WO2012119049A2

WO2012119049A2 - Nutritional compositions comprising prune extract and bioavailable curcumin

Info

Publication number: WO2012119049A2
Application number: PCT/US2012/027429
Authority: WO
Inventors: Padmavathy Krishnan; Suzette L. Pereira; Neile K. Edens
Original assignee: Abbott Laboratories
Priority date: 2011-03-02
Filing date: 2012-03-02
Publication date: 2012-09-07
Also published as: WO2012119049A3

Abstract

Disclosed are nutritional compositions including a synergistic combination of bioavailable curcumin and a prune extract. The nutritional compositions may be used to control and reduce acute and chronic inflammation, muscle wasting and cognitive decline in individuals, and particularly in adults and older adults.

Description

NUTRITIONAL COMPOSITIONS COMPRISING PRUNE EXTRACT AND

BIOAVAILABLE CURCUMIN

FIELD OF THE DISCLOSURE

[0001] The present disclosure relates to nutritional compositions comprising bioavailable curcumin and a prune extract. These nutritional compositions may be used to control inflammation, muscle wasting, and cognitive decline in an individual.

BACKGROUND OF THE DISCLOSURE

[0002] Chronic inflammation has been generally associated with various muscle wasting diseases including cancer, end-stage heart disease, end-stage renal disease, chronic obstructive pulmonary disease, and many others. In such muscle wasting diseases, muscle mass decreases due to accelerated muscle protein degradation and reduced protein synthesis. This decrease may be a partial or complete wasting away of muscle, accounting for about 5% to 10% unintentional loss of body weight.

[0003] To combat muscle wasting, exercise and general increases in activity are ordinarily generally recommended. In older adults where exercise may not be a viable alternative to properly combat muscle wasting, nutritional solutions, such as various nutritional compositions, nutritional supplements, or both, have been utilized. Even with compliance with these solutions the outcomes have not been completely satisfactory.

[0004] To combat inflammation related with these diseases, the administration of non-steroidal anti-inflammatory drugs (NSAIDs) has also been utilized, although its success to date has also been limited, and may be associated with undesirable side effects from long-term use. Specifically, long-term use of NSAIDs is associated with ulcers and other undesirable complications.

[0005] As such, there is a need for nutritional compositions and methods for treating and managing chronic inflammation, as well as its related muscle wasting diseases. It would be beneficial if such nutritional compositions and methods could also treat and manage acute inflammation, as well as other diseases that involve chronic inflammation, such as age-related cognitive decline, as well as cognitive decline resulting from

neurodegenerative diseases and conditions.

SUMMARY OF THE DISCLOSURE

[0006] The present disclosure is generally directed to nutritional compositions that include a combination of bioavailable curcumin and prune extract that can be used to treat, manage, and/or reduce chronic and acute inflammation in individuals. The bioavailable curcumin and prune extract act in a synergistic manner to reduce

inflammation, which can also lead to a reduction in muscle wasting diseases and cognitive decline in the individual.

[0007] One embodiment is directed to a nutritional composition comprising a synergistic amount of bioavailable curcumin and a prune extract, wherein the prune extract comprises from about 25% to 100% polyphenolic compounds.

[0008] Another embodiment is directed to a method of reducing inflammation in an individual. The method comprises administering to the individual a nutritional composition comprising a synergistic amount of bioavailable curcumin and a prune extract, wherein the prune extract comprises from about 25% to 100% polyphenolic compounds.

[0009] Another embodiment is directed to a method of preventing cognitive decline in an individual. The method comprises administering to the individual a nutritional composition comprising a synergistic amount of bioavailable curcumin and a prune extract, wherein the prune extract comprises from about 25% to 100% polyphenolic compounds.

[0010] It has been discovered that the combination of bioavaiable curcumin and prune extract act in a synergistic manner and may be used in a nutritional composition to provide anti-inflammatory benefits to an individual. These benefits may reduce acute and chronic inflammation caused by various diseases and medical conditions. Even at very low concentrations, the prune extract and bioavailable curcumin show synergistic antiinflammatory activity and can substantially inhibit NFKB activity, a major inflammatory mediator. [0011] Accordingly, the nutritional compositions and methods of the present disclosure may offer an alternative therapeutic option that may contribute to controlling acute and chronic inflammation and pain in individuals, and particularly adults and older adults. These benefits may be advantageously achieved without the complications seen with the previously used oral synthetic pharmacological approaches.

BRIEF DESCRIPTION OF THE FIGURES

[0012] Figure 1 depicts the anti-inflammatory activity of prune extract, curcumin, and the synergistic combination thereof as analyzed in Example 1.

DETAILED DESCRIPTION OF THE DISCLOSURE

[0013] The compositions and methods herein are directed to nutritional compositions comprising prune extract and bioavailable curcumin that can modulate acute and chronic inflammation and the diseases and conditions associated therewith in an individual. These compositions provide an easy and effective method for reducing inflammation and diseases and/or conditions associated with inflammation, including muscle wasting diseases and cognitive decline. These and other elements or features of the various embodiments are described in detail hereafter.

