Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/66—Phosphorus compounds
  • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
  • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
  • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
  • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
  • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
  • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
  • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
  • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
  • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
  • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
  • A23L33/12—Fatty acids or derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
  • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
  • A61K36/18—Magnoliophyta (angiosperms)
  • A61K36/185—Magnoliopsida (dicotyledons)
  • A61K36/80—Scrophulariaceae (Figwort family)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
  • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

• Cognitive failure which includes dysfunction or loss of cognitive function (e.g., learning, thinking, and memory), commonly occurs in association with central nervous system (CNS) disorders or conditions, including neurodegenerative diseases. Cognitive dysfunction may cause significant impairment of social or occupational functioning or both, which can interfere with the ability of an individual to perform activities of daily living and greatly impact the autonomy and quality of life of the individual.
• CNS central nervous system
• the nutritional compositions comprise Bacopa and phosphatidylserine-docosahexaenoic acid complex.
• the nutritional composition further comprises a flavoring mixture to improve the organoleptic properties of the nutritional composition.
• a method for improving or enhancing cognitive function in a subject comprises administering to the subject a nutritional composition comprising an effective amount of Bacopa and an effective amount of phosphatidylserine-docosahexaenoic acid complex.
• a nutritional composition comprising an effective amount of Bacopa and an effective amount of phosphatidylserine-docosahexaenoic acid complex is provided.
• the nutritional composition improves or enhances cognitive function when consumed by a subject.
• a nutritional composition comprising Bacopa and phosphatidylserine-docosahexaenoic acid complex.
• the nutritional composition comprises 0.001% to 10% of Bacopa by weight of the nutritional composition and 0.001% to 10% of phosphatidylserine-docosahexaenoic acid complex by weight of the nutritional composition.
• the nutritional composition further comprises 2% to 75% of a flavoring mixture by weight of the nutritional composition.
• the flavoring mixture comprises an ingredient selected from the group consisting of a vegetable juice, a fruit juice, a tropical fruit juice, a citrus fruit juice, a root vegetable juice, an acidulant, a sweetener, and combinations thereof.
• the flavoring mixture comprises an ingredient selected from the group consisting of a vegetable juice, a fruit juice, a tropical fruit juice, a citrus fruit juice, a root vegetable juice, an acidulant, a sweetener, and combinations thereof.
• the Bacopa is present in an amount of 0.001% to 10% by weight of the nutritional composition
• the phosphatidylserine- docosahexaenoic acid complex is present in an amount of 0.001% to 10% by weight of the nutritional composition.
• a method for improving or enhancing muscle function in a subject comprises administering to the subject a nutritional composition comprising Bacopa and phosphatidylserine-docosahexaenoic acid complex.
• FIGS. 1A-1E are graphs that depict the effects of PS-DHA complex on N-methyl D- aspartate dependent hippocampal Long Term Potentiation (LTP) in the presence and absence of an NMDAR antagonist as analyzed in Example 21.
• LTP Long Term Potentiation
• FIGS. 2A-2E are graphs that depict the effect of Bacopa on N-methyl D-aspartate dependent hippocampal LTP in the presence and absence of an NMDAR antagonist as analyzed in Example 21.
• FIGS. 3A-3D are graphs that depict the synergistic effect of PS-DHA complex in combination with Bacopa on N-methyl D-aspartate dependent LTP in the presence and absence of an NMDAR antagonist as analyzed in Example 21.
• FIGS. 4A-4C are graphs that depict the effects of Bacopa, PS-DHA complex, and Bacopa in combination with PS-DHA complex on acetylcholine levels in the ventral hippocampus of freely moving Sprague Dawley rats as analyzed in Example 22.
• FIG. 5 is a graph that depicts the effects of Bacopa, PS-DHA complex, and Bacopa in combination with PS-DHA complex on freezing (%) in a Contextual Fear Conditioning task conducted with Sprague Dawley rats as analyzed in Example 23. DETAILED DESCRIPTION OF THE DISCLOSURE
• the nutritional compositions comprise Bacopa and phosphatidylserine-docosahexaenoic acid complex (hereinafter "PS-DHA"). These and other essential or optional elements or features of the various embodiments are described in detail hereafter.
• PS-DHA phosphatidylserine-docosahexaenoic acid complex
• a nutritional powder may often be reconstituted to form a nutritional liquid.
