Nutrient supplement formulations for energy and Anti-inflammation

Abstract

The present invention provides compositions and dosage forms for enhancing energy and reducing inflammation. In certain embodiments, an energy composition comprises citicoline and paraxanthine in a mass ratio of 10:1 to 1:10, preferably about 1:1, delivered as an oral film, capsule, or liquid; exemplary unit doses deliver about 200–300 mg citicoline and about 200–300 mg paraxanthine. In further embodiments, an anti-inflammatory composition comprises astaxanthin, L‑citrulline, glutathione, luteolin, and palmitoylethanolamide within defined mg ranges. Liposomal and spray‑dried liposomal microparticle formulations, including reconstitution parameters, are provided. The compositions yield synergistic effects relative to individual actives, as quantified by accepted models (e.g., combination index <1). Methods of manufacturing, kits, and methods of improving mental focus, physical performance, and recovery are also described.

Description

NUTRIENT SUPPLEMENT FORMULATIONS FOR ENERGY AND ANTIINFLAMMATIONCROSS-REFERENCE TO RELATED APPLICATIONS

[0144] The present application claims benefit of priority to U.S. Provisional Patent Applications: (i) Serial Number 63 / 692,767 filed September 10, 2024; and (ii) Serial Number 63 / 768,611 filed March 7, 2025, both entitled “NUTRIENT SUPPLEMENT FORMULATIONS FOR ENERGY AND ANTI-INFLAMMATION”, the disclosures of which are hereby incorporated by reference in their entirety.BACKGROUND OF THE INVENTION1. Field of the Invention

[0145] The field of art disclosed herein pertains generally relates to compositions and methods for an edible energy composition that provides physical and mental benefits when ingested. The disclosure also relates to an edible anti-inflammatory composition that provides physical benefits when ingested.2. Description of the Related Art

[0146] Sports and athletic participation is a complex process of preparation, action and recovery. Every element of participation and success in an athletic event involves use of energy that defines an efficiency in gaining an advantage over a competitor.

[0147] An ability to have more energy to deliver active pre-event practice, more ability to sustain and perform during the event and increased ability to recover from an event can mean the difference in a competitive environment of a positive or negative result.

[0148] Labeled “sports drinks” have enhanced participation with caffeine, sugar and electrolytes although the results of these preparations have resulted in higher energy but resulted in increased agitation, post-high lows, hydration (without additional benefits) respectively.Docket No.: 1022.550W01

[0149] There is now a need for an energy and inflammation supplement that is without such dosages of caffeine and sugar.BRIEF SUMMARY

[0150] The disclosure relates to an edible energy composition that provides physical and mental benefits when ingested. The disclosure also relates to an edible anti-inflammatory composition that provides physical benefits when ingested.

[0151] Some embodiments of the present disclosure include a composition comprising ingredients that increase energy, for improving an individual's endurance, and for enhancing body / muscle recovery in athletes.

[0152] The present disclosure relates to a composition, which in some embodiments is a dietary supplement that may be useful for energy, endurance, and after-workout body / muscle recovery and, in certain embodiments, for uses related to human performance. Also described in some embodiments is the method for using the composition, such as for energy, endurance, and afterwork out body / muscle recovery and, in certain embodiments, for uses related to human sports performance. Some embodiments include kits, comprising the composition to be consumed according to a dietary regimen for increasing blood flow for energy, endurance, and after-work out body / muscle recovery in humans.

[0153] The present disclosure relates to an energy composition comprising an effective and synergistic amount of a combination of citicoline, citrulline, glutathione, and Rhodiola rosea extract, including derivatives, precursors, structurally-similar compounds, analogs and / or metabolites of these substances. In one or more embodiments, the energy composition further comprises one or more of astaxanthin, beetroot extract, vitamin C, adenosine 5 '-triphosphate (“ATP”), and paraxanthine, in various amounts in a liposomal formulation.

[0154] The present disclosure relates to an energy composition comprising an effective and synergistic amount of a combination of citicoline and paraxanthine, including derivatives, precursors, structurally-similar compounds, analogs and / or metabolites of these substances. In oneDocket No.: 1022.550W01 or more embodiments, the citicoline and paraxanthine are provided in a liposomal formulation. In one or more embodiments, the energy composition further comprises a carrier in various amounts.

[0155] In certain embodiments, a unit dosage form comprises citicoline and paraxanthine in a mass ratio from 10: 1 to 1 : 10, optionally from 4: 1 to 1 :4, and in particular embodiments about 1 : 1. In certain embodiments, a serving delivers from about 50 mg to about 500 mg citicoline and from about 50 mg to about 500 mg paraxanthine. In exemplary embodiments, a serving delivers about 200 mg citicoline and about 200 mg paraxanthine, or about 250 mg citicoline and about 250 mg paraxanthine.

[0156] In one or more embodiments, at least one of citicoline or paraxanthine is incorporated into liposomes. Liposomes may comprise phosphatidylcholine, phosphatidyl serine, phosphatidylethanolamine, phosphatidylglycerol, and cholesterol, optionally with PEGylated lipids to modulate circulation and stability. In certain embodiments, the liposomes exhibit an average hydrodynamic diameter from about 50 nm to about 500 nm, optionally from about 80 nm to about 200 nm, with a poly dispersity index below about 0.3 as determined by dynamic light scattering. Encapsulation efficiency for citicoline may be at least about 40%, and for paraxanthine at least about 30%, when prepared under the methods herein.

[0157] In another embodiment, the synergistic energy composition comprises about 120 mg to about 250 mg of citicoline, and about 120 mg to about 400 mg of paraxanthine contained within a unit dosage form in the form of an oral film for buccal administration. In another embodiment, the synergistic composition consists essentially of about 150 mg to about 250 mg of citicoline, and about 200 mg to about 400 mg of paraxanthine contained within a unit dosage form in the form of an oral film for buccal administration. In another embodiment, the synergistic composition consists essentially of about 200 mg to about 300 mg of citicoline, and about 200 mg to about 300 mg of paraxanthine contained within a unit dosage form in the form of an oral film for buccal administration. In one or more embodiments, the maximum amount of total ingredients within an oral film dosage unit is 500 mg.

[0158] The present disclosure also relates to an anti-inflammatory composition comprising an effective and synergistic amount of a combination of citrulline, glutathione, luteolin,Docket No.: 1022.550W01 palmitoylethanolamide, and astaxanthin, including derivatives, precursors, structurally-similar compounds, analogs and / or metabolites of these substances.

[0159] In one aspect, a composition is provided comprising an effective and synergistic amount of astaxanthin, L-citrulline, glutathione, luteolin, and palmitoylethanolamide. In certain embodiments, luteolin and palmitoylethanolamide are present in a ratio selected from about 1 : 1 and about 1 : 10 (luteolin:PEA), including a 1 :10 ratio corresponding to about 60 mg luteolin and about 600 mg PEA. In certain embodiments, the composition comprises about 1-50 mg astaxanthin, about 100-2000 mg L-citrulline, about 250 mg reduced glutathione, about 60 mg luteolin, and about 600 mg PEA. In other embodiments, the composition comprises about 6 mg astaxanthin, about 250 mg citrulline, about 50-800 mg glutathione, about 5-200 mg luteolin, and about 25-800 mg PEA. At least one ingredient can be provided in a liposomal formulation. The compositions may further comprise a carrier (e.g., oil, aqueous vehicle, solid excipients) and may be provided as a liquid formulation.

[0160] The disclosure further provides methods of alleviating inflammation and pain by administering any of the foregoing compositions and processes for preparing liposomal dosage forms and liquid formulations.

[0161] Some embodiments of the present disclosure can be used by athletes to increase endurance, decrease inflammation, and enhance recovery. Some embodiments of the present disclosure can be used as a healthier option for increasing energy and health improvement.

[0162] The edible compositions include gels, gel packs, liquids, syrups, and / or solids provided as a food, food product, or food composition intended for ingestion by an animal, including a human, and provides nutrition to the animal.Docket No.: 1022.550W01DETAILED DESCRIPTION

[0163] For convenience, before further description of the present invention, certain terms employed in the specification, examples and appended claims are defined here.

[0164] The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0165] As used herein, the term "about" refers to plus or minus 10% of the referenced number unless the context dictates otherwise. For example, a formulation comprising paraxanthine at about 250 mg includes an amount of paraxanthine between 225 and 275 mg. By “about” is meant a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much as 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1% to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length.

[0166] “Administering” a composition can be performed using any of the various methods and delivery systems known to those skilled in the art.

[0167] The term “bioavailability” includes, generally, the degree to which a drug or other substance becomes available to a subject following ingestion, administration, or exposure. In one embodiment, for example, the bioavailability of the paraxanthine compounds may be the bioavailability to a particular target tissue. For example, in an embodiment, the particular target tissue may require traversal of the stomach or the small intestines, therefore the bioavailability data may be obtained from this particular target tissue.

[0168] “Carrier” means any excipient, diluent, solvent, oil, or vehicle that facilitates manufacture, stability, delivery, palatability, or bioavailability of the actives and is acceptable for the intended route of administration.

[0169] As used herein, chemical compounds or simply "compounds" may be identified either by their chemical structure, chemical name, or common name. In the event that the chemical structure, chemical name, or common name conflict, the chemical structure is determinative of the identity of the compound. The compounds described herein may contain one or more chiral centersDocket No.: 1022.550W01 and / or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers, or diastereomers. Accordingly, the chemical structures depicted herein encompass all possible enantiomers and stereoisomers of the illustrated or identified compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures.

[0170] Disclosed are components to be used to prepare the disclosed compositions as well as the compositions themselves to be used within the methods and compositions disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of components including the compound are discussed, specifically contemplated is each and every combination and permutation of the components and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of components A, B, and C are disclosed as well as a class of components D, E, and F and an example of a combination component, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the disclosed compositions. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the disclosed methods.

[0171] Concentrations, amounts, and other numerical data may be expressed or presented herein in a range format. It is to be understood that such a range format is used merely for convenience and brevity and thus should be interpreted flexibly to include not only the numerical values explicitly recited as the limits or endpoints of the range, but also to include all the individual numerical values and / or sub-ranges encompassed within that range as if each numerical value (including fractions) and sub-range is explicitly recited. As an illustration, a numerical range ofDocket No.: 1022.550W01"about 1 to about 5" should be interpreted to include not only the explicitly recited values of about 1 to about 5, but also include individual values and sub-ranges within the indicated range. Thus, included in this numerical range are individual values such as 2, 2.6, 3, 3.8, and 4 and sub-ranges such as from 1-3, from 2-4, and from 3-5, etc., as well as 1, 2, 3, 4, and 5, individually.

[0172] As used herein a "concentrate" refers to an extract of a source that contains at least the same number of active fractions, compounds, or other constituents, in a smaller volume than in the source itself. In one example, a "concentrate" may be a dried powder derived from a component that does not include the use of any solvents during the concentration process.

[0173] As used herein, the term “consists essentially of’ (and grammatical variants thereof), as applied to the compositions and methods of the present invention, means that the compositions / methods may contain additional components so long as the additional components do not materially alter the composition / method. The term “materially alter,” as applied to a composition / method of the present invention, refers to an increase or decrease in the effectiveness of the composition / method of at least about 20% or more. For example, a component added to a composition of the present invention would materially alter the composition’s energy or antiinflammatory performance, defined as a >20% change vs. control in at least one pre-specified endpoint selected from PVT median reaction time, Karolinska Sleepiness Scale, CRP, IL-6, TNF- a, or VAS pain.

[0174] As used herein, “consumable” means something suitable for animal or human consumption.

[0175] The term "dosage unit" is understood to mean a unitary, i.e. a single dose which is capable of being administered to a subject or patient, and that may be readily handled and packed, remaining as a physically and chemically stable unit dose comprising either the active ingredient as such or a mixture of it with solid or liquid pharmaceutical vehicle materials.

[0176] An "effective amount," "therapeutic amount," "therapeutic effective amount," or "effective dose" is an amount or dose sufficient to elicit a desired pharmacological or therapeutic effect in a mammalian subject; typically resulting in a measurable increase in nitric oxide production or availability. Therapeutic effectiveness may further be demonstrated by a decrease inDocket No.: 1022.550W01 the symptoms of the conditions being treated. “Effective amount” means an amount sufficient to produce a measurable improvement in one or more energy-related endpoints, including subjective energy ratings, reduced fatigue, improved psychomotor vigilance task performance, reaction time, sustained attention, working memory, EEG or heart-rate-variability correlates of alertness, or step- count / activity metrics. The effective amount will vary from subject to subject and depending on the condition to be treated, the agent delivered, and the route of delivery. A person of ordinary skill in the art can perform routine titration experiments to determine such an amount. Depending upon the agent delivered, the effective amount of a composition can be delivered continuously, such as by a suppository, or at periodic intervals (for example, on one or more separate occasions). Desired time intervals of multiple amounts of a particular agent can be determined without undue experimentation by one skilled in the art.

[0177] As used herein the term “enhancing performance” is intended to mean any improvement in performance. Performance can be assessed in any manner. Certain enhancements are readily measured. For example, in a timed-event, an improved time can assess an enhanced performance. Certain performance enhancing properties can be judged subjectively by the athlete or performer or an observer. In these instances, an enhanced performance means that the performance was perceived subjectively to be improved, magnified, faster, better and the like. In certain embodiments, the disclosed methods are used to enhance athletic performance. “Athletic performance” refers to any professional or recreational activity wherein the performer, for example an athlete, exerts a physical act, such as running, swimming, golf, bowling, archery, football, baseball, basketball, soccer, hiking, cycling, dancing and the like. In certain athletic performance is improved through in improvement of endurance in the subject. In other words, administration of the disclosed compositions improves a subject's level of endurance, thereby enhancing the subject's athletic performance. In further embodiments, administration of the composition to the subject increases cognitive performance which thereby improves athletic performance. In certain embodiments, upon administration of the composition, the subject experiences improvement of at least one of mood, energy, focus, concentration or sexual desire or a reduction of at least one of anxiety, fatigue, perception of effort or perception of pain.

