presented in the table below:

[126]. From the data above it will be noted that in many instances, the presence of taurine or pinocembrin provided benefit in neurological function over the vehicle (Control #3) across the varied tests directed to attention span, concentration, memory and mood.

[127]. In some instances, each of taurine and pinocembrin when administered alone failed to give any benefit over the vehicle, yet when combined a clear benefit was noted. Reference is made in particular to Subject D where a synergism between the two compounds was noted with respect to attention span, concentration and mood. Synergisms were apparent also in Subject C for mood, Subject B for attention span and mood, and subject A for concentration and mood.

[128]. Similar studies are performed using a composition of Example 2 having pinocembrin only (i.e. without taurine), although without the need for any taurine control.

[129]. Similar studies are performed using any of the food products of Example 1, having pinocembrin and optionally taurine. Controls for the effects of pinocembrin and/or taurine are included as required.

EXAMPLE 6: Large Scale Assessment of Energy Drink Composition on Cognition

[ 130]. Healthy young subjects are recmited using opportunity sampling from a University environment. All volunteers self-report that they are in good health, do not smoke, do not consume alcohol or caffeine excessively, are not taking medication, and are not using recreational dmgs. A total of 100 subject are recruited, with equal representation of males and females from across a range of ethnic backgrounds.

[131]. In first experiment, a first test composition (250 ml) is prepared so as to mimic pinocembrin-fortified Red Bull™ energy drink (as per the composition of Example 3 herein). To test the presence of a dose -response relationship, a range of pinocembrin concentrations (against a fixed taurine concentration) may be used, such as 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 15.0 or 20.0 g/lOOOml. To test the presence of a dose -response relationship, a range of taurine concentrations (against a fixed pinocembrin concentration) may be used, such as 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0, 15.0 or 20.0 g/lOOOml. Control compositions are prepared as for the test composition, except for a first control composition is devoid of taurine, a second control composition is devoid of pinocembrin and a third control composition is devoid of both pinocembrin and taurine.

[132]. In a second experiment, a second test composition is prepared using a Red Bull™ energy drink obtained through a normal retail outlet to which Pinocembrin is added to a final concentration of 4 g/1000 ml. To test the presence of a dose-response relationship, a range of pinocembrin concentrations may be used, such as 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 15.0 or 20.0 g/lOOOml. As a control for this second experiment regular Red Bull™ energy drink obtained through a normal retail outlet is used.

[133]. All compositions are stored at 4 degrees Celsius before use.

[134]. The compositions for the first experiment and the second experiment as detailed above are used in separate experiments, and each experiment having a different set of subjects.

[135]. Cognition of subjects is quantitated for test and control compositions using the

CogTrack system, an online set of nine cognitive tests accessible at the URL www.wesnes.com. Before each test, all required task resources are downloaded within the web browser, to ensure the rates of stimuli presentation and assessment of speed and accuracy are managed on the local computer. At completion of each task data are uploaded to the administering server. This procedure negates any fluctuation in Internet connection speeds from affected the outcome of each test. [136]. Instructions for a task are presented to the subject on the computer screen, with the subject initiating the test by pressing a designated key on the computer keyboard. Task stimuli are presented on the same screen. Responses within each task are made using the keyboard. There are nine tasks in total, each of which is described below and in the order administered:

[137]. Word recall: a list of fifteen words is shown on the screen, at the rate of one word every two seconds. The subject is then allowed one minute to type all recalled words using the keyboard. Words correctly recalled and any errors are quantitated.

[138]. · Pattern separation: a series of twenty images showing familiar everyday scenes and objects are shown on the screen, at the rate of one every 3 seconds. The subject is informed that the images will all be shown again later, although intermingled with similar images

[139]. · Simple reaction time task: the subject is instmcted to press a designated keyboard key as quickly as possible when presented with a stimulus on the screen. The stimulus is a 4.5 cm by 3.5 cm image of a right facing arrow containing the word ‘YES’. The subject rests his/her index finger on the right arrow key. A total of 50 stimuli are presented on the screen using a randomly variable interval between stimuli. The speed of the subject’s response for each stimulus is recorded.

[140]. · Digit vigilance task: A computer randomly selects a target digit (1-9) and displays the digit constantly on a side portion of the screen. Digits are shown (one at a time) in the screen centre at a rapid rate. The subject must quickly press a dedicated key as where the two digits match. A total of 450 digits is presented to the subject, with 15 target digits in each block of 150 digits. Correct matches, detection speed and erroneous responses are all recorded.

[141]. · Choice reaction time task: This task has two possible stimuli in this task: a right facing arrow or a left-facing version of the arrow, having the word ‘NO’ overlaid. For each of 50 trials, one of the two stimuli is selected randomly by the computer and displayed to the subject in the screen centre, and remains until the subject enters a response. The interval between each trial is randomly varied, and the subject maintains the left and right index fingers resting on the relevant keys and responds as quickly and accurately as possible. The accuracy and speed of each response is recorded.