[0014] The term "bioavailable" as used herein, unless otherwise specified, refers to the ability of a compound to enter into and remain in the bloodstream of an individual such that the substance can be absorbed into cells in the body. As the degree of bioavailability of a compound increases, the compound becomes more likely to enter into and remain in the bloodstream where it can be absorbed and used by the body. As the degree of bioavailability of a compound decreases, the compound becomes more likely to go directly into the gastrointestinal area and be expelled from the body before entering the bloodstream.

[0015] The term "nutritional composition" as used herein, unless otherwise specified, refers to nutritional liquids and nutritional powders that comprise at least one of protein, fat, and carbohydrate and is suitable for oral administration to a human. The nutritional composition may further comprise vitamins, minerals, and other ingredients and represent a sole, primary, or supplemental source of nutrition. [0016] The term "chronic inflammation" as used herein, unless otherwise specified, refers to the prolonged response of the human body to harmful stimuli that may lead to the progressive shift in the type of cells present at the site of inflammation and is characterized by simultaneous destruction and healing of the injured tissue.

[0017] The term "acute inflammation" as used herein, unless otherwise specified, refers to sudden onset inflammation that may be marked by the classic signs of heat, redness, swelling, diarrhea, pain and loss of function, and in which vascular and exudative processes predominate.

[0018] The term "older adult" as used herein, unless otherwise specified, refers to an individual of at least 45 years of age, including at least 50 years of age, including at least 55 years of age, including at least 60 years of age, including at least 65 years of age, including at least 70 years of age, including at least 75 years of age, including at least 80 years of age or greater, and also including from about 45 years of age to about 80 years of age, further including from about 55 years of age to about 80 years of age.

[0019] The terms "controlling" or "modulating" as used herein, unless otherwise specified, in relation to chronic inflammation, unless otherwise specified are used interchangeably to refer to reducing inflammation and/or pain and/or inhibiting the activation of NFKB.

[0020] The term "susceptible" as used herein, unless otherwise specified, means having little resistance to a certain condition or disease, including being genetically predisposed, having a family history of, and/or having symptoms of the condition or disease.

[0021] The term "synergy" or "synergistic amount" as used herein, unless otherwise specified, refers to the interaction of two or more compounds so that their combined effect is greater than the additive sum of their individual effects.

[0022] The term "muscle wasting disease" as used herein unless otherwise specified means a disease that in whole or in part causes muscle atrophy. [0023] The term "neurodegenerative disease" as used herein, unless otherwise specified, 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.

[0024] The term "age-related cognitive decline" as used herein, unless otherwise specified, refers to a gradual decline in memory and cognitive (thinking) function that is a normal consequence of aging.

[0025] All percentages, parts and ratios as used herein, are by weight of the total product, unless otherwise specified. All such weights as they pertain to listed ingredients are based on the active level and, therefore, do not include solvents or by-products that may be included in commercially available materials, unless otherwise specified.

[0026] All references to singular characteristics or limitations of the present disclosure shall include the corresponding plural characteristic or limitation, and vice versa, unless otherwise specified or clearly implied to the contrary by the context in which the reference is made.

[0027] All combinations of method or process steps as used herein can be performed in any order, unless otherwise specified or clearly implied to the contrary by the context in which the referenced combination is made.

[0028] The various embodiments of the nutritional compositions of the present disclosure may also be substantially free of any optional or selected essential ingredient or feature described herein, provided that the remaining composition or powder still contains all of the required ingredients or features as described herein. In this context, and unless otherwise specified, the term "substantially free" means that the selected composition contains less than a functional amount of the optional ingredient, typically less than 1%, including less than 0.5%, including less than 0.1%, and also including zero percent, by weight of such optional or selected essential ingredient. [0029] The nutritional compositions may comprise, consist of, or consist essentially of the essential elements of the products as described herein, as well as any additional or optional element described herein or otherwise useful in nutritional product applications.

Product Form

[0030] The nutritional compositions of the present disclosure include at least bioavailable curcumin and a prune extract and may be formulated and administered in any known or otherwise suitable oral product form. Any solid, liquid, semi-solid, semi-liquid or powder form, including combinations or variations thereof, are suitable for use herein, provided that such forms allow for safe and effective oral delivery to the individual of the ingredients as also defined herein.

[0031] The nutritional compositions are most suitably 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. As applied to the nutritional compositions herein, the nutritional emulsion embodiments are most typically oil-in-water emulsions comprising an internal or discontinuous oil phase that comprises the bioavailable curcumin and prune extract as defined herein.