[0178] The term “food” includes all edible compositions regardless of form and thus includes gels, gel packs, liquids, syrups, and / or solids. A "food" or "food product" or "food composition"Docket No.: 1022.550W01 means a product or composition that is intended for ingestion by an animal, including a human, and provides nutrition to the animal.

[0179] The term “increased performance” of a subject refers to an increase in the subject's mean peak power and / or an increase in the subject's mean average power over the course of several exercise intervals. Accordingly, a subject can experience “increased performance” even if the subject's peak power and / or mean power did not increase during any given exercise interval.

[0180] In the present disclosure, by “liquid composition”, it is meant a liquid solution that is suitable for delivery through ingestion as a liquid, such as a solution or as an aerosol that can be consumed or administered as a spray, through a dropper, etc. In the present disclosure, by “solution” it is meant a homogenous mixture of two or more substances.

[0181] The term “liposomes” generally refers to uni- or multi-lamellar lipid structures that can be loaded with therapeutic agents, e.g. the therapeutic agent is encapsulated inside the liposome, and / or the therapeutic agent can be attached in the liposome or incorporated into the lipid bilayer(s). For the purposes of the invention, a “liposomal formulation” designates a composition comprising liposomes encapsulating an active ingredient, said active ingredient being designated as being “encapsulated” or even “contained in a liposomal formulation”. In the present disclosure, “liposomes” are nanoscale vesicles having an average hydrodynamic diameter of about 80-200 nm with a polydispersity index (PDI) of less than 0.3, measured by dynamic light scattering (DLS) at 25 °C using purified water as dispersant and a 173° backscatter detection angle unless otherwise specified; encapsulation efficiency (EE) for one or more actives is typically at least about 70% (e g., 70-95%) as determined by separation of non-encapsulated actives (e.g., ultracentrifugation or size-exclusion chromatography) followed by quantitative assay. Distinct therefrom, “spray- dried liposomal microparticles” are free-flowing agglomerates having a volume-median particle size of about 25-55 pm that contain said liposomes in a dehydrated state and are configured to reconstitute to the liposomal nanoscale upon contact with aqueous media. Reconstitution may be carried out by adding the microparticles to water or a physiologically acceptable aqueous buffer at 25 °C to a concentration of about 1-5 mg / mL with gentle stirring for about 5-10 minutes, optionally followed by brief sonication to disperse visible agglomerates. Following reconstitution, the resulting dispersion meets acceptance criteria confirming restoration of the nanoscale state,Docket No.: 1022.550W01 including a Z-average particle size within about 100-160 nm and a PDT of no greater than 0.25 by DLS under the foregoing conditions, with EE remaining within at least about 90% of its pre-drying value.

[0182] The term “micronized” or “micronization” are intended to mean the process of reducing the average diameter of a solid material's particles to produce particles that are only a few micrometers in diameter, and in some cases, the nanometer range. The term “ultramicronized” or is intended to mean a pharmaceutical composition in which at least about 85% by weight of the composition has particle sizes lower than about 10 microns (pm).

[0183] As used herein, the term “prevention” refers to any activity that reduces the burden of the individual later expressing disease symptoms. This can take place at primary, secondary and / or tertiary prevention levels, wherein: a) primary prevention avoids the development of symptoms / disorder / condition; b) secondary prevention activities are aimed at early stages of the condition / disorder / symptom treatment, thereby increasing opportunities for interventions to prevent progression of the condition / disorder / symptom and emergence of symptoms; and c) tertiary prevention reduces the negative impact of an already established condition / disorder / symptom by, for example, restoring function and / or reducing any condition / disorder / symptom or related complications.

[0184] The term “statistically significant” or “significantly” refers to statistical evidence that there is a difference. It is defined as the probability of making a decision to reject the null hypothesis when the null hypothesis is actually true. The decision is often made using the p-value.

[0185] “Synergistic amount” means a combination of two actives that yields an effect greater than the arithmetic sum of the effects of the constituents administered alone at the same total or fractional doses, as quantified by accepted synergy models, including but not limited to a Combination Index (CI) less than 1.0 by the Chou-Talalay method, Bliss independence exceeding additivity, or a statistically significant super-additive interaction term in a predefined analysis of variance. The term “synergistically effective amount,” as used herein, means and includes an amount of two or more active compounds that provides a synergistic effect defined above.Docket No.: 1022.550W01

[0186] A “subject” means any organism including, without limitation, a mammal such as a cat, a dog, a horse, a camel, and a primate (human or non-human). In the preferred embodiment, the subject is a human being.

[0187] As used herein, the term “treatment” refers to an intervention made in response to a disease, disorder or physiological condition manifested by a subject, particularly a subject suffering from one or more of a disorder, disease or disease state. In some embodiments, the disorder, disease or disease state is a heart disease, diabetes, hypertension, allergic reactions, asthma, arthritis, cancer, prostate diseases, and oxidative stress. In some embodiments, the treatment refers to the improvement of health or performance, including the improvement of athletic performance, improved bone health, strengthened immune response, prevention of fatigue, reduction in recovery time following exercise, and for boosting energy. The aim of treatment may include, but is not limited to, one or more of the alleviation or prevention of symptoms, slowing or stopping the progression or worsening of a disease, disorder, or condition and the remission of the disease, disorder or condition. In some embodiments, “treatment” refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already affected by a disease or disorder or undesired physiological condition as well as those in which the disease or disorder or undesired physiological condition is to be prevented.

[0188] Exemplary Embodiments

[0189] The disclosure relates to a stable, edible energy composition. The composition may be in liquid or solid form or include both liquid and solid forms. The composition may be provided in any mass or volume. For example, the composition may be provided as a solid food item in the form of bars, crackers, cookies or similar products, having the mass and shape of these types of products. The composition may also be provided as a liquid consumable such as a “shot”, drink, beverage or gel, which may be served at a wide range of temperatures from freezing (0° C) to up to about 90° C. In its various forms, the composition is stable and edible for at least two years and may be stable and edible up to about five years.

[0190] The use of the composition provides certain benefits. For example, the composition may provide energy or counter, reduce or prevent drowsiness. The composition may also provide a feeling of alertness and mental acuity. The composition may also provide a significant increase inDocket No.: 1022.550W01 the power of attention, continuity of attention, quality of working memory, quality of episodic memory, speed of memory and self-related alertness, the sum of the benefits providing a perceived feeling of energy.

[0191] The cognitive and physiological effects of the composition are sustained for an extended period of time. The effect of the composition on alertness and energy is greater than would be observed than when ingesting an equivalent amount of any if the ingredients alone. In other words, the ingredients of the composition act synergistically to produce benefits to a consumer that exceed the benefits achieved when the ingredients are taken individually.

[0192] In preferred embodiments, the composition may be provided in an aqueous medium in a volume from about 0.3 ounce to about 24 ounces. The composition may be provided in a volume from about 1 ounce to about ten 16 ounces. In one embodiment, the composition may be provided in about 0.5 fluid ounces, or about one (1) fluid ounce or about two (2) fluid ounces, or more. In a one embodiment, the composition is provided as a “shot” where the consumer ingests the ingredients in a small volume, such as from about 30 to about 60 ml and where the ingredients are in a highly concentrated form.

[0193] As used herein derivatives are defined to include, but are not limited to, precursors, metabolites, structurally-similar compounds and analogs of a particular substance. As used herein, precursors of a given substance are defined to include, but are not limited to, molecules that may be transformed, directly or indirectly, into that substance in vivo or in vitro. As used herein, metabolites of a substance are defined to include, but are not limited to, molecules that are produced in vivo by transformation of that substance. As used herein, structurally similarcompounds are defined to include, but are not limited to, molecules that are structurally similar to the identified substance but possess at least one structural difference and are functionally similar. As used herein, analogs are defined to include, but are not limited to molecules that are chemically distinct from an identified substance but which exert the same biological activity.

[0194] The energy composition comprises an effective and synergistic amount of a combination of citicoline, citrulline, glutathione, and Rhodiola rosea extract, including derivatives, precursors, structurally-similar compounds, analogs and / or metabolites of these substances. In one or more embodiments, the energy composition further comprises one or moreDocket No.: 1022.550W01 of astaxanthin, beetroot extract, vitamin C, adenosine 5 '-triphosphate (“ATP”), and paraxanthine, in various amounts.

[0195] The anti-inflammatory composition comprises an effective and synergistic amount of a combination of citrulline, glutathione, luteolin, palmitoylethanolamide, and astaxanthin, including derivatives, precursors, structurally-similar compounds, analogs and / or metabolites of these substances.

[0196] In one aspect, a composition is provided comprising an effective and synergistic amount of astaxanthin, L-citrulline, glutathione, luteolin, and palmitoylethanolamide. In certain embodiments, luteolin and palmitoylethanolamide are present in a ratio selected from about 1 : 1 and about 1 : 10 (luteolin:PEA), including a 1 : 10 ratio corresponding to about 60 mg luteolin and about 600 mg PEA. In certain embodiments, the composition comprises about 1-50 mg astaxanthin, about 100-2000 mg L-citrulline, about 250 mg reduced glutathione, about 60 mg luteolin, and about 600 mg PEA. In other embodiments, the composition comprises about 6 mg astaxanthin, about 250 mg citrulline, about 50-800 mg glutathione, about 5-100 mg luteolin, and about 25-800 mg PEA. At least one ingredient can be provided in a liposomal formulation. The compositions may further comprise a carrier (e.g., oil, aqueous vehicle, solid excipients) and may be provided as a liquid formulation.

[0197] The disclosure further provides methods of alleviating inflammation and pain by administering any of the foregoing compositions and processes for preparing liposomal dosage forms and liquid formulations.

[0198] In one or more embodiments, the anti-inflammatory composition further comprises one or more of beetroot extract, Boswellia extract, agmatine, ginger, and Cordyceps Sp. extract. In one or more embodiments, the anti-inflammatory composition further comprises one or more of Boswellia extract, agmatine, ginger, Cordyceps Sp. extract, and L-ascorbic acid.

[0199] In one embodiment, the compositions described may include one or more of vitamins, amino acids, taurine, glucuronolactone, glucono-delta-1 actone, and glucuronic acid, flavorants, sweeteners and preservatives, including precursors, structurally-similar compounds, analogs and / or metabolites of these substances. The compositions may include one or more amino acids,Docket No.: 1022.550W01 including, without limitation, precursors, structurally-similar compounds, analogs, metabolites, salts, esters or isomeric forms of amino acids.

[0200] In one or more embodiments, the ingredients of the compositions of the present invention may be comprised of micronized particles, nanonized particles, desiccated liposomal particles, or combinations thereof. In one or more embodiments, the micronized powder base may be chosen from an inert powdered base, an active powdered base having improved absorption, or combinations thereof

[0201] In one or more embodiments, the compositions described may include one or more components that are incorporated into liposomes. In one or more embodiments, the liposomes may incorporate some or all of the components. In one or more embodiments, the liposomes may incorporate components individually. In one or more embodiments, the liposomes may be provided as a dry powder. The dietary supplement composition can be dried to powder and stored at room temperature. The liposomes in powder do not degrade at room temperature at the same rate as in liquid or non-liposomal formulation. The powder when mixed with water reconstitutes liposomes.

[0202] In one or more embodiments, the liposomes of the composition of the present invention can have a diameter of between 100 nm and 10 micrometers, preferably 1 to 10 micrometers and more preferably 2 to 5 micrometers. The diameter of the liposomes can be controlled, for example, by extruding the liposomal composition through a polycarbonate filter having a known pore size. Methods for controlling the size of liposomes are well known in the art. In one or more embodiments, the powder is micronized to an average size of between 1 and 5 micrometers.

[0203] The liposomal microparticles may comprise one or lipids selected from the group consisting of fatty acids, lysolipids, sphingolipids, sphingomyelin, glycolipids, glucolipids, glycosphingolipids, palmitic acid, stearic acid, arachidonic acid, oleic acid, lipids bearing sulfonated mono-, di-, oligo- or polysaccharides, lipids with ether and ester-linked fatty acids, polymerized lipids, diacetyl phosphate, stearyl amine, cardiolipin, phospholipids, synthetic phospholipids with asymmetric acyl chains, and lipids bearing a covalently bound polymer. In some embodiments, the liposomal microparticles may comprise a phospholipid selected from the group consisting of phosphatidylcholines, lysophosphatidylcholines, phosphatidylethanolamines,Docket No.: 1022.550W01 phosphatidylinositols, phosphatidylglycerols, phosphatidic acid, phosphatidyl serines, and mixtures thereof. In some embodiments, the liposomal microparticles may comprise a phospholipid in an admixture with a modifying agent selected from the group consisting of cholesterols, stearyl amines, stearic acid, tocopherols, and mixtures thereof.

[0204] In some embodiments, the liposomal microparticles may have an average particle diameter ranging from about 25 microns to about 55 microns, for example from about 30 microns to about 55 microns, from about 35 microns to about 55 microns, from about 40 microns to about 55 microns, from about 45 microns to about 55 microns, from about 50 microns to about 55 microns, from about 25 microns to about 50 microns, from about 30 microns to about 50 microns, from about 35 microns to about 50 microns, from about 40 microns to about 50 microns, from about 45 microns to about 50 microns, from about 25 microns to about 45 microns, from about 30 microns to about 45 microns, from about 35 microns to about 45 microns, from about 40 microns to about 45 microns, from about 25 microns to about 40 microns, from about 30 microns to about 40 microns, from about 35 microns to about 40 microns, from about 25 microns to about 35 microns, from about 30 microns to about 35 microns, or from about 25 microns to about 30 microns.

[0205] Compositions and dosage forms described herein may be evaluated under ICH QI A(R2) conditions: 25°C / 60% RH (long-term) and 40°C / 75% RH (accelerated). Acceptance criteria include assay 90-110% of label, degradation products within predefined limits, organoleptic attributes within specification, disintegration / dissolution within target ranges, and microbial limits compliant with pharmacopeial standards.

[0206] In certain embodiments, an oral disintegrating film comprises pullulan, HPMC, or PVA (30-55 wt%) and a plasticizer such as glycerin or PEG (5-20 wt%). The citicoline / paraxanthine active phase is present at 15-40 wt%. Aqueous casting onto a stainless-steel belt yields a wet thickness of 300-800 pm; films are dried to a residual moisture of 2-8 wt% and slit into unit doses with total mass <500 mg. Dissolution testing follows USP Apparatus 2, 50 rpm, 900 mL simulated saliva buffer, with >85% release of both actives within 10 minutes.