• the nutritional compositions disclosed herein comprise one or more of a source of fat, a source of protein, and a source of carbohydrate.
• the nutritional composition may further comprise vitamins, minerals, and other ingredients, and may represent a sole, primary, or supplemental source of nutrition.
• the nutritional compositions disclosed herein are generally suitable for oral consumption by a human.
• fat lipid
• oil oil
• synthetic lipid materials so long as such synthetic materials are suitable for oral administration to humans.
• cognitive function refers to the learning, thinking, and memory functions (i.e., memory acquisition, memory retention and memory recall) of the brain, as well as the mental process of attention. Accordingly, the phrase “improving or enhancing cognitive function” as used herein, unless otherwise specified, refers to improving or enhancing the learning function, thinking function, memory function, attention function, and combinations thereof of a subject. Additionally, the phrase “improving or enhancing cognitive function” as used herein, refers to improving or enhancing neuroprotection.
• neurodegenerative disease refers to the progressive loss of structure or function of neurons, including the death of neurons and includes diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, dementia, amyotrophic lateral sclerosis, stroke, and schizophrenia.
• muscle function refers to one or more of muscle mass, muscle architecture, muscle strength, and muscle contractile function.
• the term "effective amount" is intended to qualify the amount of Bacopa and PS-DHA that will achieve the goal of improving or enhancing cognitive function, muscle function, or both in a subject.
• the effective amount may be administered in one or more doses.
• first embodiment As used herein, the phrases first embodiment, second embodiment, third embodiment, fourth embodiment, and fifth embodiment are used merely for ease of description. Based upon the claims as filed at the PCT stage, the first embodiment would correspond to the methods of claim 10; the fifth embodiment would correspond to the methods of claim 1 1 ; the second embodiment would correspond to the composition of claim 1 ; the third embodiment would correspond to the composition of claim 4; and the fourth embodiment would correspond to the method of claim 15. As should be apparent from the description provided herein, the methods can make use of the disclosed compositions to achieve their results (e.g., improvement or enhancement of cognitive function, muscle function, or both).
• a method for improving or enhancing cognitive function in a subject comprises administering to the subject a nutritional composition comprising an effective amount of Bacopa and an effective amount of phosphatidylserine-docosahexaenoic acid complex.
• a nutritional composition comprising an effective amount of Bacopa and an effective amount of phosphatidylserine-docosahexaenoic acid complex is provided.
• the nutritional composition improves or enhances cognitive function when consumed by a subject.
• a nutritional composition comprising Bacopa and phosphatidylserine-docosahexaenoic acid complex is provided.
• the nutritional composition comprises 0.001% to 10% of Bacopa by weight of the nutritional composition and 0.001% to 10% of phosphatidylserine-docosahexaenoic acid complex by weight of the nutritional composition.
• the flavoring mixture comprises an ingredient selected from the group consisting of a vegetable juice, a fruit juice, a tropical fruit juice, a citrus fruit juice, a root vegetable juice, an acidulant, a sweetener, and combinations thereof.
• the Bacopa is present in an amount of 0.001% to 10% by weight of the nutritional composition
• the phosphatidylserine- docosahexaenoic acid complex is present in an amount of 0.001% to 10% by weight of the nutritional composition.
• a method for improving or enhancing muscle function in a subject comprises administering to the subject a nutritional composition comprising Bacopa and phosphatidylserine-docosahexaenoic acid complex.
• the nutritional compositions according to the first, second, third, fourth, and fifth embodiments may be formulated and administered in any known or otherwise suitable oral product form.
• Any solid, liquid, semi-solid, semi-liquid, or powder product form, including combinations or variations thereof, are suitable for use herein, provided that such forms allow for safe and effective oral delivery to the subject of the ingredients as also defined herein.
• the serving when the nutritional composition is a liquid, the serving is 25 milliliters to 500 milliliters. In certain other embodiments according to the first, second, third, fourth, and fifth embodiments, when the nutritional composition is a liquid, the serving is 25 milliliters to 75 milliliters. In yet other embodiments according to the first, second, third, fourth, and fifth embodiments, when the nutritional composition is a liquid, the serving is 150 milliliters to 500 milliliters, including 177 milliliters to 296 milliliters ( ⁇ 6 fl. oz. to ⁇ 10 fl.