Bioavailable Curcumin

[0032] The term "bioavailable curcumin" refers to curcumin and derivatives and analogs thereof, including natural and synthetic derivatives of curcumin, as well as any combination of one or more of curcumin and a derivative and/or analog. In particular, the term "bioavailable curcumin" should be understood to encompass compounds having a 1,7- bis (4-hydroxyphenyl)-l,6-heptadiene-3,5-dione or 1 ,7-bis(4-hydroxyphenyl) hept-4-en-3- one skeleton wherein the phenyl groups independently may bear one or more alkoxy residues, especially one methoxy residue in the 3-position. In some embodiments, additional curcuminoids, such as demethoxycurcumin and bisdemethoxycurcumin, may also be present in the nutritional compositions. When present, demethoxycurcumin and bisdemethoxycurcumin may be present as part of a complex with curcumin. [0033] The "bioavailable curcumin" used in the synergistic nutritional compositions of the present disclosure show improved oral bioavailability as compared to curcumins that are not "bioavailable." The oral bioavailability can be determined in experiments involving oral administration of the bioavailable curcumin composition of the present disclosure (and/or a corresponding amount of non-bioavailable curcumin) to a subject and measuring the level of the curcumin in a biological sample obtained from the subject over time, wherein the biological sample may be derived from a body fluid, for example serum, plasma, whole blood, or cerebrospinal fluid, and/or a tissue, e.g. from brain, liver, kidney, or heart. For analysis, the curcumin level in the examined body fluid or tissue may be plotted against time, and the area under the curve (AUC), for example the total area under the curve from t = 0 (time of administration) to t = infinity (= AUC0- infinity), or the area under the curve within a defined period, e.g. from t = 0 to t = 6 hours (AUC0-6H), may be calculated. In general, a higher AUC relative to the AUC obtained by administration of non-bioavailable curcumin indicates an improved bioavailability. The absolute bioavailability may be calculated from the resulting AUC data as percentage based on the corresponding AUC data obtained from intravenous administration of curcumins.

[0034] In some embodiments, the bioavailable curcumin amount in the blood, determined as AUC0-6H after a single oral administration of a dose of the bioavailable curcumin-containing nutritional composition of the present disclosure corresponding to 20 mg of total curcumin to a human subject or an animal subject, preferably a rat, is significantly higher than after oral administration of the same amount of non-bioavailable curcumin in the composition, preferably at least 2 times, at least 3 times, at least 4 times, at least 6 times, at least 8 times, at least 10 times, or at least 15 times, and, for example, up to 30 times higher.

[0035] As used herein, the amount of curcumin in the blood being "significantly higher" means a statistically significant increase of this parameter in subjects after oral administration of 20 mg of bioavailable curcumin in the nutritional composition of the present disclosure as compared to the control 20 mg of curcumin that is not bioavailable. A statistical test known in the art, such as ANOVA or Student's t-test, may be used to determine the significance of this difference, wherein the p-value is at least <0.1, <0.5, <0.01, <0.005, <0.001 or O.0001. [0036] Conventionally, curcumin has suffered low bioavailability when taken orally, and thus when formulated at higher concentrations to counter its inherent poor bioavailability to achieve the desired systemic delivery, the products often take on an intense undesirable yellow color. The present nutritional compositions, however, use bioavailable curcumin, which has an improved bioavailability as compared to

conventionally used curcumin. As such, curcumin can be utilized in lower concentrations in the nutritional compositions and methods of the present disclosure, while still maintaining its anti-inflammatory activity.

[0037] Bioavailable curcumin can be prepared in a number of ways including, for example, using Meltrex® or similar melt-extrusion technology to prepare extruded solids and improve the bioavailability of the curcumin as compared to curcumin not produced by melt extrusion. Meltrex® or similar melt-extrusion technology methods are known in the art and can be applied to produce bioavailable curcumin by one skilled in the art based on the disclosure herein.

[0038] In another embodiment, curcumin can be co-supplemented with piperine (generally extracted from black pepper) to increase the bioavailability and hence the absorbability of curcumin. In one embodiment, the piperine is co-supplemented in an amount of about 20 mg to increase the bioavailability of the curcumin.

[0039] In another embodiment, the curcumin may be solubilized in an oil having an HLB of from about 0.7 to about 14 (polar oils) such that the resulting oil mixture provides increased bioavailability of curcumin. One suitable polar oil for dissolving the curcumin is a medium chain triglyceride oil (MCT oil).

[0040] In one embodiment, the bioavailable curcumin is Meriva Bioavailable Curcumin, commercially available from Idena SPA (Milan, Italy).