[0207] Synergistic effects may be established by the Chou-Talalay method, isobologram analysis, and / or factorial ANOVA interaction terms. Energy / focus endpoints may include PVTDocket No.: 1022.550W01 median reaction time, Karolinska Sleepiness Scale, and perceived exertion during standardized tasks. Anti-inflammatory endpoints may include CRP, TNF-a, IL-6, and symptom scales. Study designs may include randomized, double-blind, cross-over trials with washout periods sufficient to eliminate carryover effects.

[0208] In some embodiments, the synergistic compositions are provided in the form of a liquid drink. In some embodiments, the synergistic compositions are provided in the form of a powdered formulation for mixing with liquid to form a liquid drink. In some embodiments, the synergistic compositions are provided in the form of an oral film. a. Energy Formulation

[0209] In certain embodiments, the composition comprises an effective and synergistic amount of a combination of citicoline and paraxanthine. In certain embodiments, a unit dosage form comprises citicoline and paraxanthine in a mass ratio from 10: 1 to 1 : 10, optionally from 4: 1 to 1 :4, and in particular embodiments about 1 : 1. In certain embodiments, a serving delivers from about 50 mg to about 500 mg citicoline and from about 50 mg to about 500 mg paraxanthine. In exemplary embodiments, a serving delivers about 200 mg citicoline and about 200 mg paraxanthine, or about 250 mg citicoline and about 250 mg paraxanthine.

[0210] In one or more embodiments, the composition is formulated as a powder blend suitable for hard capsules, sachets, or direct-compress tablets. Typical solid excipients include microcrystalline cellulose, maltodextrin, silica, magnesium stearate, stearic acid, croscarmellose sodium, and flavors or sweeteners as applicable. In one or more embodiments, the powder may be dispersed in or co-packed with an oil carrier, such as soybean oil, medium-chain triglyceride oil, sunflower oil, or mixed tocopherol-stabilized oil, for filling into soft gelatin capsules. In such embodiments, the powder may be suspended or partially dissolved to yield a thixotropic fill suitable for softgel encapsulation.

[0211] In one or more embodiments, the composition is provided as a liquid. Aqueous liquids may include water, glycerin, propanediol, and food-grade buffers adjusted to a pH compatible with citicoline stability. Oil-based liquids may include soybean oil or other nutraceutical oils, optionallyDocket No.: 1022.550W01 with emulsifiers or surfactants such as lecithin, polysorbates, or polyglyceryl esters to maintain dispersion.

[0212] In one or more embodiments, at least one of citicoline or paraxanthine is incorporated into liposomes. Liposomes may comprise phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylglycerol, and cholesterol, optionally with PEGylated lipids to modulate circulation and stability. In certain embodiments, the liposomes exhibit an average hydrodynamic diameter from about 50 nm to about 500 nm, optionally from about 80 nm to about 200 nm, with a poly dispersity index below about 0.3 as determined by dynamic light scattering. Encapsulation efficiency for citicoline may be at least about 40%, and for paraxanthine at least about 30%, when prepared under the methods herein.

[0213] In some embodiments, the energy composition comprises an effective and synergistic amount of a combination of citicoline and paraxanthine. In some embodiments, the composition further comprises citrulline, glutathione, salidroside, or combinations thereof in effective amounts.

[0214] In some embodiments, the energy composition may further comprise additional active ingredients selected from the group consisting of astaxanthin, beetroot extract, vitamin C, adenosine 5 '-triphosphate, and paraxanthine, in various effective amounts.

[0215] In certain embodiments, the energy composition consists essentially of an effective and synergistic amount of a combination of citicoline, paraxanthine, citrulline, glutathione, and salidroside in various amounts. In certain embodiments, the composition consists essentially of an effective and synergistic amount of a combination of citicoline, citrulline, glutathione, paraxanthine, salidroside and one or more additional active ingredients selected from the group consisting of astaxanthin, beetroot extract, vitamin C, and ATP, in various amounts.

[0216] In some embodiments the energy composition is provided in the form of a powdered drink where the powder may comprise additional inactive ingredients such as flavors, thickening agents, gelling agents, sweeteners, colorants, and preservatives.

[0217] In one embodiment, the composition comprises an effective and synergistic amount of a combination of citicoline, citrulline, glutathione, salidroside, paraxanthine, and beetroot extract.Docket No.: 1022.550W01

[0218] In another embodiment, the energy composition comprises an effective and synergistic amount of a combination of citicoline, citrulline, glutathione, salidroside, astaxanthin, beetroot extract, vitamin C, and adenosine 5 '-triphosphate (“ATP”).

[0219] In another embodiment, the energy composition comprises an effective and synergistic amount of a combination of citicoline, citrulline, glutathione, salidroside, astaxanthin, beetroot extract, vitamin C, ATP, and paraxanthine.

[0220] In another embodiment, the energy composition comprises an effective and synergistic amount of a combination of citicoline, citrulline, glutathione, salidroside, astaxanthin, beetroot extract, and paraxanthine.

[0221] In another embodiment, the energy composition comprises an effective and synergistic amount of a combination of citicoline and paraxanthine.

[0222] In certain embodiments, the synergistic combination of the active ingredients of citicoline and paraxanthine, which provides increased energy when administered to human subjects, as well as antioxidant benefits. For example, the composition may have a positive effect on pre-exercise, recovery after strenuous exercise, vascular health, and connective tissue recovery. Combinations that add the additional ingredients may also have the same positive effects.

[0223] In one or more embodiments, the synergistic composition comprises at least the active ingredients citicoline and paraxanthine, in varying concentrations. Some embodiments of the present disclosure can be used by athletes to increase energy and endurance, decrease inflammation, and enhance recovery. Some embodiments of the present disclosure can be used as a healthier option for increasing energy and as a natural option for health improvement.

[0224] In one or more embodiments, the synergistic composition comprises at least the active ingredients citicoline (cytidine 5 '-diphosphocholine; CDP-choline) when this is used as an exogenous sodium salt), paraxanthine, and one or more additional ingredients selected from L- citrulline malate (an a-amino acid), reduced glutathione, and salidroside, in varying concentrations.Docket No.: 1022.550W01

[0225] In one or more embodiments, the synergistic composition comprises at least the active ingredients citicoline, L-citrulline malate, paraxanthine, reduced glutathione, and salidroside, and one or more additional active ingredients selected from the group consisting of consisting of astaxanthin, beetroot extract, vitamin C, ATP, and paraxanthine, in various amounts.

[0226] In another embodiment, the synergistic composition comprises at least the active ingredients citicoline, L-citrulline malate, reduced glutathione, salidroside, paraxanthine, and beetroot extract, in varying concentrations.

[0227] In another embodiment, the synergistic composition comprises at least the active ingredients citicoline, L-citrulline malate, reduced glutathione, salidroside, paraxanthine, beetroot extract, and adenosine 5 '-triphosphate (“ATP”), in varying concentrations.

[0228] In another embodiment, the synergistic composition comprises at least the active ingredients citicoline, L-citrulline malate, reduced glutathione, salidroside, paraxanthine, beetroot extract, vitamin C, and ATP, in varying concentrations.

[0229] In another example, the citicoline and paraxanthine each comprise from about 10 wt % to about 90 wt % of the composition. In another example, the citicoline and paraxanthine each comprise from about 15 wt % to about 80 wt % of the composition. In another example, the citicoline and paraxanthine each comprise from about 20 wt % to about 70 wt % of the composition.

[0230] In another example, the citicoline comprises at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 wt% or more of the composition. In another example, the paraxanthine comprises at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75 wt% or more of the composition. In another example, the glutathione comprises at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or more of the composition. In another example, the salidroside comprises at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 wt% or more of the composition.

[0231] Further disclosed herein is a method of improving energy, mental focus and physical performance in a subject in need thereof comprising administering to the subject a composition comprising about 50 mg to about 500 mg of paraxanthine. In another embodiment, the composition comprises about 100 mg to about 450 mg of paraxanthine. In another embodiment, the compositionDocket No.: 1022.550W01 comprises about 150 mg to about 350 mg of paraxanthine. In another embodiment, the composition comprises about 200 mg to about 300 mg of paraxanthine. In another embodiment, the composition comprises about 250 mg of paraxanthine. In another embodiment, the composition consists essentially of about 200 mg to about 400 mg of paraxanthine. In another embodiment, the composition consists essentially of about 200 mg, about 250 mg, about 300 mg, or about 400 mg of paraxanthine.

[0232] Further disclosed herein is a method of improving energy, mental focus and physical performance in a subject in need thereof comprising administering to the subject a composition comprising about 100 mg to about 300 mg of citicoline, and about 100 mg to about 400 mg of paraxanthine. In another embodiment, the synergistic composition comprises about 120 mg to about 250 mg of citicoline, and about 120 mg to about 400 mg of paraxanthine contained within a unit dosage form in the form of an oral film for buccal administration. In another embodiment, the synergistic composition consists essentially of about 150 mg to about 250 mg of citicoline, and about 200 mg to about 400 mg of paraxanthine contained within a unit dosage form in the form of an oral film for buccal administration. In another embodiment, the synergistic composition consists essentially of about 200 mg to about 300 mg of citicoline, and about 200 mg to about 300 mg of paraxanthine contained within a unit dosage form in the form of an oral film for buccal administration. In another embodiment, the synergistic composition consists essentially of about 200 mg to about 300 mg of citicoline, and about 200 mg to about 300 mg of paraxanthine contained within a unit dosage form in the form of an oral film for buccal administration with a total dosage amount of 500 mg or less. i. Citicoline

[0233] In one or more embodiments, the disclosed compositions comprise embodiments wherein choline is provided by an ingredient selected from the group consisting of choline chloride, choline bitartrate, citicoline (CDP-choline), L-alpha-glycerophosphocholine (Alpha- GPC), lecithin, phosphatidylcholine, and mixtures thereof.

[0234] As used herein, “citicoline” refers to CDP-choline (cytidine 5 '-diphosphocholine), including all pharmaceutically acceptable salts, solvates, hydrates, polymorphs, stereoisomers, and prodrugs. Citicoline “derivatives, precursors, structurally-similar compounds, analogs and / orDocket No.: 1022.550W01 metabolites” include, without limitation, cytidine and choline precursors such as cytidine monophosphate, cytidine diphosphate, cytidine triphosphate, choline, choline bitartrate, choline chloride, choline alfoscerate (alpha-GPC), phosphocholine, glycerophosphocholine, and metabolites thereof.

[0235] In one or more embodiments, the choline is present as citicoline. The composition can be administered to the individual in a daily dose that provides 5.5 mg / day to 5,500 mg / day of the citicoline. In one or more embodiments, the disclosed compositions comprise embodiments provided in a dose form comprising citicoline in 50-1500 mg, 100-1200 mg, 200-1000 mg, 200- 750 mg, 200-500 mg, 200-400 mg, or 200-300 mg.

[0236] In certain embodiments the composition is provided in a dose form wherein the citicoline comprises at least 1, 5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30 wt % or more of the claimed composition. In certain embodiments the composition is provided in a dose form wherein the composition comprises at least 10, 25, 50, 100, 150, 200, 250, 300 mg or more of citicoline.

[0237] In one embodiment, a supplement formulation can include citicoline at from about 1 wt % to about 45 wt %. In other embodiments, supplement formulations can include citicoline at from about 2 wt % to about 45 wt %, at from about 2.5 wt % to about 40 wt %, at from about 3 wt % to about 45 wt %, at from about 3.5 wt % to about 40 wt %, at from about 4.5 wt % to about 35 wt %, at from about 1 wt % to about 30 wt %, at from about 2 wt % to about 25 wt %, at from about 3 wt % to about 20 wt %, or from about 5 wt % to about 18 wt %..

[0238] In another embodiment, the citicoline is present in the composition from about 1 wt % to about 60 wt %. In another example, the citicoline can be present in the composition from about 1.5 wt % to about 50 wt %. In yet another example, the citicoline can be present in the composition from about 2 wt % to about 45 wt %. In a further example, the citicoline can be present in the composition from about 5 wt % to about 60 wt %. In yet a further example, the citicoline can be present in the composition from about 10 wt % to about 50 wt %. In yet another example, the citicoline can be present from about 5 wt % to about 45 wt %. In another embodiment, the citicoline comprises at comprises at least 1, 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 wt % or more of the claimed composition.Docket No.: 1022.550W01 ii. Citrulline

[0239] Citrulline is an alpha-amino acid, and can be any bioavailable form of citrulline, including, for example, citrulline malate. In one or more embodiments, the disclosed compositions comprise embodiments wherein citrulline is present as L-citrulline DL-malate, which combines two-parts L-citrulline with one-part DL-malic acid, wherein citrulline is present in an amount from about 0.1 to about 4 g.

[0240] In certain embodiments the composition is provided in a dose form comprising L- citrulline DL-malate in a range selected from: 50 to 8000 mg, 50 to 6000 mg, 50 to 4000 mg, 100 to 2500 mg; 150 to 2000 mg; 200 to 1500 mg; 250 to 1000 mg; 400 to 800 mg; or about 750 mg.

[0241] In certain embodiments the composition is provided in a dose form wherein the citrulline comprises at least 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50 wt % or more of the claimed composition. In certain embodiments the composition is provided in a dose form wherein the composition comprises at least 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1200, 1500, 1750, 2000 mg or more of citrulline.

[0242] In certain embodiments the composition is provided in a dose form wherein the L- citrulline DL-malate 2: 1 comprises at least 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50 wt % or more of the claimed composition. In certain embodiments the composition is provided in a dose form wherein the composition comprises at least 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1200, 1500, 1750, 2000 mg or more of L-citrulline DL-malate.