• the nutritional compositions are formed as aqueous emulsions, including water-in- oil emulsions, oil-in-water emulsions, or complex (e.g., oil-in-water-in-oil emulsions) or other emulsion systems.
• the nutritional compositions are formed as an oil-in-water emulsion comprising an internal or discontinuous oil phase that comprises Bacopa and PS-DHA as defined herein.
• the Bacopa is a mixture of Bacosides A and B.
• the Bacopa may have a total Bacoside content of 20% to 100%, including 30% to 90%, including 40% to 80%, and also including 50%> to 70%>.
• the nutritional composition utilizes debitterized Bacopa.
• debitterized Bacopa allows for a nutritional composition with an improved flavor profile.
• debitterized Bacopa refers to Bacopa in which all, or substantially all, of the native cucurbitacin, bitter peptides, and bitter phenolic compounds have been removed.
• debitterized Bacopa refers to Bacopa in which greater than 50%, greater than 60%, greater than 70%, greater than 80%, or greater than 90% of the native cucurbitacin, bitter peptides, and bitter phenolic compounds are removed from the Bacopa.
• Debitterized Bacopa is commercially available upon request from Natural Remedies (India). Generally, Bacopa may be debitterized by removing the cucurbitacin, bitter peptides, and bitter phenolic compounds.
• the nutritional composition comprises 0.001% to 5% Bacopa by weight of the nutritional composition, including 0.1% to 3% Bacopa by weight of the nutritional composition, including 0.5%> to 2% Bacopa by weight of the nutritional composition, and also including 0.5% to 1.5% Bacopa by weight of the nutritional composition.
• the nutritional composition comprises Bacopa in amounts ranging from 0.001% to 0.037%, from 0.002% to 0.094%, from 0.02% to 0.187%, from 0.025% to 0.561%, and from 0.04% to 1.121%, by weight of the nutritional composition.
• the nutritional compositions comprise Bacopa in amount sufficient to provide a subject with 100-4,000 milligrams, including 100-2,000 milligrams, including from 100 milligrams to 1,000 milligrams, including from 200 milligrams to 600 milligrams, per day of Bacopa.
• the total daily amount of Bacopa may be administered to a subject in a single undivided dose, or may be split into one, two, three, four or more doses per day.
• the nutritional compositions according to the first, second, third, fourth, and fifth embodiments comprise PS-DHA.
• the nutritional composition comprises an effective amount of PS-DHA.
• PS-DHA is a conjugated form of phosphatidylserine (PS) to docosahexaenoic acid (DHA) or a DHA enriched form of PS, with palmitic acid at the Sn-1 position and DHA at the Sn-2 position.
• PS-DHA in the nutritional compositions provide enhanced bioavailability of both PS and DHA in the brain as conjugated DHA allows for a more efficient uptake of DHA by the brain as compared to DHA in triglyceride form.
• Bacopa possesses strong antioxidant properties. PS-DHA is highly susceptible to oxidation and may therefore induce oxidative stress in neuronal cell membranes that negatively affect the membrane fluidity and cell function. In combination, Bacopa may prevent the oxidation of dietary and membrane PS-DHA resulting in a complementary or synergistic mode of action, and may therefore be more efficacious in improving or enhancing cognitive function.
• PS is a phospholipid component constituting 10% of the total phospholipids present in the human body, and 15% of PS is found in the brain.
• DHA is an omega-3 polyunsaturated fatty acid (PUFA) and is abundant in the brain and retina, accounting for 40% of the PUFAs in the brain and 60% of the PUFAs in the retina.
• PUFA omega-3 polyunsaturated fatty acid
• DHA is essential for the proper functioning of adult brains, deficiencies of which have been associated with cognitive decline.
• brain is enriched with DHA conjugated to PS (i.e., PS-DHA) to maintain the neuronal membrane function, there is a preferential dietary uptake of PS-DHA compared to DHA alone in triglyceride form. Therefore, PS-DHA supplementation results in enhanced bioavailability of both DHA and PS phospholipids in brain than DHA supplementation in triglyceride form.
• the nutritional composition comprises 0.001% to 10% PS-DHA by weight of the nutritional composition. In certain other embodiments according to the first, second, third, fourth, and fifth embodiments, the nutritional composition comprises 0.001% to 5% PS-DHA by weight of the nutritional composition, including 0.1% to 3% PS-DHA by weight of the nutritional composition, including 0.5% to 2% PS-DHA by weight of the nutritional composition, and also including 1% to 1.5% PS-DHA by weight of the nutritional composition.