[0041] The bioavailable curcumin concentration in the nutritional compositions may range from at least 0.001%, including from about 0.002% to about 1.0%, including from about 0.005%) to about 0.8%>, also including from about 0.03%> to about 0.3%>, and also including from about 0.1% to about 0.25%, by weight of the nutritional composition. [0042] The nutritional compositions of the present disclosure desirably include sufficient bioavailable curcumin to provide an individual with at least 1 milligram, including at least 3 milligrams, including from about 10 milligrams to about 10,000 milligrams, including from about 100 milligrams to about 4000 milligrams, including from about 400 milligrams to about 2000 milligrams, including from about 400 milligrams to about 1800 milligrams, and also including from about 1200 milligrams to about 1800 milligrams, per day of bioavailable curcumin. In some embodiments, the nutritional compositions include sufficient bioavailable curcumin to provide an individual with from about 50 milligrams to about 700 milligrams, including from about 50 milligrams to about 650 milligrams, including from about 50 milligrams to about 600 milligrams, including from about 50 milligrams to about 550 milligrams, including from about 75 milligrams to about 550 milligrams, including from about 100 milligrams to about 500 milligrams, including from about 100 milligrams to about 450 milligrams, including about 400 milligrams, per day of bioavailable curcumin. The total daily amount of bioavailable curcumin 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.

Prune Extract

[0043] In addition to the bioavailable curcumin, the nutritional compositions of the present disclosure include a concentrated prune extract, wherein the concentrated prune extract includes at least three different polyphenol types, including hydroxycinnamic acid, flavanol, and flavonoid, as well as a combination of water soluble (chlorogenic acid) and oil soluble (quercetin) polyphenols. In one specific embodiment, a suitable prune extract is derived from the species Prunus domes tica.

[0044] Prune extracts suitable for use in the nutritional compositions of the present disclosure desirably include a combination of flavonoids (e.g., quercetin, rutin, daidzin, genistin, epicatechin, 7-methoxycoumarin), procyanadins (or proanthocyanidins), and hydroxycinnamic acids (e.g., p-coumaric acid, caffeic, ferulic, chlorogenic, neochlorogenic).

[0045] The term "prune extract" as used herein refers to the extracted concentrate including polyphenolic compounds from prunes, plums, dates, grapes, figs, and

combinations thereof and is in a concentrated form. The prune extract comprises at least 5%, or at least 10%, or at least 15%, or at least 25%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% or even 100%, including from about 5% to 100%, including from about 10%> to 100%, including from about 25%o to 100%), including from about 50%> to 100%) and further including from about 75%) to 100%) by weight polyphenolic compounds. In some embodiments, the prune extract comprises from about 25% to about 75%, including from about 25% to about 65%, including from about 30% to about 60%, including from about 40% to about 60%, including from about 45% to about 55%, including about 50% by weight polyphenolic compounds.

[0046] The nutritional compositions of the present disclosure desirably include sufficient prune extract to provide an individual with from about 0.1 grams to about 10 grams, including from about 0.5 grams to about 10 grams, including from about 1 gram to about 8 grams, including from about 2 grams to about 7 grams, and also including from about 3 grams to about 6 grams, per day of prune extract. In some embodiments, the nutritional compositions include sufficient prune extract to provide an individual with from about 0.5 grams to about 4 grams, including from about 0.5 grams to about 3.5 grams, including from about 1 gram to about 3 grams, including from about 1.5 grams to about 2.5 grams, including about 1 gram to about 2 grams, per day of prune extract. The total daily amount of prune extract 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.

[0047] The prune extract concentration in the nutritional compositions may range up to 15%), including up to 10%, including from about 0.1% to about 10%, and also including from about 0.1% to about 8.0%>, and also including from about 0.2% to about 5.0%), and also including from about 0.3% to about 3%, and also including from about 0.4% to about 1.5%, by weight of the nutritional composition. One suitable commercially available prune extract is PE60 (60% polyphenols) (PL Thomas, Morristown, New Jersey).

Macronutrients

[0048] The nutritional compositions of the present disclosure may further comprise one or more optional macronutrients in addition to the bioavailable curcumin and prune extract described herein. The optional macronutrients include proteins, lipids, carbohydrates, and combinations thereof. The nutritional compositions are desirably formulated as dietary products containing all three macronutrients.

[0049] Macronutrients suitable for use herein include any protein, lipid, or carbohydrate or source thereof that is known for or otherwise suitable for use in an oral nutritional composition, provided that the optional macronutrient is safe and effective for oral administration and is otherwise compatible with the other ingredients in the nutritional composition.

[0050] The concentration or amount of optional lipid, carbohydrate, and protein in the nutritional composition can vary considerably depending upon the particular product form (e.g., bars or other solid dosage forms, milk or soy-based liquids or other clear beverages, reconstitutable powders etc.) and the various other formulations and targeted dietary needs. These optional macronutrients are most typically formulated within any of the embodied ranges described in the following tables.

Each numerical value preceded by the term "about"

Each numerical value preceded by the term "about" Carbohydrate

[0051] Optional carbohydrates suitable for use in the nutritional compositions may be simple, complex, or variations or combinations thereof, all of which are optionally in addition to the prune extract and the bioavailable curcumin as described herein. Non- limiting examples of suitable carbohydrates include hydrolyzed or modified starch or cornstarch, maltodextrin, isomaltulose, sucromalt, glucose polymers, sucrose, corn syrup, corn syrup solids, rice-derived carbohydrate, glucose, fructose, lactose, high fructose corn syrup, honey, sugar alcohols (e.g., maltitol, erythritol, sorbitol), and combinations thereof.