[0243] Citrulline can be present as the active substance (ii) in a combination product of the present invention in a more or less purified form, especially in the form of a plant extract. It can also come in a free form or as derivatives. Citrulline derivatives that are acceptable according to the present invention especially include complex forms, protected forms (like esterified forms and forms wherein the amine function is protected by the tert-butoxycarbonyl group, i.e. Boc) or salts, as well as precursors thereof, like ornithine or glutamine. As an example, a combination product of the invention may include, as an active substance (ii), at least one substance selected from the group consisting of: D, L-citrulline, L-citrulline, D, L-citrulline malate, L-citrulline malate, L-Docket No.: 1022.550W01 citrulline monoacetate, L-citrulline hydrochloride, L-citrulline methylester, L-citrulline ethylester, L-citrulline-n-hexylester, L-citrulline (benzoylmethyl)ester, alpha-N-benzoyl-L-citrulline methylester, B-Boc-citrulline, N1 -2, 4-dinitrophenyl-D, L-citrulline and their mixtures in whatever proportions. Citrulline may come in a purified form or as a plant extract containing the same, especially as a plant extract belonging to the cucurbitaceae plant family.

[0244] In one example, the formulation can include citrulline at from about 10 wt % to about 55 wt %. In other examples, supplement formulations can include citrulline at from about 10 wt % to about 60 wt %, at from about 15 wt % to about 55 wt %, at from about 20 wt % to about 50 wt %, at from about 25 wt % to about 50 wt %, at from about 30 wt % to about 45 wt %, or from about 35 wt % to about 45 wt %.

[0245] In one or more embodiments, the citrulline includes derivatives thereof, such as citrulline malate, and the like. Supplement formulations containing both malic acid and citrulline can include these ingredients in any beneficial relative amount, and such can be varied depending on the forms of malic acid and citrulline used, and to suit individual needs. Non-limiting examples of ratios of malic acid to citrulline include a L 1 ratio, a 1 :2 ratio, a 1 :3 ratio, a 1 :4 ratio, a 1 :5 ratio, a 1.5: 1 ratio, a 2:1 ratio, a 3: 1 ratio, and the like. In one example, the malic acid and citrulline can be present at a 1 :2 ratio. iii. Glutathione

[0246] Glutathione is a tripeptide containing a free thiol group. Glutathione exists in the body in two forms, a reduced form (reduced glutathione, GSH) and an oxidized form. The GSH includes glutamic acid, cysteine, and glycine-covalently joined end-to-end. GSH is crucial for scavenging damaging free radicals. It is also required for the body's natural immune response and is important in the cellular detoxification of damaging chemicals.

[0247] In one or more embodiments, the glutathione includes derivatives thereof, such as glutathione disulfide, and the like. In one embodiment, a supplement formulation can include glutathione at from about 1 wt % to about 45 wt %. In other embodiments, supplement formulations can include glutathione at from about 2.5 wt % to about 45 wt %, at from about 5 wt % to about 40 wt %, at from about 5 wt % to about 45 wt %, at from about 5 wt % to about 40 wtDocket No.: 1022.550W01%, at from about 5 wt % to about 35 wt %, at from about 5 wt % to about 30 wt %, or at from about 5 wt % to about 25 wt %.

[0248] In one or more embodiments, the glutathione includes derivatives thereof, such as glutathione disulfide, and the like. In one or more embodiments, the glutathione comprises glutathione (L-Glutamyl-L-Cysteinyl-Glycine, Glu-Cys-Gly). The glutathione may be in its reduced form with a free thiol group (GSH) or in its oxidized form with a disulfide bond (GSSG). In one preferred embodiment, the oligopeptide is oxidized glutathione (GSSG). Under appropriate circumstances, as will be understood by one with ordinary skill in the art; in order to help achieve the above-mentioned benefits, it is desirable to include a different oligopeptide such as glutathione oxidized or reduced or Peptide T.

[0249] In certain embodiments the composition of the present invention is provided in a dose form comprising reduced glutathione provided in a range selected from: 100 to 900 mg; 150 to 850 mg; 200 to 800 mg; 250 to 800 mg; 300 to 700 mg; 400 to 700 mg; 400 to 600 mg; 450 to 550 mg; or about 500 mg.

[0250] In certain embodiments the composition is provided in a dose form wherein the reduced glutathione comprises at least 1, 2, 5, 10, 11, 12, 13, 14, 15, 20, 25, wt % or more of the claimed composition. In certain embodiments the composition is provided in a dose form wherein the composition comprises at least 10, 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500 mg or more of reduced glutathione.

[0251] The ratio of the weight percentage of citrulline and glutathione can also vary. In one embodiment, the citrulline and glutathione can be present in the composition at a weight percent concentration ranging from about 1:5 to about 20: 1, respectively. In another embodiment, the citrulline and glutathione can be present in the composition at a weight percent concentration ranging from about 2.5:1 to about 15: 1, respectively. In another embodiment, the citrulline and glutathione can be present in the composition at a weight percent concentration ranging from about 5: 1 to about 15: 1, respectively. In another embodiment, the citrulline and glutathione can be present in the composition at a weight percent concentration ranging from about 8: 1 to about 12: 1, respectively. In yet another embodiment, the citrulline and glutathione can be present in the composition at a weight percent concentration of about 10: 1, respectively.Docket No.: 1022.550W01 iv. Rhodiola rosea extract and / or Salidrosides

[0252] In one embodiment, the extract of Rhodiola rosea contains a bioactive selected from the group consisting of eleutherosides, rosavins, and salidrosides. In another embodiment, pure salidroside is used. The present disclosure relates to energy drink compositions comprising salidroside (4-(2-hydroxyethyl)phenyl P-D-glucopyranoside) as a bioactive ingredient, wherein the salidroside is produced by a microbial fermentation process that obviates the need to harvest botanical sources, including endangered Rhodiola species, and yields a highly purified material. In certain embodiments, the fermentation-derived salidroside is isolated and crystallized to a chemical purity of at least about 98.0% by HPLC area percent on a dry basis, with each of rosavin, rosarin, rosin, and other Rhodiola marker compounds present below 0.1% w / w, and in some embodiments below the analytical limit of detection.

[0253] In one aspect, the beverage matrix is an aqueous, acidified ready-to-drink system in which salidroside is present at a level effective to deliver a functional amount per single-serve container without imparting undesirable organoleptic effects. The salidroside component may be present at about 10 mg to about 600 mg per serving, in some embodiments about 50 mg to about 300 mg, depending on the intended use occasion. Because the glycosidic linkage of salidroside is susceptible to base-catalyzed hydrolysis, the beverage pH is maintained between about 2.8 and about 4.5, adjusted with one or more edible acids such as citric, malic, tartaric, and / or phosphoric acid. Stability may be further enhanced by reducing dissolved oxygen (e.g., nitrogen sparging), incorporating chelating agents at flavor-compatible levels, and selecting light- and oxygen-barrier packaging. In certain embodiments, salidroside is microencapsulated within a carbohydrate, polymeric, lipid, or cyclodextrin shell to modulate release and protect against hydrolysis or oxidative degradation during processing and storage.

[0254] The compositions may optionally include nutrients and co-actives that complement the role of salidroside in supporting perceived energy and resilience, provided such components do not materially diminish salidroside stability or sensory quality.

[0255] A method of manufacture is provided in which fermentation-derived salidroside is dissolved into chilled, deaerated process water under moderate agitation, followed by addition of acidulants, buffers, and any magnesium salts to establish the target pH and ionic environment.Docket No.: 1022.550W01Where a microencapsulated form is employed, the encapsulate is added after acidification under low shear to minimize shell rupture. Flavor, sweetener, color, preservative, and optional co-actives are incorporated and the batch is brought to volume. To avoid thermal stress, the beverage may be cold-filled under hygienic or aseptic conditions, or stabilized using non-thermal methods such as high-pressure processing; alternatively, salidroside may be segregated in a frangible reservoir integrated into the closure and released into the beverage immediately prior to consumption, thereby minimizing in-package aqueous residence time. Each lot of finished product may be verified for salidroside identity and potency by HPLC or LC-MS, and for the absence or nearabsence of Rhodiola-specific concomitants, thereby confirming that the active is produced by a fermentation process that bypasses plant harvesting and supplies only pure salidroside.

[0256] In use, the compositions are administered as a beverage in one or more servings per day. A single serving may deliver about 50 mg to about 300 mg salidroside and be consumed proximate to periods of increased physical or cognitive demand. The foregoing ranges, processing steps, and optional ingredients can be varied by a person of ordinary skill in the art without departing from the scope of the present disclosure; unless otherwise indicated, all numerical values recited herein include reasonable manufacturing tolerances and encompass the ranges and sub-ranges derivable therefrom.

[0257] In one embodiment, the composition also comprises at least 0.25% by weight of salidroside. In one embodiment, the extract of Rhodiola rosea comprises at least 0.5% by weight of salidroside, more preferably at least 0.75% by weight of salidroside, still more preferably at least 1% by weight of salidroside, with respect to the total weight of dry extract of Rhodiola rosea. In another embodiment, the extract of Rhodiola rosea comprises at least 0.1, 0.2, 0.25, 0.3, 0.4, 0.5, 0.75, 1% by weight of salidroside, with respect to the total weight of dry extract of Rhodiola rosea.

[0258] In another embodiment, the Rhodiola rosea extract comprises at least 1.5% by weight of rosavin and at least 0.25% by weight of salidroside, preferably at least 2% by weight of rosavin and at least 0.5% by weight of salidroside, more preferably, at least 2.5% by weight of rosavin and at least 0.75% by weight of salidroside, still more preferably at least 3% by weight of rosavin andDocket No.: 1022.550W01 at least 1% by weight of salidroside, with respect to the total weight of dry extract of Rhodiola rosea.

[0259] In one embodiment, the Rhodiola rosea extract is present in the composition from about 1 wt % to about 50 wt %. In another example, the Rhodiola rosea extract can be present in the composition from about 1.5 wt % to about 40 wt %. In yet another example, the Rhodiola rosea extract can be present in the composition from about 2 wt % to about 30 wt %. In a further example, the Rhodiola rosea extract can be present in the composition from about 5 wt % to about 25 wt %. In yet a further example, the Rhodiola rosea extract can be present in the composition from about 5 wt % to about 20 wt %. In yet another example, the Rhodiola rosea extract can be present from about 5 wt % to about 18 wt %.

[0260] In certain embodiments the composition is provided in a dose form wherein the salidroside comprises at least 1, 2, 5, 10, 11, 12, 13, 14, 15, 20, 25, wt % or more of the claimed composition. In certain embodiments the composition is provided in a dose form wherein the composition comprises at least 10, 25, 50, 100, 150, 200, 250, 300 mg or more of salidroside.

[0261] In one or more embodiments, the disclosed compositions comprise from about 100 to about 500 mg Rhodiola rosea extract (3-5% rosavins and 2-4% salidroside). In another embodiment, the disclosed compositions comprise from about 150 to about 400 mg Rhodiola rosea extract (3-5% rosavins and 2-4% salidroside). In another embodiment, the disclosed compositions comprise from about 200 to about 300 mg Rhodiola rosea extract (3-5% rosavins and 2-4% salidroside). In certain embodiments the composition is provided in a dose form wherein the composition comprises at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100 mg or more of salidroside. v. Astaxanthin

[0262] Astaxanthin is a xanthophyll contained in Crustacea such as shrimp, and crab; fish and shellfish such as salmon, sea bream, carp, goldfish, starfish, barnacle, krill, squid, and octopus; plants such as petals of Adonis ramosa; Aves such as chicken; microorganisms such as green algae (Haematococcus pluvialis), Euglena (Euglena heliorubescens), Chlorella (Chlorela zofmgiensis), red yeast (Phaffia rhodozyma), thermophilic bacteria (Meiothermus ruber) and the like. TheDocket No.: 1022.550W01 astaxanthin used in the present invention may be extracted from these natural products, obtained by culturing astaxanthin-producing microorganisms or chemically synthesized.

[0263] In one or more embodiments, the astaxanthin comprises a natural or synthetic ester or synthetic diol derivative. In one or more embodiments, the amounts of astaxanthin used within the presently disclosed supplements and compositions of the invention comprises a daily dose of 0.5-24 mg, 0.5-18 mg, 0.5-12 mg, 1-18 mg, 1-12 mg, 4-12 mg, and other ranges, and up to 24 mg, including 6-12 mg. According to another embodiment, the therapeutically effective amount of the astaxanthin is from about 10 mg / day to about 10 g / day. According to another embodiment, the therapeutically effective amount of the astaxanthin is from about 0.01 mg / kg body weight to about 10 g / kg body weight.

[0264] In certain embodiments the composition of the present invention is provided in a dose form comprising astaxanthin provided in a range selected from: 0.5-24 mg; 1-18 mg; 2-12 mg, 3- 15 mg; 4-10 mg; 5-8 mg; or about 5-7 mg. In certain embodiments the composition is provided in a dose form wherein the composition comprises at least 0.5, 1, 2, 3, 4, 5, 6 mg or more of astaxanthin.

[0265] In another embodiment, the astaxanthin is present in the composition from about 0.05 wt % to about 15 wt %. In another example, the astaxanthin can be present in the composition from about 0.05 wt % to about 10 wt %. In yet another example, the astaxanthin can be present in the composition from about 0.06 wt % to about 5 wt %. In a further example, the astaxanthin can be present in the composition from about 0.07 wt % to about 2.5 wt %. In yet a further example, the astaxanthin can be present in the composition from about 0.6 wt % to about 1.5 wt %. In yet another example, the astaxanthin can be present from about 0.5 wt % to about 1 wt %. In another embodiment, the astaxanthin comprises at comprises at least 0.05, 0.075, 0.1, 0.2, 0.3 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5 wt % or more of the claimed composition. vi. Beetroot extract

[0266] The beetroot extract for use in the present composition may be selected from any suitable beetroot source including red beets such as Detroit Dark Red, Red Ace, Early Wonder Tall Top, Bull's Blood, Forono, Ruby Queen, Chioggia, Cylindra or Gladiator, yellow or gold beetsDocket No.: 1022.550W01 such as Yellow Detroit, Golden, Touchstone Gold or Boldor or white beets such as Avalanche, Baby White, Blankoma or Sugar. In one embodiment of the synergistic composition, the beetroot extract is substantially derived from the taproot portion of the beetroot.