• the nutritional compositions comprise PS-DHA in amount sufficient to provide a subject with from 100 milligrams to 2000 milligrams, including from 200 milligrams to 2000 milligrams, including from 200 milligrams to 1000 milligrams, including from 500 milligrams to 1500 milligrams, including from 1000 milligrams to 1400 milligrams, per day of PS-DHA.
• the total daily amount of PS-DHA may be administered to an individual in a single undivided dose, or may be split into one, two, three, four or more doses per day.
• the nutritional composition comprises PS-DHA in an amount sufficient to provide a total daily amount of PS-DHA in the range of from 100 milligrams to 2000 milligrams, including from 200 milligrams to 2000 milligrams, including from 200 milligrams to 1000 milligrams, including from 500 milligrams to 1500 milligrams, including from 1000 milligrams to 1400 milligrams, by consumption of two servings of the nutritional compositions per day wherein the amount of PS-DHA may be divided evenly (i.e., the same amount in each serving) or unevenly between the two servings.
• the nutritional composition comprises PS-DHA in an amount of 100 to 1800 milligrams per serving, including 100-1200 milligrams per serving.
• nutritional compositions comprising a combination of Bacopa and PS-DHA may produce an added benefit on cognitive functioning by producing a synergistic effect in enhancing N-Methyl-D-aspartate receptor (NMDAR) and 2-amino-3-(5-methyl-3-oxo-l,2-oxazol-4- yl)propanoic acid receptor (AMPAR) dependent hippocampal synaptic plasticity, which is a molecular mechanism involved in learning and memory.
• NMDAR N-Methyl-D-aspartate receptor
• AMPAR 2-amino-3-(5-methyl-3-oxo-l,2-oxazol-4- yl)propanoic acid receptor
• Bacopa and PS-DHA may produce a sequential action by improving memory acquisition that is essential for the process of learning, and by improving memory retention and memory recall that is necessary for the retrieval of learned processes as compared to administration of PS and DHA separately (i.e., in an non-complexed form).
• PS-DHA offers benefits such as the maintenance of neuronal membrane fluidity, which is essential for synaptic receptor function, and neurotransmitter release, which is essential for the cognitive performance of a subject. While PS-DHA may be taken up by the brain from the diet to provide the above benefits, PS-DHA is highly susceptible to oxidation and may therefore induce oxidative stress in neuronal membranes that may, in turn, negatively affect the neuronal health and function.
• the presently disclosed nutritional compositions comprising a combination of Bacopa and PS-DHA may enhance cognitive function or reduce cognitive impairment, particularly in subjects suffering from age-related cognitive decline or a neurodegenerative disease, by enhancing acetylcholine levels.
• Previous studies have suggested that cognitive decline due to Alzheimer's disease and during normal aging may be at least partly attributable to acetylcholine depletion due to cholinergic neuronal degeneration. Therefore, by enhancing acetylcholine levels, the presently disclosed nutritional compositions comprising a combination of Bacopa and PS-DHA may enhance or improve cognitive function or reduce cognitive impairment.
• age-related cognitive decline and neurodegenerative disease are often associated with a lack of coordinated movement due to an impairment of skeletal muscle function.
• the activation of nicotinic acetylcholine receptors by acetylcholine at the skeletal muscle fibers is necessary for skeletal muscle function by regulating the ligand gated sodium ion channels.
• Acetylcholine depletion due to cholinergic neuronal degeneration plays a major role in impaired muscle function associated with age-related cognitive decline and neurodegenerative disease.
• the presently disclosed nutritional compositions comprising a combination of Bacopa and PS-DHA may enhance muscle function in a subject suffering from age-related cognitive decline or neurodegenerative disease by enhancing acetylcholine levels.
• the nutritional compositions and methods according to the first, second, third, fourth, and fifth embodiments of the present disclosure offer an alternative therapeutic or nutritional intervention option that may contribute to the improvement or enhancement of cognitive function, muscle function, as well as to the reduction of cognitive impairment or brain dysfunction or both, in subjects, and particularly in adults, older adults, and the elderly.
• the nutritional composition comprises a flavoring mixture.