[0052] Optional carbohydrates suitable for use herein also include soluble dietary fiber, non-limiting examples of which include gum Arabic, fructooligosaccharide (FOS), sodium carboxymethyl cellulose, guar gum, citrus pectin, low and high methoxy pectin, oat and barley glucans, carrageenan, psyllium and combinations thereof. Insoluble dietary fiber is also suitable as a carbohydrate source herein, non-limiting examples of which include oat hull fiber, pea hull fiber, soy hull fiber, soy cotyledon fiber, sugar beet fiber, cellulose, corn bran, and combinations thereof.

Protein

[0053] Optional proteins suitable for use in the nutritional compositions include hydrolyzed, partially hydrolyzed or non-hydrolyzed proteins or protein sources, and can be derived from any known or otherwise suitable source such as milk (e.g., casein, whey), animal (e.g., meat, fish, egg albumen), cereal (e.g., rice, corn), vegetable (e.g., soy, pea, potato), or combinations thereof. The proteins for use herein can also include, or be entirely or partially replaced by, free amino acids known for use in nutritional products, non-limiting examples of which include L-tryptophan, L-glutamine, L-tyrosine, L- methionine, L-cysteine, taurine, L-arginine, L-carnitine, and combinations thereof.

Lipid

[0054] Optional lipids suitable for use in the nutritional compositions 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. Optional Ingredients

[0055] The nutritional compositions may further comprise other optional ingredients that may modify the physical, nutritional, chemical, hedonic or processing characteristics of the products or serve as pharmaceutical or additional nutritional components when used in a targeted population. Many such 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 composition.

[0056] Non-limiting examples of such other optional ingredients include preservatives, anti-oxidants, buffers, pharmaceutical actives, sweeteners, colorants, flavors, flavor enhancers, thickening agents and stabilizers, emulsifying agents, lubricants, and combinations thereof.

[0057] The nutritional compositions may further include 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.

[0058] The nutritional compositions may also include 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, 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.

Methods of Manufacture

[0059] The nutritional compositions may be prepared by any known or otherwise effective manufacturing technique for preparing the selected product form. Many such techniques are known for any given product form such as nutritional liquids and nutritional powders and can easily be applied by one of ordinary skill in the nutrition and formulation arts to the nutritional products described herein. [0060] Liquid, milk or soy-based nutritional liquids, for example, may be prepared by first forming an oil and fiber blend containing all formulation oils, any emulsifier, fiber and fat- soluble vitamins. Additional slurries (typically a carbohydrate and two protein slurries) are prepared separately by mixing the carbohydrate and minerals together and the protein in water. The slurries are then mixed together with the oil blend. The resulting mixture is homogenized, heat processed, standardized with any water-soluble vitamins, flavored and the liquid terminally sterilized or aseptically filled or dried to produce a powder.

[0061] The compositions of the present disclosure may also be manufactured by other known or otherwise suitable techniques not specifically described herein without departing from the spirit and scope of the present disclosure. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive and that all changes and equivalents also come within the description of the present disclosure.

Methods of Use

[0062] The methods of using the nutritional compositions of the present disclosure include the oral administration of the nutritional compositions that include a prune extract in combination with bioavailable curcumin, to treat and/or prevent and/or manage and/or control and/or reduce and/or modulate inflammation generally, including both acute inflammation and chronic inflammation in adults and older adults. The methods are also directed at treating and/or preventing and/or managing and/or controlling and/or reducing and/or modulating muscle wasting diseases associated with chronic inflammation (e.g., skeletal muscle loss resulting from age-associated wasting, wasting associated with long-term hospitalization, wasting associated with muscle disuse, wasting associated with muscle immobilization, and wasting associated with chemotherapy or long-term steroid use), cachexia due to cancer, human immunodeficiency virus/acquired immune deficiency syndrome (HIV/ AIDS), autoimmune diseases, chronic obstructive pulmonary disease (COPD), end stage renal disease (ESRD), coronary artery disease, diabetes, inflammatory bowel disease, kidney disease, arthritis, allergy, asthma, and combinations thereof in individuals, as well as conditions directly related to acute inflammation, such as acute respiratory distress syndrome (ARDS), "flare up" during ulcerative colitis, Crohns' disease, and rheumatoid arthritis. [0063] Additionally, the nutritional compositions can be utilized to prevent or minimize cognitive decline, which can also be related to inflammation. Particularly, the nutritional compositions including prune extract and bioavailable curcumin can be administered to treat and/or prevent and/or manage and/or reduce and/or modulate age- related cognitive decline or cognitive decline associated with a neurodegenerative disease.