[0267] In one embodiment, the beetroot extract for use in the present composition comprises at least about 1.5% by dry weight of the composition. In another embodiment, the beetroot extract comprises about 0.1-90% of the dry weight of the composition (w / w), such as about 1-50%, or about 5-25% of the dry weight of the composition, or such as 0.1-5%, or about 0.5-2% w / w. In a further embodiment, the composition comprises a daily dosage of about 10 mg-50 g of beetroot extract and preferably, about 50-5000 mg.

[0268] In one embodiment of the synergistic composition, the beetroot extract comprises from about 5 wt % to about 90 wt % of the claimed composition. In another embodiment of the composition, the beetroot extract comprises from about 10 wt % to about 80 wt % of the claimed composition. In another embodiment of the composition, the beetroot extract comprises at least 10, 15, 20, 25, 30, 35, 40, 45, 50 wt % or more of the claimed composition.

[0269] In certain embodiments the composition is provided in a dose form wherein the beetroot extract is provided in a range selected from: 100 to 900 mg; 150 to 850 mg; 200 to 800 mg; 250 to 800 mg; 300 to 700 mg; 400 to 700 mg; 400 to 600 mg; 450 to 550 mg; or about 500 mg.

[0270] In certain embodiments the composition is provided in a dose form wherein the beetroot extract comprises at least 1, 2, 5, 10, 11, 12, 13, 14, 15, 20, 25, wt % or more of the claimed composition. In certain embodiments the composition is provided in a dose form wherein the composition comprises at least 10, 25, 50, 100, 150, 200, 250 mg or more of beetroot extract.

[0271] In another embodiment, the dose of the beetroot extract may be 5 mg / kg / day to 1000 mg / kg / day on a dry weight basis. In one aspect, the dose may be 5 mg / kg / or more, 100 mg / kg / or more, 200 mg / kg / or more, 300 mg / kg / or more, 400 mg / kg / or more, 500 mg / kg / or more, 600 mg / kg / or more, 700 mg / kg / or more, 800 mg / kg / or more, or 900 mg / kg / or more. In another aspect, the dose may be 1000 mg / kg / or less, 900 mg / kg / or less, 800 mg / kg / or less, 700 mg / kg / or less, 600 mg / kg / or less, 500 mg / kg / or less, 400 mg / kg / or less, 300 mg / kg / or less, 200 mg / kg / or less, 100 mg / kg / or less, 50 mg / kg / or less, or 10 mg / kg / or less.Docket No.: 1022.550W01 vii. Vitamin C

[0272] Vitamin C, also known as L-ascorbic acid, is a water-soluble vitamin that must be provided in the human diet because it is not synthesized by the body. It is physiologically required for synthesis of many essential tissues as well as biomolecules including neurotransmitters, fat transport molecules and for catabolism of a portion of the body's cholesterol. Vitamin C is also an effective antioxidant in vivo for protecting many proteins, fats, carbohydrates and nucleic acids from damaging reactive oxygen and free radical species.

[0273] In one embodiment, vitamin C is added to compositions of the disclosure as ascorbic acid. In preferred examples, ascorbic acid may be present from 50 mg to 1000 mg in a single serving. In particularly preferred examples, ascorbic acid may be present from 250 mg to 750 mg in a single serving. In preferred examples, a serving size is about 2 to about 24 ounces. In some embodiments, the supplement comprises an amount of vitamin C sufficient to provide at least 10, 15, 20, 25% or more of the recommended daily intake (RDI) of vitamin C.

[0274] In some embodiments, the supplement comprises at least about 200 mg vitamin C (ascorbic acid), such as at least about 300 mg, at least about 500 mg, at least about 750 mg, at least about 1000 mg, at least about 1250, at least about 1500, or at least about 2000 mg of vitamin C. In some embodiments, the supplement comprises 200mg, 500 mg, 750 mg, 1000 mg, 1250, 1500, 2000 or 3000 mg of vitamin C. In some embodiments, the compositions comprise about 200-3000 mg, from about 400-2000 mg, about 500-1000 mg of vitamin C. viii. Adenosine 5’ Triphosphate (ATP)

[0275] The present disclosure relates to energy drink compositions comprising adenosine 5'- triphosphate (“ATP”) or a nutritionally acceptable salt thereof, such as disodium ATP, trisodium ATP, or magnesium ATP. In certain embodiments, the composition provides ATP in an amount effective to support cellular energy transfer and exercise performance without imparting instability or undesirable organoleptic effects to the finished beverage. The ATP component may be present at about 10 mg to about 1000 mg per single-serve container, in some embodiments about 50 mg to about 500 mg, calculated as anhydrous ATP equivalents. The ATP may be provided neat, as a dry -blend premix, or microencapsulated to enhance stability during processing and storage.Docket No.: 1022.550W01

[0276] In some embodiments, the beverage matrix is an aqueous, acidified system suitable for ready-to-drink products, having a pH of about 2.8 to about 4.5 adjusted with one or more foodgrade acids, for example citric, malic, phosphoric, or tartaric acid. Because ATP is susceptible to hydrolysis in aqueous, heat- and acid-exposed environments, the formulation may further include measures that limit degradation, such as inclusion of magnesium ions that complex with ATP, incorporation of chelating agents (e.g., sodium hexametaphosphate or EDTA at flavor-compatible levels) to sequester trace metals, dissolved oxygen control via nitrogen sparging, selection of low- temperature unit operations, and use of light- and oxygen-barrier packaging. In certain embodiments, ATP is provided as a microencapsulated particulate, for example within a lipid, carbohydrate, or cyclodextrin shell, to modulate release and protect against pH- and temperature- induced hydrolysis until ingestion.

[0277] The energy drink may further comprise ingredients that are complementary to ATP’s role in cellular bioenergetics. In some embodiments, the composition includes magnesium salts as ATP cofactors, ribose as a pentose substrate, and B-complex vitamins (e.g., niacinamide, pyridoxine, cobalamin) that serve as coenzymes in oxidative metabolism. Optional actives such as caffeine, L-citrulline, creatine, taurine, or electrolytes may be incorporated provided they do not materially interfere with ATP stability or taste. Sweeteners may include sucrose, glucose, fructose, or non-nutritive sweeteners; flavor systems may incorporate natural and / or artificial flavors with bitterness modulators to mask any nucleotide-associated notes. The beverage may be still or carbonated, and in certain embodiments osmolality is maintained between about 150 and about 500 mOsm / kg to balance palatability and gastric tolerance.

[0278] A method of manufacture is provided in which ATP or an ATP salt is dissolved or dispersed into chilled, deaerated process water under agitation, followed by addition of buffer acids and magnesium salts to establish a target pH and ionic environment compatible with ATP stability. Where microencapsulated ATP is used, the encapsulate is added post-acidification under low shear to limit shell rupture. Flavor, sweetener, color, and preservative systems are then incorporated, and the beverage is finished to volume. To avoid thermal stress, the product may be cold-filled under hygienic or aseptic conditions, or subjected to non-thermal stabilization such as high-pressure processing. In another embodiment, ATP is sequestered in a separate chamber or frangible capsuleDocket No.: 1022.550W01 integrated into the closure and released into the beverage immediately prior to consumption, thereby minimizing in-package dwell time in aqueous solution.

[0279] In use, the compositions described herein are administered as a beverage in one or more servings per day. In certain embodiments, a single serving delivers about 50 mg to about 400 mg ATP equivalents and is consumed within about 15 to about 90 minutes prior to physical activity or periods of heightened cognitive demand. The foregoing ranges, ingredient selections, and processing methods can be varied without departing from the scope of the disclosure; all numerical values recited herein are intended to include the variations and equivalents that would be understood by a person of ordinary skill in the art.

[0280] In one embodiment, the adenosine 5’ triphosphate for use in the present composition comprises at least about 1.5% of the composition. In another embodiment, the adenosine 5’ triphosphate comprises about 0.1-90% of the dry weight of the composition (w / w), such as about 1-50%, or about 5-25% of the dry weight of the composition, or such as 0.1-5%, or about 0.5-2% w / w. In a further embodiment, the composition comprises a daily dosage of about 0.1 g to about 10 g of adenosine 5’ triphosphate and in another embodiment, about 50-8000 mg.

[0281] In one embodiment of the synergistic composition, the adenosine 5’ triphosphate comprises from about 5 wt % to about 90 wt % of the claimed composition. In another embodiment of the composition, the adenosine 5’ triphosphate comprises from about 10 wt % to about 80 wt % of the claimed composition. In another embodiment of the composition, the Adenosine 5’ triphosphate comprises at least 1, 2, 5, 10, 11, 12, 13, 14, 15, 20, 25, wt % or more of the claimed composition.

[0282] In certain embodiments the composition is provided in a dose form wherein the adenosine 5’ triphosphate is provided in a range selected from: 100 to 8000 mg; 150 to 7000 mg; 200 to 6000 mg; 250 to 5000 mg; 300 to 4000 mg; 400 to 3000 mg; 500 to 3000 mg; 1000 to 2500 mg; or about 2000 mg. ix. Paraxanthine

[0283] Disclosed are compositions comprising paraxanthine and the related uses thereof. As used herein, “paraxanthine” refers to 1,7-dimethylxanthine, including all pharmaceuticallyDocket No.: 1022.550W01 acceptable salts, solvates, hydrates, polymorphs, isotopologues, and prodrugs. Paraxanthine “derivatives, precursors, structurally-similar compounds, analogs and / or metabolites” include, without limitation, xanthine analogs exhibiting similar adenosinergic activity or pharmacology such as 7-methylxanthine, 1 -methylxanthine, theobromine, theophylline, and prodrug forms.

[0284] Paraxanthine may be produced synthetically or may be isolated from a natural source or through fermentation. Paraxanthine isolated from such sources may be purified to 95% or greater purity. Optionally, less purification may be used such that combination of paraxanthine for 50%, or even less, of the material. In some embodiments, it may be preferable to utilize paraxanthine isolated from a natural source which may include other congeners of paraxanthine typically found in paraxanthine sources.

[0285] In certain embodiments, the composition is formulated such that a dose contains paraxanthine ranging from about 1 to about 1000 mg (e.g., about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 75 mg, 100, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg, and the like, or any range or value therein). In certain embodiments, the composition is formulated such that a dose contains 200-400 mg paraxanthine.

[0286] In certain embodiments, the composition is formulated such that paraxanthine comprises at least about 1% of the composition. In another embodiment, the paraxanthine comprises about 1-25% of the dry weight of the composition (w / w), such as about 1-20%, or about 1.5-15% of the dry weight of the composition, or such as 0.1-10%, or about 0.5-5% w / w. In a further embodiment, the composition comprises a daily dosage of about 25 mg to about 800 mg of paraxanthine and in another embodiment, about 50-300 mg.

[0287] In one embodiment of the synergistic composition, the paraxanthine comprises from about 5 wt % to about 90 wt % of the claimed composition. In another embodiment of the composition, the paraxanthine comprises from about 10 wt % to about 80 wt % of the claimed composition. In another embodiment of the composition, the paraxanthine comprises at least 0.1, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3 wt % or more of the claimed composition.Docket No.: 1022.550W01

[0288] In certain embodiments the composition is provided in a dose form wherein the paraxanthine is provided in a range selected from: 10 to 1000 mg; 25 to 800 mg; 50 to 500 mg; 75 to 400 mg; 100 to 400 mg; 200 to 400 mg; or about 400 mg. In certain embodiments the composition is provided in a dose form wherein the composition comprises at least 10, 25, 50, 75, 100, 125, 150 or more of paraxanthine. In certain embodiments, the composition is formulated such that a dose contains paraxanthine each ranging from about 1 to about 1000 mg (e.g., about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 75 mg, 100, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg, and the like, or any range or value therein) and chlorogenic acid ranging from 400 to about 3000 mg (e.g., about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1500 mg, about 2000 mg, about 2500 mg, or about 3000 mg and the like, or any range or value therein). x. Sideritis spp.

[0289] In one or more embodiments, the synergistic formulations and compositions of the present invention comprise Sideritis spp. plant material. In one or more embodiments, the Sideritis material is obtained from one or more of the various species of the Sideritis plant.

[0290] Sideritis (Sideritis L.) is a genus of plants belonging to the Lamiaceae family. This genus contains some 140 species, which may be subdivided into roughly 320 subspecies, ecotypes and cultivars. It is composed of annual or perennial herbaceous plants and small shrubs. Several species are used as tisanes and are sold as Greek mountain tea. The geographical area of the genus stretches from the Atlantic islands of Western Europe and North-West Africa (Macaronesia), to the Mediterranean region and Russia, Tibet and Western China.

[0291] In one or more embodiments, the Sideritis material is obtained from preparations and extracts of the Sideritis genus (Sideritis ssp ).Docket No.: 1022.550W01

[0292] In another embodiment, the Sideritis material is obtained from preparations and extracts of plants from the species Sideritis euboa, Sideritis scardica, Sideritis raiseri, Sideritis pisidica, Sideritis perfoliate, or their mixtures.

[0293] In another embodiment, the Sideritis material is obtained from preparations and extracts of the aerial plant parts that are harvested when they are in bloom.

[0294] The most important antioxidant components of Sideritis are the flavonoids such as the 3-and 8-disubstituted flavones, glycosidic flavonoids, aglycal flavonoids, poly-hydroxy-flavones and phenylpropanate esters of flavonoids.

[0295] The composition can comprise, for example, about 2% to about 30% Sideritis material. In one embodiment, the composition can comprise about 4% to about 25% Sideritis material. In another embodiment, the composition can comprise about 10% to about 20% Sideritis material. In another embodiment, the composition can comprise about 12% to about 18% Sideritis material. It is further understood that the percentages disclosed in this paragraph may vary, or be offset, by an amount corresponding to the amount of any bioenhancer that is added to increase the bioavailability of the Sideritis material.

[0296] The compositions of the invention can comprise one or more Sideritis material extract. Sideritis material extract may contain hericenones and erinacines. Sideritis material extracts for use with the invention may be standardized to contain one or more of these hericenones and erinacines in an amount of about 100%, 99% 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 2%, or any amount intervening these amounts. In a non-limiting embodiment, the Sideritis material extract is standardized to about 5% of one or more hericenones and erinacines. In another non-limiting embodiment, the Sideritis material extract is standardized to about 10-20% of one or more flavonoid.