• the flavoring mixture improves the organoleptic properties (e.g., taste, mouth feel, and aftertaste) of the nutritional composition comprising Bacopa and PS-DHA.
• the organoleptic properties e.g., taste, mouth feel, and aftertaste
• Bacopa has a bitter, earthy flavor
• PS-DHA has a fishy flavor.
• a method for improving the organoleptic properties of a nutritional composition comprising Bacopa and PS-DHA comprises adding a flavoring mixture to the nutritional composition.
• juice is used herein to refer to various of the constituents of the flavoring mixture, it should be understood that the term is intended broadly so as to include natural juices (i.e., in the form extracted from a fruit or vegetable without any additional water added or removed) as well as diluted juices (i.e., with additional water added to a natural juice), concentrated juices (i.e., with some amount of removed from a natural juice) and powdered or dehydrated juices.
• the juice is a liquid juice, including a natural juice.
• the juice is a powdered or dehydrated juice.
• the vegetable juice may be virtually any vegetable juice that can be utilized to improve the organoleptic properties of a nutritional composition comprising Bacopa and PS-DHA.
• vegetable juices include vegetable juice selected from the group consisting of celery juice, spinach juice, kale juice, lettuce juice, cabbage juice, and combinations thereof.
• the acidulant is selected from a non-limiting group of acids consisting of citric acid, ascorbic acid, sorbic acid, benzoic acid, malic acid, tartaric acid, phosphoric acid, salts thereof, and combinations thereof.
• the nutritional composition when the nutritional composition contains sweetener(s), the sweetener(s) are non-caloric.
• the nutritional composition includes a flavoring mixture comprising natural flavors, artificial flavors, and combinations thereof.
• natural flavors include vegetable flavors, fruit flavors, tropical fruit flavors, citrus fruit flavors, root vegetable flavors, and combinations thereof.
• the natural flavors, artificial flavors, and combinations thereof may be provided as a liquid, a powder, and combinations thereof.
• natural flavors may correspond to the previously listed juices of the same general category (e.g., for vegetable - celery juice and natural celery flavor; for fruit - apple juice and natural apple flavor; etc.).
• artificial flavors that mimic the natural flavor may be utilized in the flavoring mixture so long as the artificial flavor is suitable for use in oral nutritional compositions and is otherwise compatible with any other selected ingredients or features in the nutritional composition.
• the nutritional composition comprises a flavoring mixture, which comprises by weight percent: 25% to 35% apple juice; 20% to 30% carrot juice; 15% to 25% orange juice; 5% to 15%) beetroot juice; 2% to 10% celery juice; 2% to 10% tomato juice; 2% to 10% passion fruit juice; 2% to 10% pineapple juice; up to 0.50% citric acid; and up to 0.50% sucralose.
• a flavoring mixture is effective for improving the organoleptic properties of the nutritional composition by masking the bitter, earthy tones of Bacopa and the fishy flavor imparted by PS- DHA.
• the nutritional composition may comprise one or more of a source of fat, a source of protein, and a source of carbohydrate.
• the nutritional composition further comprises an ingredient selected from the group consisting of at least one source of protein, at least one source of carbohydrate, and combinations thereof.
• the nutritional composition may include at least one source of fat.
• the nutritional composition may include no fat, or essentially no fat (i.e., less than 0.5 grams of fat per serving).
• any source of fat may be used so long as it is suitable for use in oral nutritional compositions and is otherwise compatible with any other selected ingredients or features present in the nutritional composition.
• the source of fat may be derived from plants, animals, and combinations thereof.
• suitable sources of fat for use in the nutritional compositions described herein include coconut oil, fractionated coconut oil, soy oil, corn oil, olive oil, safflower oil, high oleic safflower oil, high GLA-safflower oil, MCT oil (medium chain triglycerides), sunflower oil, high oleic sunflower oil, palm and palm kernel oils, palm olein, canola oil, flaxseed oil, borage oil, cottonseed oils, evening primrose oil, blackcurrant seed oil, transgenic oil sources, fungal oils, marine oils (e.g., tuna, sardine) and so forth.