[0064] The individual desirably consumes at least one serving of the nutritional composition daily, and in some 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. The methods 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 methods of the present disclosure are preferably applied on a daily basis, wherein the daily

administration is maintained continuously for at least 3 days, including at least 5 days, including at least 1 month, including at least 6 weeks, including at least 8 weeks, including at least 2 months, including at least 6 months, desirably for at least 18-24 months, desirably as a long term, continuous, daily, dietary supplement.

[0065] The methods of the present disclosure as described herein are also intended to include the use of such methods in "at risk" individuals, including individuals unaffected by or not otherwise afflicted with muscle wasting diseases, neurodegenerative diseases, etc., for the purpose of preventing, minimizing, or delaying the development of such diseases or conditions over time. For such prevention purposes, the methods of the present disclosure preferably include continuous, daily administration of the compositions as described herein. Such preventive methods may be directed at adults or others, particularly older adults, who are at risk or susceptible to developing muscle wasting and/or neurodegenerative diseases due to, for example, overall health, family history,

environmental conditions, and the like.

[0066] In one specific embodiment, the methods of the present disclosure are directed to reducing chronic inflammation associated with muscle wasting disease, by which is meant that the methods are used in individuals afflicted by, or otherwise susceptible to developing muscle wasting disease. These methods can be used to slow the onset or progression of muscle wasting in an individual resulting from diseases such as cachexia due to cancer, sarcopenia, human immunodeficiency virus/acquired immune deficiency syndrome (HIV/ AIDS), autoimmune diseases, end-stage heart disease, chronic obstructive pulmonary disease (COPD), end stage renal disease (ESRD) by reducing and controlling the inflammation that plays a role in the progression of such muscle wasting in the individual.

[0067] In another specific embodiment, the methods of the present disclosure are directed to the treatment or prevention or management of cognitive decline, including age- related cognitive decline and cognitive decline associated with neurodegenerative diseases, by which is meant that the methods are used in individuals afflicted by or otherwise susceptible to cognitive decline by reducing and controlling the inflammation that plays a role in the progression of cognitive decline in the individual.

EXAMPLES

[0068] The following examples illustrate specific embodiments and or features of the nutritional products of the present disclosure. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present disclosure, as many variations thereof are possible without departing from the spirit and scope of the disclosure.

[0069] The exemplified products are nutritional products prepared in accordance with manufacturing methods well known in the nutrition industry for preparing nutritional emulsions and powders.

Example 1

[0070] In this Example, the efficacies of prune extract alone, bioavailable curcumin alone, and the combination of prune extract and bioavailable curcumin for their anti-inflammatory activities in an in vitro model of chronic inflammation are evaluated. For the cell based assays described herein, the curcumin form evaluated need not be bioavailable to evaluate activity. This curcumin form, however, is rendered bioavailable as defined herein for in vivo use in accordance with the present disclosure. [0071] A cell based assay system is established by using an NFKB reporter stable cell line for measuring the activity of NFKB transcription factor. This assay system is utilized to screen compounds that inhibit the activation of NFKB induced by TNFa on A549/NFKB-1UC reporter stable cell line, available from Panomics (Santa Clara,

California), where the activity is measured in terms of luciferase activity.

[0072] To prepare the cell line, one seed A549/NFKB-1UC cells at 3 X 10⁵/well is combined with 1 ml of initial growth medium (Dulbecco's Modified Eagle's medium (ATCC P/N 30-2002) + 10% fetal bovine serum (ATCC P/N 30-2020) + 1% Pen-Strep (ATCC P/N 30-2300)) in a twelve -well plate. The culture is incubated in a humidified incubator at 37°C and 5% C0₂ for 24 hours to allow cells to recover and attach. The media is washed and replaced with 1 ml of serum free medium (Dulbecco's Modified Eagle's medium + 1% Pen-Strep). The cells are then pretreated for one hour at 37°C and 5% C0₂ with one of the following test compounds: (1) 10 μg/ml prune extract (available as PE60 from Polifenoles Naturales, S.L., Las Palmas, Spain); (2) 25 μg/ml PE60; (3) 5 μg/ml bioavailable curcumin (available as Curcumin C3 complex, Sabinsa Corporation, East Windsor, New Jersey); (4) 10 μg/ml prune extract + 5 μg/ml bioavailable curcumin; or (5) 25 μg/ml prune extract + 5 μg/ml bioavailable curcumin. TNFa is added to achieve a final concentration of 2 ng/mL to all wells except the control untreated cells and the cells are incubated in a humidified incubator at 37°C and 5% C0₂ for 6 hours.

[0073] Lysis buffer is prepared for addition to the cells by adding four volumes of water to one volume of 5X lysis buffer, available from Promega Corporation (Madison, Wisconsin). The growth medium is removed from the cells and the cells are then washed with PBS once prior to adding 100 μΐ IX lysis buffer. The cells are rocked several times to ensure complete coverage of the cells with lysis buffer and then the cells are frozen at -80°C overnight.