[0297] In a specific, non-limiting example, the composition of the invention comprises about 10-20% Sideritis material extract standardized to about 10-20% flavonoids. In another embodiment, the composition comprises about 100 mg to 1000 mg of Sideritis material standardized to about 5% to about 99% Sideritis material. In another embodiment, the composition can comprise 100 mg Sideritis material standardized to about 20% flavonoids.Docket No.: 1022.550W01

[0298] In certain embodiments the composition of the present invention is provided in a dose form comprising Sideritis material extract are provided in an amount selected from: 50 to 10000 mg; 50 to 5000 mg; 100 to 4000 mg; 100 to 3000 mg; 100 to 2000 mg; 100 to 1000 mg; 100 to 600 mg; 100 to 500 mg; or about 100 mg.

[0299] In certain embodiments the composition is provided in a dose form wherein the Sideritis material extract comprises at least 1, 2, 5, 10, 11, 12, 13, 14, 15, 16, 18, 20, 24 wt % or more of the claimed composition. In certain embodiments the composition is provided in a dose form wherein the composition comprises at least 10, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500 mg or more of Sideritis material extract.

[0300] Energy Formulation Examples

[0301] Example 1 (powder with oil carrier): A unit dose comprising about 200 mg citicoline and about 200 mg paraxanthine is blended with microcrystalline cellulose and silicon dioxide to form a free-flowing powder. The blend is suspended in soybean oil containing 0.05% mixed tocopherols and filled into soft gelatin capsules at a fill weight appropriate to deliver the stated actives per capsule.

[0302] Example 2 (powder with oil carrier): A unit dose comprising about 250 mg citicoline and about 250 mg paraxanthine is formulated as a powder as above and dispersed in soybean oil for encapsulation. The mass ratio of actives is about 1 : 1 and the combined actives represent from about 5% to about 40% of the total fill weight depending on excipient loading.

[0303] Example 3 (liquid): An aqueous liquid composition provides about 200 mg citicoline and about 200 mg paraxanthine per 10 mL serving, buffered to pH 6.5-7.4, optionally sweetened and flavored for palatability. Alternatively, an oil-continuous liquid employs soybean oil as the carrier, with the actives maintained in a stable dispersion by lecithin.

[0304] Example 4 (liposomal): A liposomal dispersion is prepared in which citicoline and paraxanthine are co-encapsulated in phosphatidyl choline / cholesterol liposomes sized to about 120 nm with a poly dispersity index below 0.25. Each 10 mL serving contains about 200 mg citicoline and about 200 mg paraxanthine.Docket No.: 1022.550W01

[0305] In use, a subject in need of increased energy, alertness, or cognitive performance is administered an effective amount of any composition described herein. In certain embodiments, administration occurs once or multiple times daily, such that the total daily intake of citicoline is from about 50 mg to about 1000 mg and the total daily intake of paraxanthine is from about 50 mg to about 1000 mg, optionally with the two actives delivered at about a 1: 1 mass ratio. In certain embodiments, the compositions are administered prior to or during physical or cognitive tasks requiring sustained attention or psychomotor performance.

[0306] Synergy can be demonstrated by predefining an energy-related endpoint and comparing the observed effect size of the combination to the sum of effect sizes for the individual components at fractional doses. In one embodiment, psychomotor vigilance task lapses and median reaction time are measured over a two-hour post-dose period; a combination index below 1.0 indicates synergy. In another embodiment, a validated Subjective Units of Energy scale is used in conjunction with EEG beta power or heart rate variability markers; super-additive effects relative to monotherapies support the definition of “synergistic amount.” In cellular models, ATP levels, adenosine receptor-linked cAMP signaling, or neuron firing rates are recorded to quantify Bliss or Loewe synergy.

[0307] In some embodiments, liposomal citicoline and paraxanthine are prepared by thin-film hydration followed by size reduction. A lipid mixture containing phosphatidylcholine and cholesterol is dissolved in an organic solvent and evaporated to form a thin film. An aqueous phase containing citicoline and paraxanthine at target concentrations is used to hydrate the film under agitation to form multilam ellar vesicles. The dispersion is subjected to high-pressure homogenization or probe sonication to achieve the desired size distribution. The liposomal dispersion is optionally diafiltered to remove unencapsulated actives and is then blended with a carrier to produce a pourable liquid or dried by lyophilization or spray-drying to yield a powder for reconstitution.

[0308] In alternative embodiments, ethanol injection, microfluidic mixing, or reverse-phase evaporation techniques are employed to achieve high encapsulation efficiency and narrow size distribution. For softgel fills, the active-containing liposomal or micellar dispersion may be admixed with soybean oil and antioxidants prior to encapsulation.Docket No.: 1022.550W01

[0309] In one or more embodiments, the citicoline is a powder with about 200 mg citicoline and about 200 mg paraxanthine and may be used with a soybean oil carrier. In one or more embodiments, the citicoline is a powder with about 250 mg citicoline and about 250 mg paraxanthine and may be used with a soybean oil carrier. In one or more embodiments, the citicoline is a liquid with about 200 mg citicoline and about 200 mg paraxanthine. In one or more embodiments, at least one of citicoline or paraxanthine is provided in a liposomal formulation. In one or more embodiments, the composition further comprises a carrier in various amounts, including but not limited to soybean oil.

[0310] The disclosed compositions provide rapid-onset and sustained energy support with improved tolerability profdes, deliver predictable pharmacokinetics via oil carriers or liposomal encapsulation, and enable synergistic performance benefits at lower individual component doses than would otherwise be required.

[0311] Tables 1-4 provide a set of components that may be provided in a dry powdered form or introduced into such a liquid. The amounts provided in tables 1-4 are particularly useful to form compositions having a total final volume of about 2 to 24 fluid ounces.Table 1.Component Amount (mg)Citicoline 100-400Paraxanthine 100-400Table 2.Component Amount (mg)Citicoline 200-300Paraxanthine 150-250Table 3.Component Amount (mg)Citicoline 250-350L-Citrulline Malate 700-800Docket No.: 1022.550W01

[0312] In one example, an orodispersible “energy” film (citicoline and paraxanthine) is produced. An orodispersible film is prepared by solvent casting a pullulan / hydroxypropyl methylcellulose (HPMC) matrix plasticized with glycerin. A casting solution is produced by dispersing pullulan and HPMC at a solids ratio of about 60:40 (w / w polymer basis) in purified water to a total solids content of about 10-15% (w / w). Glycerin is added at about 15% (w / w) relative to total polymer, together with a saliva-compatible buffer to maintain pH 6.0-7.0, a nonionic wetting agent at <0.2% (w / w), and optional flavor and sweetener suitable for buccal administration. Citicoline (CDP-choline) and paraxanthine are dissolved or dispersed in the casting solution such that each unit dose delivers about 200-250 mg citicoline and about 200-250 mg paraxanthine; the unit dose may be provided as a single laminated film or as two co-administered film strips whose combined area yields the stated dose. The deaerated solution is cast onto a controlled-gap substrate to a wet thickness selected to achieve a dry film thickness of about 80- 150 pm per layer and dried in a forced-air oven at about 40-55 °C until residual moisture falls within a target range of about 3-7% (w / w). Dried webs are slit and cut to individual doses and packaged in foil-laminate sachets under low-humidity conditions. Quality control includes identity and assay by a validated chromatographic method, content uniformity on not fewer than ten units with a target %RSD <6.0% and individual assays within 85-115% of label claim, loss on drying or coulometric Karl Fischer moisture within 3-7% (w / w), and residual solvent testing by headspace GC in accordance with ICH Q3C with Class 3 solvents maintained below permitted daily exposure and, where ethanol or isopropanol are used in processing, below 5000 ppm each. In-vitro dissolution is performed using USP Apparatus 2 (paddle) at 50 rpm in 900 mL of simulatedDocket No.: 1022.550W01 saliva buffer at 37 ± 0.5 °C with sampling at 1, 3, 5, and 10 minutes; acceptance criteria specify not less than 85% release of each active at 10 minutes, with profile characterization by modelindependent metrics. Stability is assessed under ICH Q1A(R2) conditions with predefined pulls for appearance, assay, degradation products, moisture, and dissolution; acceptance windows are set to preserve label claim and dissolution performance over shelf-life. This example is prophetic and describes a contemplated manufacturing and testing plan rather than actual production lots. b. Inflammation Formulations

[0313] In certain embodiments, the composition comprises an effective and synergistic amount of a combination of astaxanthin, citrulline, glutathione, luteolin, and palmitoylethanolamide.

[0314] In some embodiments, the composition may further comprise additional active ingredients selected from the group consisting of beetroot extract, Boswellia, agmatine, ginger, vitamin C, and adenosine 5 '-triphosphate, in various amounts.

[0315] As used herein, “astaxanthin” refers to all stereoisomers and esters of 3,3 '-dihydroxy - P,P-carotene-4,4'-dione, including natural or synthetic sources and pharmaceutically or nutraceutically acceptable derivatives.

[0316] “Citrulline” means L-citrulline and its salts (e.g., L-citrulline malate) and prodrugs.

[0317] “Glutathione” means reduced glutathione (GSH), oxidized glutathione (GSSG) where context appropriate, and prodrugs and derivatives (e.g., S-acetyl-L -glutathione).

[0318] “Luteolin” includes luteolin aglycone and luteolin glycosides (e.g., luteolin-7-O- glucoside), salts, solvates, and prodrugs.

[0319] “Palmitoylethanolamide” (“PEA”) includes micronized and ultramicronized forms, salts, polymorphs, solvates, and structural analogs (e.g., oleoylethanolamide where expressly recited).

[0320] “Synergistic amount” means that the combination yields an effect greater than the arithmetic sum of effects of the constituents administered alone at corresponding doses, as evidenced by a Combination Index (CI) < 1.0 (Chou-Talalay), Bliss independence exceedingDocket No.: 1022.550W01 additivity, and / or a statistically significant super-additive interaction in a pre-specified analysis of variance.

[0321] “Effective amount” means an amount sufficient to produce a measurable improvement in one or more anti-inflammatory or pain-related endpoints, including but not limited to reductions in IL-6, TNF-a, CRP, PGE2, COX-2 expression, NF-KB activity, NLRP3 inflammasome markers, or improvements in validated pain scales (e.g., VAS, WOMAC), mobility, or recovery metrics.

[0322] In certain embodiments, the composition comprises an effective and synergistic amount of a combination of astaxanthin, luteolin, and palmitoylethanolamide. In certain embodiments, the composition consists essentially of an effective and synergistic amount of a combination of astaxanthin, luteolin, and palmitoylethanolamide. In certain embodiments, the effective and synergistic amount of a combination of astaxanthin, luteolin, and palmitoylethanolamide is provided in an oral dissolvable film.

[0323] In certain embodiments, the composition consists essentially of an effective and synergistic amount of a combination of beetroot extract, citrulline, glutathione, luteolin, and palmitoylethanolamide. In certain embodiments, the composition consists essentially of an effective and synergistic amount of a combination of beetroot extract, citrulline, glutathione, luteolin, palmitoyl ethanol ami de and one or more ingredients selected from the group consisting of astaxanthin, Boswellia, agmatine, ginger, vitamin C, and adenosine 5 '-triphosphate, in various amounts.

[0324] In some embodiments the composition is provided in the form of a powdered drink where the powder may comprise additional inactive ingredients such as flavors, thickening agents, gelling agents, sweeteners, colorants, and preservatives.

[0325] In one or more embodiments, the composition comprises an effective and synergistic amount of a combination of astaxanthin, citrulline, glutathione, luteolin, and palmitoylethanolamide, wherein one or more ingredients are in a liposomal formulation.

[0326] In one or more embodiments, the composition comprises an effective and synergistic amount of a combination of astaxanthin, citrulline, glutathione, luteolin, palmitoylethanolamide,Docket No.: 1022.550W01 and at least one additional component selected from the group consisting of beetroot extract, Boswellia extract, agmatine, ginger, Cordyceps Sp. extract, L-ascorbic acid, and guluronic acid.

[0327] In certain embodiments, the synergistic combination of the active ingredients of astaxanthin, citrulline, glutathione, luteolin, and palmitoylethanolamide, which provides increased energy when administered to human subjects, as well as antioxidant benefits. For example, the composition may have a positive effect on pre-exercise, recovery after strenuous exercise, vascular health, and connective tissue recovery. Combinations that add the additional ingredients may also have the same positive effects.

[0328] In one or more embodiments, the synergistic composition comprises at least the active ingredients astaxanthin, citrulline, glutathione, luteolin, and palmitoylethanolamide, in varying concentrations. Some embodiments of the present disclosure can be used to decrease inflammation.

[0329] In one or more embodiments, the synergistic composition consists essentially of the active ingredients astaxanthin, L-citrulline malate (an a-amino acid), reduced glutathione (GSH), luteolin (3',4',5,7-tetrahydroxyflavone), and palmitoylethanolamide (PEA), in varying concentrations.

[0330] In one or more embodiments, the synergistic composition comprises at least the active ingredients astaxanthin, citrulline, glutathione, luteolin, and palmitoylethanolamide, and one or more additional active ingredients selected from the group consisting of consisting of beetroot extract, Boswellia extract, agmatine, ginger, vitamin C, and adenosine 5 '-triphosphate, in various amounts.

[0331] In certain embodiments, a serving (unit dose) comprises: astaxanthin from about 1 mg to about 50 mg; L-citrulline from about 100 mg to about 2000 mg (e.g., about 250 mg); glutathione (reduced) from about 50 mg to about 800 mg (e.g., about 250 mg); luteolin from about 5 mg to about 100 mg (e.g., about 60 mg); and palmitoylethanolamide from about 25 mg to about 800 mg (e.g., about 600 mg). In certain embodiments, luteolin:PEA is about 1 : 1. In other embodiments, luteolin:PEA is about 1 :10 (e.g., 60 mg:600 mg). More generally, the mass ratio of luteolin EA can be from about 1 : 1 to about 1 : 12, optionally from about 1:2 to about 1: 10. In certainDocket No.: 1022.550W01 embodiments, the actives are present in a mass-normalized profile yielding an aggregate antiinflammatory effect at least equivalent to the Example compositions described herein.