• coconut oil fractionated coconut oil, soy oil, corn oil, olive oil, safflower oil, high oleic safflower oil
• the nutritional composition may include at least one source of carbohydrate. In certain embodiments according to the first, second, third, fourth, and fifth embodiments, the nutritional composition may comprise 0.1 grams to 100 grams of at least one source of carbohydrate per serving. In other embodiments according to the first, second, third, fourth, and fifth embodiments, the nutritional composition may comprise 5 grams to 90 grams of at least one source of carbohydrate per serving. In yet other embodiments according to the first, second, third, fourth, and fifth embodiments, the nutritional composition may comprise 20 grams to 60 grams of at least one source of carbohydrate per serving.
• the nutritional composition may further comprise other optional ingredients that may modify the physical, nutritional, chemical, hedonic or processing characteristics of the nutritional composition or serve as pharmaceutical or additional nutritional components when used in a targeted population.
• optional ingredients are known or otherwise suitable for use in other nutritional products and may also be used in the nutritional compositions described herein, provided that such optional ingredients are safe and effective for oral administration and are compatible with the essential and other ingredients in the nutritional composition.
• Non-limiting examples of such other optional ingredients include preservatives, antioxidants, buffers, pharmaceutical actives, colorants, flavor enhancers, thickening agents and stabilizers, emulsifying agents, lubricants, and combinations thereof.
• the nutritional composition may further comprise one or more minerals, non- limiting examples of which include phosphorus, sodium, chloride, magnesium, manganese, iron, copper, zinc, iodine, calcium, potassium, chromium, molybdenum, selenium, and combinations thereof.
• minerals non- limiting examples of which include phosphorus, sodium, chloride, magnesium, manganese, iron, copper, zinc, iodine, calcium, potassium, chromium, molybdenum, selenium, and combinations thereof.
• the nutritional composition may further comprise one or more vitamins, non- limiting examples of which include carotenoids (e.g., beta-carotene, zeaxanthin, lutein, lycopene), biotin, choline, inositol, folic acid, pantothenic acid, TPAN, choline, vitamin A, thiamine (vitamin Bl), riboflavin (vitamin B2) niacin (vitamin B3), pyridoxine (vitamin B6), cyanocobalamin (vitamin B12), ascorbic acid (vitamin C), vitamin D, vitamin E, vitamin K, and various salts, esters, or other derivatives thereof, and combinations thereof.
• carotenoids e.g., beta-carotene, zeaxanthin, lutein, lycopene
• biotin choline
• inositol folic acid
• pantothenic acid TPAN
• choline vitamin A
• the various embodiments of the nutritional composition according to the first, second, third, fourth, and fifth embodiments disclosed herein may be prepared by any process or suitable method (now known or known in the future) for making a selected product form, such as a nutritional solid, a nutritional powder, or a nutritional liquid. Many such techniques are known for any given product form such as nutritional liquids or nutritional powders and can easily be applied by one of ordinary skill in the art to the various embodiments of the nutritional composition according to the first, second, third, fourth, and fifth embodiments disclosed herein.
• the resulting slurries are then blended together with heated agitation and the pH adjusted to 6.6-7, after which the nutritional composition is subjected to high-temperature short- time (HTST) processing during which the nutritional composition is heat treated, emulsified and homogenized, and then allowed to cool.
• HTST high-temperature short- time
• Water soluble vitamins and ascorbic acid are added, the pH is adjusted to the desired range if necessary, optional flavoring is added, and water is added to achieve the desired total solid level.
• the nutritional composition is then aseptically packaged to form an aseptically packaged nutritional liquid emulsion.
• the spray drying step may likewise include any spray drying technique that is known for or otherwise suitable for use in the production of nutritional powders. Many different spray drying methods and techniques are known for use in the nutrition field, all of which are suitable for use in the manufacture of the spray dried nutritional powders herein.
• One method of preparing the spray dried nutritional powder comprises forming and homogenizing an aqueous slurry or liquid comprising predigested fat, and optionally protein, carbohydrate, and other sources of fat, and then spray drying the slurry or liquid to produce a spray dried nutritional powder.
• the method may further comprise the step of spray drying, dry mixing, or otherwise adding additional nutritional ingredients, including any one or more of the ingredients described herein, to the spray dried nutritional powder.
• the nutritional compositions may improve or enhance a cognitive impairment, or brain dysfunction, or both, associated with age-related cognitive decline or cognitive decline associated with a neurodegenerative disease by enhancing synaptic plasticity, which is controlled by N-methyl-D-aspartate receptor (NMDAR).