[0074] Luciferase assay reagent is prepared by adding luciferase assay buffer (10 ml) to a vial containing the lyophilized luciferase assay substrate. The vial is mixed and placed in a luminometer. The cell plates, containing 20 μΐ of cell lysate per well, are placed into the luminometer with an injector, which adds 100 μΐ of luciferase assay reagent per well and the well is immediately read for relative light units (RLU). Average RLU values for each set of triplicate wells using Winglow software are calculated and the average RLU values versus the concentration of test compound. The relative percent inhibition of TNFa-mediated NFKB activation on A549 cells is then calculated. The results are shown in Figure 1.

[0075] As shown in Figure 1 , bioavailable curcumin and prune extract both demonstrate anti-inflammatory activity independently, with the exception of prune extract at 10 μg/ml, which did not show any activity. Specifically, bioavailable curcumin alone (5 μg/ml) shows approximately a 12% inhibition, and prune extract alone (25 μg/ml) shows approximately a 21 % inhibition of NFKB activation. The synergistic combination of bioavailable curcumin (5 μg/ml) and prune extract (25 μg/ml), and the synergistic combination of bioavailable curcumin (5 μg/ml) and prune extract (10 μg/ml), however, both show significant synergistic activity for inhibiting NFKB activation. Specifically, the combination of bioavailable curcumin (5 μg/ml) with 10 μg/ml prune extract shows approximately 21 % inhibition and the combination of bioavailable curcumin (5 μg/ml) with 25 μg/ml prune extract shows approximately 50% inhibition of NFKB activation. These data indicate that the combination of prune extract and bioavailable curcumin act in a synergistic manner to promote anti-inflammatory activities in cells.

Examples 2-5

[0076] Examples 2-5 illustrate nutritional emulsions of the present disclosure, the ingredients of which are listed in Table 1 below. All ingredient amounts are listed as kg per 1000 kg batch of product, unless otherwise specified.

Table 1

Ingredient 3x. 2 3x. 3 3x. 4 3x. 5

Water Q.S Q.S. Q.S. Q.S.

Maltodextrin 120.0 120.0 120.0 120.0

Sucrose 71.38 71.38 71.38 71.38

Milk Protein Concentrate 14.65 13.65 12.65 11.65

Canola Oil 27.5 27.5 27.5 27.5

Sodium Caseinate 30.68 31.68 32.68 33.68

Soy Protein Concentrate 14.05 14.05 14.05 14.05

Corn Oil 15.70 15.70 15.70 15.70

Prune Extract PE60 0.4 1.5 3.0 5.0

Bioavailable Curcumin 0.01 0.04 0.10 1.0

Whey Protein Concentrate 3.50 3.50 3.50 3.50

Magnesium Phosphate 1.92 1.92 1.92 1.92

Potassium Citrate 6.92 6.92 6.92 6.92 Sodium Citrate 0.903 0.903 0.903 0.903

Lecithin 1.50 1.50 1.50 1.50

Sodium Tripolyphosphate 1.06 1.06 1.06 1.06

Potassium Phosphate dibasic 0.730 0.730 0.730 0.730

Potassium Chloride 1.04 1.04 1.04 1.04

Ascorbic Acid 0.235 0.235 0.235 0.235

Carrageenan 0.150 0.150 0.150 0.150

Potassium Hydroxide 0.136 0.136 0.136 0.136

TM/UTM Premix 0.1684 0.1684 0.1684 0.1684

Gellan Gum 0.050 0.050 0.050 0.050

Vitamin A, D, E Premix 0.0758 0.0758 0.0758 0.0758

Water sol. Vitamin premix 0.0728 0.0728 0.0728 0.0728

Potassium Iodide 0.00022 0.00022 0.00022 0.00022

Chromium Chloride 0.000217 0.000217 0.000217 0.000217

Flavor 3.3 3.3 3.3 3.3

Examples 6-10

[0077] Examples 6-10 illustrate nutritional powders of the present disclosure, the ingredients of which are listed in Table 2 below. These products are prepared by spray drying methods in separate batches, are reconstituted with water prior to use to the desired target ingredient concentrations. All ingredient amounts are listed as kg per 1000 kg batch of product, unless otherwise specified.