[142]. · Spatial working memory task: An array of nine lights is shown on the screen for a 10 second period. Four of the nine light bulbs are lit. The subject must memorise the location of each lit bulbs. After 36 presentations of the array, each time with only a single bulb lit. For each presentation the subject must decide if the lit bulb was one of those lit in the original array (if positive, the right keyboard arrow is pressed, otherwise the left arrow is pressed). The images remain on the screen until the subject responds by the left and right keyboard arrows. Over the series of bulb presentations, each bulb is randomly lit four times, with the two same positions not being shown consecutively, and no more than four target or distractor stimuli being presented consecutively. The accuracy and speed of the subject’s response on each occasion is recorded.

[143]. · Numeric working memory task: A series of five digits (each different to the other) is shown on the screen at the rate of one digit per 1.2 seconds. The subject must hold the digits in memory. Next, a series of 30 probe digits is shown, each remaining on the screen until the subject responds, by response is made by indicating if the digit was in the original series (if positive, the right keyboard arrow is pressed, otherwise the left arrow is pressed). For the series of 30 probe digits, each of the digits (i.e. 0-9) is randomly shown three times, subject to the mles that the same digit is not presented consecutively and no more than four target or four distractor stimuli are presented consecutively. The accuracy and speed of the subject’s response to each probe digit is recorded.

[144]. Delayed word recall task: The subject is allowed 60 seconds to enter (by keyboard) as many words as can be recalled from an earlier presented list, and in any order. The number of words correctly recalled and the number of erroneous words recalled are recorded. [145]. Word recognition task: An original list of fifteen words plus fifteen distractor words are shown to the subject consecutively in a random order. For each word the subject indicates if it was from the original list of words (if positive, the right keyboard arrow is pressed, otherwise the left arrow is pressed). Each word remains displayed until the subject responds.

[146]. Pattern separation task (second stage): The original images and the twenty similar distractor images are presented to the subject sequentially. One-half of the original images are shown before the distractor version, and one-half after. For each image the subject indicates if it was identical to the preceding image (if positive, the right keyboard arrow is pressed, otherwise the left arrow is pressed). Each image remains until the subject responds. The accuracy and speed of the subject’s responses are recorded.

[147]. The accuracy scores of the tasks are loaded together on one factor, and the speed scores on another factor. The three speed scores are added to give an attentional intensity index. The accuracy scores are combined to give a sustained attention index. The accuracy scores from the working memory and four episodic memory tasks are combined to give a memory capacity index. The speed scores from the numeric working memory, spatial working memory, word recognition and pattern separation tasks are loaded together on a single factor and combined to create a speed of retrieval index.

[148]. Those skilled in the art will appreciate that the invention described herein is susceptible to further variations and modifications other than those specifically described. It is understood that the invention comprises all such variations and modifications which fall within the spirit and scope of the present invention.

[149]. Subjects’ mood and alertness is self-rated by the use of visual analogue scales and questionnaires. [150]. A scale used in caffeine research is exploited. The self-rating captures mood changes and involves seven descriptors, ‘relaxed’, ‘alert’, ‘jittery’, ‘tired’, ‘tense’, ‘headache’ and ‘overall mood. Each description is followed by a 10 cm line scale which the subject marks according to how he/she feels at the time. A rating of from 0-100 is given.

[151]. The Bond-Lader mood and alertness test is used, which incorporates a set of sixteen

100 mm scales yielding well validated factor scores for alertness, calmness and contentment.

[152]. The Profile of Mood States (POMS; McNair) is used, involving a 65-point self- report questionnaire to give six validated factor scores: tension, depression, anger, vigour, fatigue and confusion, plus a total score termed total mood disturbance.

[153]. In terms of the study procedure, subjects having given informed consent to participate in the study are instmcted to attend the study at 08:00 on four days at seven day intervals. Subjects are told to not consume alcohol for 24 h prior to each attendance, and to have fasted since 20:00 the evening before. Each volunteer must consume a standardised breakfast.

[154]. The initial study day is set aside to familiarise subjects with the CogTrack tasks. Height and weight measurements are taken to calculate BMI. Over the three following study days, the CogTrack tasks and the three self-rating scales are undertaken. Subjects then ingest all of their allocated treatment drink within five minutes. The same assessment procedures are repeated at 30, 60 and 90 min after ingestion of the drink, except for the Bond-Lader VAS and POMS tests which were repeated only at 90 minutes.

[155]. Statistical analyses are conducted using a statistical package (SAS). Mixed model repeated measure analyses of variance (ANOVAs) are performed on the change from control data. Each of the following are fixed factors: study drink (three levels), time of testing (three levels), sequence (six levels), and the interaction between study drink and Time of testing, were fitted as fixed factors. Subjects are fitted as a random factor. The compound symmetry covariance structure is used. Degrees of freedom are adjusted using the Kenward-Roger approximation.

[156]. Similar studies are performed using a composition of Example 2 having pinocembrin only (i.e. without taurine), although without the need for any taurine control.

[157]. Similar studies are performed using any of the food products of Example 1, having pinocembrin and optionally taurine. Controls for the effects of pinocembrin and/or taurine are included as required.

[158]. While the invention has been disclosed in connection with the preferred embodiments shown and described in detail, various modifications and improvements thereon will become readily apparent to those skilled in the art.