• NMDAR N-methyl-D-aspartate receptor
• Deficits in synaptic plasticity, or neuronal death, or both, can result in one or more of cognitive impairment and brain dysfunction.
• the nutritional composition restores the suboptimum level of NMDAR activity to optimum levels, even during weak stimulation, and, at the same time, prevents neuronal death from NMDAR over-activation.
• administering the presently disclosed nutritional composition to the subject improves or enhances the NMDAR and 2-amino-3-(5-methyl-3-oxo-l,2-oxazol-4-yl)propanoic acid receptor (AMPAR) mediated hippocampal synaptic plasticity, which may be another key mechanism underlying learning and memory.
• AMPAR 2-amino-3-(5-methyl-3-oxo-l,2-oxazol-4-yl)propanoic acid receptor
• administering the presently disclosed nutritional composition to the subject prevents or reduces the over-activation of NMDAR, which may result in neuronal death.
• administering the presently disclosed nutritional composition to the subject improves or enhances neuronal membrane fluidity.
• administering the presently disclosed nutritional composition to the subject enhances acetylcholine levels.
• the methods of the present disclosure may be directed to subjects who have a neurodegenerative disease or condition, or a disease or condition related to a neurodegenerative disease or condition
• the methods of the present disclosure as described herein are also intended in certain embodiments to include the use of such methods in "at risk" subjects, including subjects unaffected by or not otherwise afflicted with neurodegenerative diseases or conditions such as those described above, for the purpose of preventing, minimizing, or delaying the development of such diseases or conditions over time.
• the methods of the present disclosure preferably include continuous, daily administration of the various embodiments of the nutritional compositions as described herein.
• Such preventive methods may be directed at adults or others, particularly older adults, who are susceptible to developing neurodegenerative diseases due to hereditary considerations, environmental considerations, and the like.
• the subject may consume at least one serving of the nutritional composition daily, and in certain other embodiments, may consume two, three, or even more servings per day.
• Each serving is desirably administered as a single, undivided dose, although the serving may also be divided into two or more partial or divided servings to be taken at two or more times during the day.
• Certain embodiments of the methods and nutritional compositions according to the first, second, third, fourth, and fifth embodiments of the present disclosure include continuous day after day administration, as well as periodic or limited administration, although continuous day after day administration is generally desirable.
• the nutritional composition is administered on a daily basis, wherein the daily administration is maintained continuously for 3 days to 1 week, including 5 days to 2 weeks, including 1 month to 6 weeks, including 8 weeks to 2 months, including for 6 months, and also including 18-24 months, desirably as a long term, continuous, daily, dietary supplement.
• the exemplified nutritional compositions are prepared in accordance with manufacturing methods well known in the nutrition industry for preparing nutritional liquids (e.g., emulsions and clear liquids) and powders.
• Examples 1-5 illustrate certain embodiments according to the first, second, third, and fourth embodiments disclosed herein, of a nutritional composition in the form of a nutritional liquid emulsion. All ingredient amounts are listed as kg per 1000 kg batch of product, unless otherwise specified.
• Vitamin A palmitate 0.003 0.003 0.003 0.003 0.003 0.003
• Examples 6-10 illustrate certain embodiments according to the first, second, third, and fourth embodiments disclosed herein, of a nutritional composition in the form of a nutritional liquid emulsion. All ingredient amounts are listed as kg per 1000 kg batch of product, unless otherwise specified.
• PS-DHA was prepared as a 60, 30 or 15 mM stock solution in a mix (10% Cremphor El (ref: C5135, Sigma, batch: 1439553 13509161) - 5% ethanol (ref: 20820.293, VWR, batch: 07K210530)-85%> ACSF) from powder on each day of experimentation. This stock solution was then 1000X diluted into ACSF to reach the final 60, 30 or 15 ⁇ concentration.
• MEA microelectrode array
• Software for stimulation, recordings and analysis were commercially available from Multi Channel Systems: MC Stim (3.2.4 release) and MC Rack (4.0.0 release), respectively.
• All of the experiments were carried out with 3 -dimensional MEA (Ayanda Biosystems, S.A., CH- 1015 Lausanne, Switzerland) that consist of 60 tip-shaped and 60 ⁇ m-high electrodes spaced by 100 ⁇ .
• the MEA electrodes were made of platinum with k ⁇ 450 ⁇ impedance ⁇ 600 k ⁇ .