Table 2

Ingredient Ex. 6 Ex. 7 Ex. 8 Ex. 9 Ex. 10

Maltodextrin 448.3 471.3 435.3 424.3 419.3

Sucrose 145.5 120.5 145.5 145.5 145.5

Calcium Caseinate 129.1 129.1 129.1 129.1 129.1

Isolated Soy Protein 57.7 57.7 57.7 61.7 57.7

FOS Powder 33.6 33.6 33.6 33.6 32.6

HO sunflower oil 59.9 55.5 61.24 57.2 62.58

Prune Extract PE60 4 7.5 10.0 12.5 15.0

Bioavailable Curcumin 0.02 0.04 0.10 1.0 1.1

Canola Oil 55.1 53.7 56.4 52.42 57.78

Soy Oil 26.7 26.0 27.37 25.36 28.04

Potassium Citrate 10.3 10.3 10.3 10.3 10.3

Sodium Citrate 5.8 5.8 5.8 5.8 5.8

Potassium Chloride 5.2 5.2 5.2 5.2 5.2

Magnesium Chloride 4.7 4.7 4.7 4.7 4.7

Potassium hydroxide 3.1 3.1 3.1 3.1 3.1

Sodium phosphate dibasic dihydrate 3.0 3.0 3.0 3.0 3.0

Sodium chloride 2.5 2.5 2.5 2.5 2.5

Choline Chloride 1.8 1.8 1.8 1.8 1.8

Vanilla Flavor 1.8 1.8 1.8 1.8 1.8

Sodium phosphate monobasic 1.6 1.6 1.6 1.6 1.6 monohydrate

Potassium phosphate dibasic trihydrate 1.1 1.1 1.1 1.1 1.1

Flavor 1.0 1.0 1.0 1.0 1.0

Vitamin premix 1.0 1.0 1.0 1.0 1.0 Ascorbyl palmitate 0.243 0.243 0.243 0.243 0.243

Ascorbic acid 0.240 0.240 0.240 0.240 0.240

Antioxidant 0.116 0.116 0.116 0.116 0.116

Ferrous sulfate 0.010 0.090 0.030 0.020 0.070

Vitamin premix 0.065 0.065 0.065 0.065 0.065

Zinc sulfate monohydrate 0.057 0.057 0.057 0.057 0.057

Manganese sulfate 0.045 0.045 0.045 0.045 0.045

Mineral mix copper sulfate 0.035 0.035 0.035 0.035 0.035

Beta carotene 30% 0.005 0.005 0.005 0.005 0.005

Chromium chloride 0.001 0.001 0.001 0.001 0.001

Sodium molybdate 0.0012 0.0012 0.0012 0.0012 0.0012

Potassium iodide 0.001 0.001 0.001 0.001 0.001

Sodium selenite 0.0004 0.0004 0.0004 0.0004 0.0004

Citric acid AN AN AN AN AN

Potassium hydroxide AN AN AN AN AN

Magnesium sulfate dry AN AN AN AN AN

Ultra micronized tricalcium phosphate AN AN AN AN AN

Ascorbic acid AN AN AN AN AN

AN = As Needed

Claims

WHAT IS CLAIMED IS:

1. A nutritional composition comprising a synergistic amount of bioavailable curcumin and a prune extract, wherein the prune extract comprises from about 25% to 100%) polyphenolic compounds.

2. The nutritional composition of claim 1 comprising from about 0.002% to about 1.0% bioavailable curcumin by weight of the nutritional composition and from about 0.1% to about 8% prune extract by weight of the nutritional composition.

3. The nutritional composition of claim 1 comprising from about 0.1% to about 0.25% bioavailable curcumin by weight of the nutritional composition and from about 0.4% to about 1.5% prune extract by weight of the nutritional composition.

4. The nutritional composition of claim 1 further including at least one of a protein, a carbohydrate, a lipid, vitamins and minerals.

5. The nutritional composition of claim 1 wherein the prune extract comprises from about 50%> to 100% polyphenolic compounds.

6. The nutritional composition of claim 1 wherein the prune extract is derived from the species Prunus domestica.

7. A method of reducing inflammation in an individual, the method comprising administering to the individual a nutritional composition comprising a synergistic amount of bioavailable curcumin and a prune extract, wherein the prune extract comprises from about 25%o to 100% polyphenolic compounds.

8. The method of claim 7 wherein the nutritional composition comprises from about 0.002% to about 1.0% bioavailable curcumin by weight of the nutritional

composition and from about 0.1% to about 8.0% prune extract by weight of the nutritional composition.

9. The method of claim 7 wherein the nutritional composition comprises from about 0.1% to about 0.25% bioavailable curcumin by weight of the nutritional composition and from about 0.4% to about 1.5% prune extract by weight of the nutritional composition.

10. The method of claim 7 wherein the nutritional composition provides from about 100 mg/day to about 2000 mg/day of bioavailable curcumin and from about 0.5 g/day to about 8 g/day of prune extract to the individual.

11. The method of claim 7 wherein the nutritional composition further includes at least one of a protein, a carbohydrate, a lipid, vitamins and minerals.

12. The method of claim 7 wherein the prune extract is derived from the species Prunus domestica.

13. The method of claim 7 wherein the prune extract comprises from about 50% to 100%) polyphenolic compounds.

14. A method of preventing cognitive decline in an individual, the method comprising administering to the individual a nutritional composition comprising a synergistic amount of bioavailable curcumin and a prune extract, wherein the prune extract comprises from about 25% to 100% polyphenol compounds.

15. The method of claim 14 wherein the nutritional composition comprises from about 0.002% to about 1.0% bioavailable curcumin by weight of the nutritional composition and from about 0.1% to about 8.0% prune extract by weight of the nutritional composition.