[159]. Accordingly, the spirit and scope of the present invention is not to be limited by the foregoing examples but is to be understood in the broadest sense allowable by law.

Claims

CLAIMS:

1. A composition comprising

(i) a flavonoid capable of traversing the blood-brain barrier of a human to affect a cell, a tissue, a structure, or an organ of the human central nervous system, and/or

(ii) one or more human compatible nutrient(s), solvent(s)s or solute(s), and/or

(iii) one or more pharmaceutically acceptable excipients.

2. The composition of claim 1, wherein the flavonoid is a flavanone such as dihydroxyflavanone and/or a (2S)-flavan-4-one.

3. The composition of claim 1 or claim 2, wherein the flavonoid is of the type naturally synthesized in a plant cell, although is not necessarily obtained from a plant cell for use in the composition.

4. The composition of any one of claims 1 to 3, wherein the flavanone is (2S)-5,7- dihydroxy-2 -phenyl-2, 3-dihydrochromen-4-one, or a functional derivative thereof.

5. The composition of any one of claims 1 to 4, wherein the one or more human compatible nutrient(s) is any one or more of: a fat, an oil, a carbohydrate, a protein.

6. The composition of any one of claims 1 to 5, wherein the one or more human compatible nutrient(s) is, or is a component of, a food product.

7. The composition of any one of claims 1 to 5, wherein the food product is a meat-based food product, a dairy-based food product, or a plant-based food product.

8. The composition of any one of claims 1 to 4, wherein the solvent(s) and/or solute(s) are provided by a carbonated drink product, an energy drink product, a sports drink product, a coffee drink product, a tea drink product, a fruit or a vegetable juice drink product, an alcoholic drink product, a smoothie drink product, a flavoured drink product, a functional drink product, a malt drink product, a seltzer water product, or a kombucha drink product.

9. The composition of any one of claims 1 to 7 comprising an organic acid.

10. The composition of claim 8, wherein the organic acid is an amino sulfonic acid.

11. The composition of claim 9, wherein the amino sulfonic acid is 2-aminoethane- 1 -sulfonic acid or a functional derivative thereof.

12. The composition of any one of claims 8 to 10, wherein the organic acid is of the type naturally synthesized in an animal cell, although is not necessarily obtained from an animal cell for use in the composition.

13. The composition of any one of claims 1 to 11 wherein the flavonoid is capable of effecting a cell, a tissue, a structure, or an organ of the human central nervous system.

14. The composition of any one of claims 1 to 12 wherein the flavonoid and/or the organic acid (where present) is/are capable of effecting a cell, a tissue, a stmcture, or an organ of the human central nervous system in any one or more of the following parameters: modulation of inflammation, modulation of neural cell membrane permeability, inhibiting the receptor for advanced glycation end products (RAGE), modulating mitochondrion-mediated apoptosis, reduction in reactive oxygen species, modulation of neurotransmission, potentiation of the striatum/hippocampus, membrane stabilization, modulation of neural cell volume, and inhibition of glutamate-mediate neurotoxicity.

15. The composition of any one of claims 1 to 13 wherein the flavonoid and/or the organic acid (where present) is capable of effecting a human in any one or more of the following parameters: cognitive function, problem solving, alertness, attention span, memory, concentration, and mood.

16. The composition of any one of claims 1 to 14 further comprising caffeine.

17. The composition of any one of claims 1 to 15, wherein the flavonoid is present at a concentration of at least about 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 15.0 or 20.0 g/lOOOg, or between about any two of the aforementioned concentrations.

18. The composition of any one of claims 9 to 17, wherein the organic acid is present at a concentration of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0, 15.0 or 20.0 g/lOOOg, or between about any two of the aforementioned concentrations.

19. A method for effecting a cell, a tissue, a structure, or an organ of the human central nervous system, the method comprising the steps of administering the composition of any one of claims 1 to 18 to a mammalian subject in need or desirous thereof.

20. The method of claim 19, wherein the effecting of a cell, a tissue, a structure, or an organ of the human central nervous system is an effect in any one or more of the following parameters: modulation of inflammation, modulation of neural cell membrane permeability, inhibiting the receptor for advanced glycation end products (RAGE), modulating mitochondrion-mediated apoptosis, reduction in reactive oxygen species, modulation of neurotransmission, potentiation of the striatum/hippocampus, membrane stabilization, modulation of neural cell volume, and inhibition of glutamate -mediate neurotoxicity.

21. The method of claim 19 or claim 20, wherein the effecting is affecting a human in any one or more of the following parameters: cognitive function, problem solving, alertness, attention span, memory, concentration, and mood.

22. A method of treating or preventing a condition associated with an impairment in any one or more of the following parameters: cognitive function, problem solving, alertness, attention span, memory, concentration, and mood, the method comprising the steps of administering to a mammalian subject in need thereof an effective amount of a composition according to any one of claims 1 to 18.

23. Use of the composition of any one of claims 1 to 18 in the treatment or prevention of a condition associated with an impairment in any one or more of the following parameters: cognitive function, problem solving, alertness, attention span, memory, concentration, and mood.