• acetylcholine depletion due to cholinergic neuronal degeneration plays a significant role in impaired muscle function and coordinated movement associated with age-related cognitive decline and Alzheimer's disease.
• interventions that can enhance in vivo acetylcholine levels may be effective for improving or enhancing cognitive function, muscle function, or both in a subject suffering from age-related cognitive decline, Alzheimer's disease, or other neurodegenerative diseases.
• Each animal was placed into a stereotaxic frame (Kopf Instruments, USA).
• One guide cannula was inserted into both brain hemispheres according to the Paxinos and Watson (1982) brain atlas.
• Each guide fits an I-shaped probe with 4 mm exposed surface of hospal membrane (BrainLink, The Netherlands).
• the guide was fixed to the skull with dental cement and a stainless steel screw.
• Treatments were administered acutely by oral gavage at least 4 days following surgery.
• the treatments administered to each group of animals are shown in Table 12 below.
• the Group II animals received 40 milligrams (mg) of PS-DHA per kilogram (kg) of body weight (b.w.).
• the probes in the animals were connected with flexible PEEK tubing to a micro-perfusion pump (Syringe pump UV 8301501 , TSE, Germany) and perfused with artificial cerebrospinal fluid (perfusate), containing 147 mM NaCl, 3.0 mM KC1, 1.2 mM CaCl 2 , and 1.2 mM MgCl 2 with a flow rate of 1.5 ⁇ / ⁇ .
• microdialysis samples were collected off-line for 20 minute periods into mini- vials containing 10 of 0.02 M formic/ascorbic acid by an automated fraction collector (CMA 142, Sweden). Three samples were collected for basal concentration determination and 12 samples were collected after administration of the treatment. After collection, samples were stored at -80 °C for acetylcholine analysis.
• Concentrations of the neurotransmitters were determined by HPLC with tandem mass spectrometry (MS/MS) detection.
• MS analyses were performed using an API 3000, 4000, or 5000 MS/MS system consisting of an API 3000, 4000, or 5000 MS/MS detector and a Turbo Ion Spray interface (both from Applied Biosystems, The Netherlands). Data was calibrated and quantified using the AnalystTM data system (Applied Biosystems, version 1.4.2/1.5.1).
• the combination of PS-DHA and Bacopa may be efficacious in enhancing acetylcholine levels, which may reduce the acetylcholine depletion associated with aging or neurodegenerative diseases. Accordingly, the combination of PS-DHA and Bacopa may improve or enhance cognitive function or reduce the cognitive impairment by enhancing acetylcholine levels. Additionally, the combination of PS-DHA and Bacopa may enhance muscle function or may reduce muscle dysfunction or lack of coordinated movement by enhancing acetylcholine levels.
• Hippocampal dysfunction due to altered NMD A and AMP A mediated synaptic plasticity is known to cause spatial memory deficits and cognitive decline.
• the hippocampus is involved in spatial memory both in humans and rodents.
• CFC Contextual Fear Conditioning
• PS-DHA 40 mg/kg b.w.
• the PS-DHA and Bacopa were formulated in corn oil vehicle. Treatments were administered to the animals by oral gavage at a dose volume of 2 ml/kg b.w. All animals were administered a treatment once daily for a period of 44 days. Treatments were administered to the animals at approximately the same time every day. Each animal was observed daily for any physical or physiological changes. The treatments were prepared fresh each day and were vortexed properly before administering to each animal.
• Contextual Fear Conditioning Task Animals were acclimatized to experimenters prior to training. During training each animal was placed inside the conditioning chamber for either 5 seconds or 180 seconds for context (CS) conditioning. This time period is known as the Placement to Shock Interval (PSI). Following PSI, a foot-shock of 1.5 mA for 2 seconds was delivered for CS-US paired conditioning. After a post shock interval of 30 seconds, the animal was placed back into its home cage and the conditioning chamber was cleaned with a 70% alcohol solution. Twenty four hours after the training session, each animal was re-exposed to the conditioning chamber (only CS, no US) for 5 minutes, during which its freezing behavior was recorded. The freezing score was recorded by observers blind to the experimental conditions.
• PSI Placement to Shock Interval
• An exemplary flavoring mixture was prepared according to the formulation provided in the below Table 14. It is contemplated that such flavoring mixture could be mixed with Bacopa and PS-DHA in the relative amounts as described herein.

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