[0332] In another example, the astaxanthin, citrulline, glutathione, luteolin, and palmitoylethanolamide each comprise from about 10 wt % to about 90 wt % of the composition. In another example, the astaxanthin, citrulline, glutathione, luteolin, and palmitoylethanolamide each comprise from about 15 wt % to about 80 wt % of the composition. In another example, the astaxanthin, citrulline, glutathione, luteolin, and palmitoylethanolamide each comprise from about 20 wt % to about 70 wt % of the composition.

[0333] In another example, the astaxanthin comprises at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 wt% or more of the composition. In another example, the L-citrulline comprises at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75 wt% or more of the composition. In another example, the glutathione comprises at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or more of the composition. In another example, the luteolin comprises at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 wt% or more of the composition. In another example, the palmitoylethanolamide comprises at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 wt% or more of the composition.

[0334] Further disclosed herein is a method of inhibiting inflammation in a subject in need thereof comprising administering to the subject a composition comprising about 25 mg to about 500 mg of astaxanthin, about 100 mg to about 2000 mg of citrulline, about 50 mg to about 800 mg of glutathione, about 5 mg to about 100 mg of luteolin, and about 25 mg to about 800 mg of palmitoylethanolamide.

[0335] Further disclosed herein is a method of inhibiting inflammation in a subject in need thereof comprising administering to the subject a composition comprising about 100 mg to about 2000 mg of citrulline, about 50 mg to about 800 mg of glutathione, about 5 mg to about 100 mg of luteolin, about 25 mg to about 800 mg of palmitoylethanolamide, and about 1 mg to about 50 mg of astaxanthin.

[0336] Further disclosed herein is a method of inhibiting pain and inflammation in a subject in need thereof comprising administering to the subject a composition comprising about 5 mg toDocket No.: 1022.550W01 about 100 mg of luteolin, about 25 mg to about 800 mg of palmitoyl ethanol ami de, and about 1 mg to about 50 mg of astaxanthin.

[0337] In another embodiment, the anti-inflammatory composition comprises from about 400 mg to about 600 mg of palmitoylethanolamide, about 25 mg to about 60 mg of luteolin, and about 2 mg to about 25 mg of astaxanthin. In another embodiment, the anti-inflammatory composition comprises from about 400 mg to about 500 mg of palmitoylethanolamide, about 40 mg to about 60 mg of luteolin, and about 5 mg to about 12 mg of astaxanthin. In another embodiment, the antiinflammatory composition comprises from about 450 mg to about 500 mg of palmitoylethanolamide, about 45 mg to about 50 mg of luteolin, and about 5 mg to about 10 mg of astaxanthin.

[0338] In another embodiment, the anti-inflammatory composition comprises from about 400 mg to about 600 mg of palmitoylethanolamide, about 25 mg to about 60 mg of luteolin, and about 2 mg to about 25 mg of astaxanthin contained within a unit dosage form in the form of an oral film for buccal administration.

[0339] In another embodiment, the anti-inflammatory composition comprises from about 80- 100% of palmitoylethanolamide, about 0-20% of luteolin, and about 0-5% mg of astaxanthin. In another embodiment, the anti-inflammatory composition comprises from about 80-100% of palmitoylethanolamide, about 0-20% of luteolin, and about 0-5% mg of astaxanthin. In another embodiment, the anti-inflammatory composition comprises from about 85-95% of palmitoylethanolamide, about 5-15% of luteolin, and about 3-12% mg of astaxanthin.

[0340] In one or more embodiments, the synergistic composition comprises palmitoylethanolamide (PEA) in from about 20: 1 ratio to about 5:1 ratio with luteolin. In another embodiment, the synergistic composition comprises palmitoylethanolamide (PEA) in from about 10: 1 ratio with luteolin.

[0341] In certain embodiments, the subject is at risk of developing inflammatory disease or condition. In further embodiments, the subject has been diagnosed with an inflammatory disease or condition. In exemplary implementations, the subject has been diagnosed with diabetes, Crohn'sDocket No.: 1022.550W01 disease, rheumatoid arthritis, fibromyalgia, systemic lupus erythematosus, glomerulonephritis, scleroderma, or multiple sclerosis.

[0342] In still further embodiments, the one or more additional ingredient is selected from omega-3 fatty acids, vitamin D, vitamin B, protein, selenium, fast digestive carbohydrates like sugar, vitamin K, calcium, vitamin A, ashwagandha (Withania somnifera), Acetylcholine, Acetyl L-Carnitine, tyrosine, N-acetyl-L-tyrosine, Ergothionecine, tryptophan, 5-HTP, arginine, citrulline, norvaline, GABA, Dopa (Velvet Bean), Kanna (serotonin), L-theanine, phosphatidylcholine, alpha-GPC (L-alpha glycerylphosphoryl choline), Citicoline (Cytidine diphosphate choline (CPD Choline)), Choline Bitartrate, Bacopa Monnieri, Phosphatidylserine, pilocarpine, and cevimeline Amburana cearensis, Lippia sidoides, Paullinia cupana, Plathymiscium floribundum, tetrahydrocurcumin, and Solanum asperum.

[0343] According to certain embodiments, improving joint health comprises alleviating or reducing the severity of at least one symptom of osteoarthritis, such as, for example, pain, stiffness, tenderness, reduced flexibility, grating sensation, bone spurs, swelling, or any combination thereof. Thus, in some embodiments, there is provided a method of reducing the severity of at least one symptom of osteoarthritis in a subject with osteoarthritis, comprising administering to the subject an herbal composition of the present disclosure.

[0344] In one or more embodiments, the disclosed compositions comprise embodiments wherein the citrulline is present in a 1 :5 to 20:1 ratio, 2.5: 1 to 15: 1 ratio, 5: 1 to 15: 1 ratio, 8: 1 to about 12:1 ratio, 9: 1 to about 11 : 1 ratio or 10: 1 ratio with the glutathione. i. Beetroot extract

[0345] In one embodiment, the beetroot extract for use in the present composition comprises at least about 1.5% by dry weight of the composition. In another embodiment, the beetroot extract comprises about 0.1-90% of the dry weight of the composition (w / w), such as about 1-50%, or about 5-25% of the dry weight of the composition, or such as 0.1-5%, or about 0.5-2% w / w. In a further embodiment, the composition comprises a daily dosage of about 10 mg-50 g of beetroot extract and preferably, about 50-5000 mg.Docket No.: 1022.550W01

[0346] In one embodiment of the synergistic composition, the beetroot extract comprises from about 5 wt % to about 90 wt % of the claimed composition. In another embodiment of the composition, the beetroot extract comprises from about 10 wt % to about 80 wt % of the claimed composition. In another embodiment of the composition, the beetroot extract comprises at least 10, 15, 20, 25, 30, 35, 40, 45, 50 wt % or more of the claimed composition.

[0347] In certain embodiments the composition is provided in a dose form wherein the beetroot extract is provided in a range selected from: 100 to 900 mg; 150 to 850 mg; 200 to 800 mg; 250 to 800 mg; 300 to 700 mg; 400 to 700 mg; 400 to 600 mg; 450 to 550 mg; or about 500 mg.

[0348] In certain embodiments the composition is provided in a dose form wherein the beetroot extract comprises at least 1, 2, 5, 10, 11, 12, 13, 14, 15, 20, 25, wt % or more of the claimed composition. In certain embodiments the composition is provided in a dose form wherein the composition comprises at least 10, 25, 50, 100, 150, 200, 250 mg or more of beetroot extract.

[0349] In another embodiment, the dose of the beetroot extract may be 5 mg / kg / day to 1000 mg / kg / day on a dry weight basis. In one aspect, the dose may be 5 mg / kg / or more, 100 mg / kg / or more, 200 mg / kg / or more, 300 mg / kg / or more, 400 mg / kg / or more, 500 mg / kg / or more, 600 mg / kg / or more, 700 mg / kg / or more, 800 mg / kg / or more, or 900 mg / kg / or more. In another aspect, the dose may be 1000 mg / kg / or less, 900 mg / kg / or less, 800 mg / kg / or less, 700 mg / kg / or less, 600 mg / kg / or less, 500 mg / kg / or less, 400 mg / kg / or less, 300 mg / kg / or less, 200 mg / kg / or less, 100 mg / kg / or less, 50 mg / kg / or less, or 10 mg / kg / or less. ii. Citrulline

[0350] In certain embodiments the composition is provided in a dose form wherein the citrulline comprises at least 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50 wt % or more of the claimed composition. In certain embodiments the composition is provided in a dose form wherein the composition comprises at least 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1200, 1400, 1600, 1800, 2000 mg or more of citrulline.

[0351] In one or more embodiments, the disclosed compositions comprise embodiments wherein citrulline is present as L-citrulline DL-malate 2: 1, which combines two-parts L-citrulline with one-part DL-malic acid, wherein citrulline is present in an amount from about 0.1 to aboutDocket No.: 1022.550W014g. In certain embodiments the composition is provided in a dose form comprising L-citrulline DL-malate 2:1 in a range selected from: 50 to 4000 mg, 100 to 2500 mg; 150 to 2000 mg; 200 to 1500 mg; 250 to 1000 mg; 400 to 800 mg; or about 750 mg.

[0352] In certain embodiments the composition is provided in a dose form wherein the L- citrulline DL-malate 2: 1 comprises at least 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50 wt % or more of the claimed composition. In certain embodiments the composition is provided in a dose form wherein the composition comprises at least 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1200, 1400, 1600, 1800, 2000 mg or more of L- citrulline DL-malate 2: 1.

[0353] Citrulline can be present as the active substance (ii) in a combination product of the present invention in a more or less purified form, especially in the form of a plant extract. It can also come in a free form or as derivatives. Citrulline derivatives that are acceptable according to the present invention especially include complex forms, protected forms (like esterified forms and forms wherein the amine function is protected by the tert-butoxycarbonyl group, i.e. Boc) or salts, as well as precursors thereof, like ornithine or glutamine. As an example, a combination product of the invention may include, as an active substance (ii), at least one substance selected from the group consisting of: D, L-citrulline, L-citrulline, D, L-citrulline malate, L-citrulline malate, L- citrulline monoacetate, L-citrulline hydrochloride, L-citrulline methylester, L-citrulline ethylester, L-citrulline-n-hexylester, L-citrulline (benzoylmethyl)ester, alpha-N-benzoyl-L-citrulline methylester, B-Boc-citrulline, N1 -2, 4-dinitrophenyl-D, L-citrulline and their mixtures in whatever proportions. Citrulline may come in a purified form or as a plant extract containing the same, especially as a plant extract belonging to the cucurbitaceae plant family.

[0354] In one example, the formulation can include citrulline at from about 10 wt % to about 55 wt %. In other examples, supplement formulations can include citrulline at from about 10 wt % to about 60 wt %, at from about 15 wt % to about 55 wt %, at from about 20 wt % to about 50 wt %, at from about 25 wt % to about 50 wt %, at from about 30 wt % to about 45 wt %, or from about 35 wt % to about 45 wt %.

[0355] In one or more embodiments, the citrulline includes derivatives thereof, such as citrulline malate, and the like. Supplement formulations containing both malic acid and citrullineDocket No.: 1022.550W01 can include these ingredients in any beneficial relative amount, and such can be varied depending on the forms of malic acid and citrulline used, and to suit individual needs. Non-limiting examples of ratios of malic acid to citrulline include a 1 : 1 ratio, a 1 :2 ratio, a 1 :3 ratio, a 1 :4 ratio, a 1 :5 ratio, a 1.5: 1 ratio, a 2:1 ratio, a 3: 1 ratio, and the like. In one example, the malic acid and citrulline can be present at a 1 :2 ratio.

[0356] In one embodiment, a supplement formulation can include citrulline at from about 1 wt % to about 65 wt %. In other embodiments, supplement formulations can include citrulline at from about 10 wt % to about 55 wt %, at from about 15 wt % to about 45 wt %, at from about 10 wt % to about 45 wt %, at from about 10 wt % to about 40 wt %, at from about 5 wt % to about 35 wt %, at from about 20 wt % to about 45 wt %, or at from about 25 wt % to about 45 wt %.

[0357] In another embodiment, the L-citrulline is present in the composition from about 10 wt % to about 90 wt %. In another example, the L-citrulline can be present in the composition from about 15 wt % to about 50 wt %. In yet another example, the L-citrulline can be present in the composition from about 25 wt % to about 45 wt %. In a further example, the L-citrulline can be present in the composition from about 5 wt % to about 60 wt %. In yet a further example, the L- citrulline can be present in the composition from about 10 wt % to about 50 wt %. In yet another example, the L-citrulline can be present from about 15 wt % to about 45 wt %. In another embodiment, the L-citrulline comprises at comprises at least 10, 15, 20, 25, 30, 35, 40, 45, 50 wt % or more of the claimed composition. iii. Glutathione

[0358] In one or more embodiments, the glutathione includes derivatives thereof, such as glutathione disulfide, and the like. In one or more embodiments, the glutathione comprises glutathione (L-Glutamyl-L-Cysteinyl-Glycine, Glu-Cys-Gly). The glutathione may be in its reduced form with a free thiol group (GSH) or in its oxidized form with a disulfide bond (GSSG). In one preferred embodiment, the oligopeptide is oxidized glutathione (GSSG). Under appropriate circumstances, as will be understood by one with ordinary skill in the art; in order to help achieve the above-mentioned benefits, it is desirable to include a different oligopeptide such as glutathione oxidized or reduced or Peptide T.Docket No.: 1022.550W01

[0359] In one or more embodiments, the disclosed compositions comprise embodiments wherein the glutathione is selected from the group consisting of oxidized L-glutathione, reduced L-glutathione and glutathione.

[0360] In one or more embodiments, the disclosed compositions comprise embodiments wherein glutathione is present in an amount of 300-1500 mg, 400-1200 mg, 500-1000 mg or 400- 800 mg. In one or more embodiments, the disclosed compositions comprise embodiments wherein glutathione is present as reduced glutathione and is present in an amount of 100 to 1500 mg; 150 to 1400 mg; 200 to 1300 mg; 250 to 1200 mg; 300 to 1100 mg; 400 to 1000 mg; 450 to 1000 mg; or 500 to 1000 mg.

[0361] In one example, the glutathione can comprise from about 4 wt % to about 98 wt % of the composition. In another example, the glutathione can comprise from 10 wt % to 60 wt % of the composition.

[0362] In one or more embodiments, the glutathione includes derivatives thereof, such as glutathione disulfide, and the like. In one embodiment, a supplement formulation can include glutathione at from about 1 wt % to about 45 wt %. In other embodiments, supplement formulations can include glutathione at from about 2.5 wt % to about 45 wt %, at from about 5 wt % to about 40 wt %, at from about 5 wt % to about 45 wt %, at from about 5 wt % to about 40 wt %, at from about 5 wt % to about 35 wt %, at from about 5 wt % to about 30 wt %, or at from about 5 wt % to about 25 wt %.

[0363] In certain embodiments the composition of the present invention is provided in a dose form comprising reduced glutathione provided in a range selected from: 100 to 900 mg; 150 to 850 mg; 200 to 800 mg; 250 to 800 mg; 300 to 700 mg; 400 to 700 mg; 400 to 600 mg; 450 to 550 mg; or about 500 mg.

[0364] In certain embodiments the composition is provided in a dose form wherein the reduced glutathione comprises at least 1, 2, 5, 10, 11, 12, 13, 14, 15, 20, 25, wt % or more of the claimed composition. In certain embodiments the composition is provided in a dose form wherein the composition comprises at least 10, 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500 mg or more of reduced glutathione.Docket No.: 1022.550W01

[0365] The ratio of the weight percentage of citrulline and glutathione can also vary. In one embodiment, the citrulline and glutathione can be present in the composition at a weight percent concentration ranging from about 1:5 to about 20: 1, respectively. In another embodiment, the citrulline and glutathione can be present in the composition at a weight percent concentration ranging from about 2.5:1 to about 15:1, respectively. In another embodiment, the citrulline and glutathione can be present in the composition at a weight percent concentration ranging from about 5: 1 to about 15:1, respectively. In another embodiment, the citrulline and glutathione can be present in the composition at a weight percent concentration ranging from about 8: 1 to about 12: 1, respectively. In yet another embodiment, the citrulline and glutathione can be present in the composition at a weight percent concentration of about 10:1, respectively. iv. Luteolin

[0366] Luteolin, 3',4',5,7-tetrahydroxyflavone, is a phenolic phytochemical belonging to the flavone class of flavonoids that exists in many types of plants including fruits, vegetables, and medicinal herbs. In one or more embodiments, the compositions of the present invention comprise luteolin.

[0367] In one or more embodiments, the disclosed compositions comprise embodiments wherein luteolin is present in an amount of 10-800 mg, 20-600 mg, 30-500 mg or 40-400 mg. In one or more embodiments, the disclosed compositions comprise embodiments wherein luteolin is present in an amount of from about 10 to 1000 mg; 15 to 800 mg; 20 to 600 mg; 25 to 500 mg; 30 to 400 mg; 35 to 300 mg; 40 to 200 mg; or 45 to 100 mg.

[0368] In one example, the luteolin can comprise from about 1 wt % to about 98 wt % of the composition. In another example, the luteolin can comprise from 1 wt % to 60 wt % of the composition.

[0369] In one or more embodiments, the luteolin includes derivatives thereof, and the like. In one embodiment, a supplement formulation can include luteolin at from about 1 wt % to about 45 wt %. In other embodiments, supplement formulations can include luteolin at from about 2.5 wt % to about 45 wt %, at from about 5 wt % to about 40 wt %, at from about 5 wt % to about 45 wtDocket No.: 1022.550W01%, at from about 5 wt % to about 40 wt %, at from about 5 wt % to about 35 wt %, at from about 5 wt % to about 30 wt %, or at from about 5 wt % to about 25 wt %.

[0370] In certain embodiments the composition is provided in a dose form wherein the luteolin comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 wt % or more of the claimed composition. In certain embodiments the composition is provided in a dose form wherein the composition comprises at least 1, 2.5, 5, 10, 15, 20, 25, 30, 35, 40, 45 mg or more of luteolin.

[0371] The ratio of the weight percentage of palmitoylethanolamide and luteolin can also vary. In one embodiment, the palmitoylethanolamide and luteolin can be present in the composition at a weight percent concentration ranging from about 1 :5 to about 20: 1, respectively. In another embodiment, the palmitoylethanolamide and luteolin can be present in the composition at a weight percent concentration ranging from about 2.5: 1 to about 15:1, respectively. In another embodiment, the palmitoylethanolamide and luteolin can be present in the composition at a weight percent concentration ranging from about 5: 1 to about 15:1, respectively. In another embodiment, the palmitoylethanolamide and luteolin can be present in the composition at a weight percent concentration ranging from about 8: 1 to about 12: 1, respectively. In yet another embodiment, the palmitoylethanolamide and luteolin can be present in the composition at a weight percent concentration of about 10: 1, respectively. v. Palmitoylethanolamide

[0372] Palmitoylethanolamide (PEA or N-(2hydroxyethyl)-palmitamide) is a is an endogenous fatty acid amide and lipid modulator. PEA is lipophilic in nature and almost insoluble in water. Due to these considerations, PEA in supplements is usually emulsified, micronized, or utilized as a specialized delivery system to improve bioavailability and functionality. In one embodiment, crystalline dispersion technology can be used such as LipiSperse® (Pharmako Biotechnologies Pty Ltd., Frenchs Forest, Australia) uses a combination of surfactants, polar lipids and solvents to increase the wettability of lipophilic substances in aqueous environments.

[0373] In one or more embodiments, the compositions of the present invention comprising palmitoylethanolamide can be formulated as, e.g., liposomes, micelles (e.g., those composed ofDocket No.: 1022.550W01 biodegradable natural or / and synthetic polymers, such as lactosomes), microspheres, microparticles or nanoparticles, whether or not designed for sustained release.

[0374] In one or more embodiments, the compositions of the present invention include palmitoylethanolamide (PEA), alternatively in a non-micronized form (non-micronized PEA), or in a micronized form (PEA-m), or in an ultrami cronized form (PEA-um).

[0375] The term “palmitoylethanolamide (or PEA) in a non-micronized form” means PEA having a particle size distribution, defined as a percentage by volume and measured with the laser light scattering method, represented by a distribution curve having the mode above 10 microns, preferably above 20 microns.

[0376] The term “palmitoylethanolamide (or PEA) in a micronized form” means PEA having a particle size distribution, defined as a percentage by volume and measured with the laser light scattering method, represented by a distribution curve having the mode between 6 microns and 10 microns.

[0377] The term “palmitoylethanolamide (or PEA) in an ultramicronized form” means PEA having a particle size distribution, defined as a percentage by volume and measured with the laser light scattering method, represented by a distribution curve having the mode below 6 microns and above 0.5 microns.

[0378] Palmitoylethanolamide can be synthetized as described in U.S. Pat. No. 5,990,170. Non- micronized PEA can be obtained by finely grounding the product from the synthesis; a product with a particle size ranging between 50.0 and 100.0 pm can be obtained. PEA-m can be obtained as described in the U.S. Pat. No. 6,548,550 Bl and it has a particle size ranging between 2.0 and 10.0 pm. PEA-um can be obtained as described in the patent application WO 2011 / 027373 Al and it has a particle size ranging between 0.8 and 6.0 pm.

[0379] In one or more embodiments, the disclosed compositions comprise embodiments wherein palmitoyl ethanol ami de is present in an amount of 300-1500 mg, 400-1200 mg, 500-1000 mg or 400-800 mg. In one or more embodiments, the disclosed compositions comprise embodiments wherein palmitoylethanolamide is present in an amount of 100 to 1500 mg; 150 toDocket No.: 1022.550W011400 mg; 200 to 1300 mg; 250 to 1200 mg; 300 to 1100 mg; 400 to 1000 mg; 450 to 1000 mg; or 500 to 1000 mg.

[0380] In one example, the palmitoylethanolamide can comprise from about 4 wt % to about 98 wt % of the composition. In another example, the palmitoylethanolamide can comprise from 10 wt % to 60 wt % of the composition.

[0381] In one or more embodiments, the palmitoylethanolamide includes derivatives thereof. In one embodiment, a supplement formulation can include palmitoylethanolamide at from about 1 wt % to about 45 wt %. In other embodiments, supplement formulations can include palmitoylethanolamide at from about 2.5 wt % to about 45 wt %, at from about 5 wt % to about 40 wt %, at from about 5 wt % to about 45 wt %, at from about 5 wt % to about 40 wt %, at from about 5 wt % to about 35 wt %, at from about 5 wt % to about 30 wt %, or at from about 5 wt % to about 25 wt %.

[0382] In certain embodiments the composition of the present invention is provided in a dose form comprising palmitoylethanolamide provided in a range selected from: 100 to 900 mg; 150 to 850 mg; 200 to 800 mg; 250 to 800 mg; 300 to 700 mg; 400 to 700 mg; 400 to 600 mg; 450 to 550 mg; or about 500 mg.

[0383] In certain embodiments the composition is provided in a dose form wherein the palmitoylethanolamide comprises at least 1, 2, 5, 10, 11, 12, 13, 14, 15, 20, 25, wt % or more of the claimed composition. In certain embodiments the composition is provided in a dose form wherein the composition comprises at least 10, 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500 mg or more of palmitoylethanolamide. vi. Astaxanthin

[0384] In one or more embodiments, the astaxanthin comprises a natural or synthetic ester or synthetic diol derivative. In one or more embodiments, the amounts of astaxanthin used within the presently disclosed supplements and compositions of the invention comprises a daily dose of 0.5-24 mg, 0.5-18 mg, 0.5-12 mg, 1-18 mg, 1-12 mg, 4-12 mg, and other ranges, and up to 24 mg, including 6-12 mg. According to another embodiment, the therapeutically effective amount of the astaxanthin is from about 10 mg / day to about 10 g / day. According to another embodiment, theDocket No.: 1022.550W01 therapeutically effective amount of the astaxanthin is from about 0.01 mg / kg body weight to about 10 g / kg body weight.

[0385] In certain embodiments the composition of the present invention is provided in a dose form comprising astaxanthin provided in a range selected from: 0.5-24 mg; 1-18 mg; 2-12 mg, 3- 15 mg; 4-10 mg; 5-8 mg; or about 5-7 mg. In certain embodiments the composition is provided in a dose form wherein the composition comprises at least 0.5, 1, 2, 3, 4, 5, 6 mg or more of astaxanthin.

[0386] In another embodiment, the astaxanthin is present in the composition from about 0.05 wt % to about 15 wt %. In another example, the astaxanthin can be present in the composition from about 0.05 wt % to about 10 wt %. In yet another example, the astaxanthin can be present in the composition from about 0.06 wt % to about 5 wt %. In a further example, the astaxanthin can be present in the composition from about 0.07 wt % to about 2.5 wt %. In yet a further example, the astaxanthin can be present in the composition from about 0.6 wt % to about 1.5 wt %. In yet another example, the astaxanthin can be present from about 0.5 wt % to about 1 wt %. In another embodiment, the astaxanthin comprises at comprises at least 0.05, 0.075, 0.1, 0.2, 0.3 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5 wt % or more of the claimed composition. vii. Agmatine

[0387] In one or more embodiments, the anti-inflammatory formulations and compositions of the present invention comprise agmatine and / or salt thereof in addition to or in place of the palmitoylethanolamide. In one or more embodiments, the anti-inflammatory formulations and compositions of the present invention comprise agmatine and / or salt thereof in place of the palmitoylethanolamide. In one or more embodiments, the agmatine is a salt selected from the group comprising agmatine dihydrochloride, agmatine orotate, agmatine phosphate, and agmatine sulfate. In one or more embodiments, the agmatine is a sulfate salt of agmatine.

[0388] Agmatine (also known as N-(4-aminobutyl)guanidine) is a natural metabolite of the amino acid arginine. It is formed when arginine is decarboxylated by the enzyme arginine decarboxylase and is found naturally in ragweed pollen, ergot fungi, octopus muscle, herring sperm, sponges, and the mammalian brain.Docket No.: 1022.550W01

[0389] In one or more embodiments, the disclosed compositions comprise embodiments wherein agmatine is present in an amount of 300-1500 mg, 400-1200 mg, 500-1000 mg or 400- 800 mg. In one or more embodiments, the disclosed compositions comprise embodiments wherein agmatine is present in an amount of 100 to 1500 mg; 150 to 1400 mg; 200 to 1300 mg; 250 to 1200 mg; 300 to 1100 mg; 400 to 1000 mg; 450 to 1000 mg; or 500 to 1000 mg.

[0390] In one example, the agmatine can comprise from about 4 wt % to about 98 wt % of the composition. In another example, the agmatine can comprise from 10 wt % to 60 wt % of the composition. In one or more embodiments, the agmatine includes derivatives thereof. In one embodiment, a supplement formulation can include agmatine at from about 1 wt % to about 45 wt %. In other embodiments, supplement formulations can include agmatine at from about 2.5 wt % to about 45 wt %, at from about 5 wt % to about 40 wt %, at from about 5 wt % to about 45 wt %, at from about 5 wt % to about 40 wt %, at from about 5 wt % to about 35 wt %, at from about 5 wt % to about 30 wt %, or at from about 5 wt % to about 25 wt %. viii. Boswellia Extract

[0391] In one or more embodiments, the anti-inflammatory formulations and compositions of the present invention comprise Boswellia sp. extracts in addition to or in place of the palmitoylethanolamide. In one or more embodiments, the anti-inflammatory formulations and compositions of the present invention comprise Boswellia sp. extracts in place of the palmitoylethanolamide. In one or more embodiments, the Boswellia sp. extracts is an extract of one or more gum resins from Boswellia species as a Boswellia extract.

[0392] In one or more embodiments, the Boswellia sp. extracts is an extract of one or more gum resins from Boswellia species selected from the group consisting of Boswellia serrata, Boswellia cat ter ii, Boswellia papyrifera, Boswelliaameero, Boswellia bullala, Boswellia dalzielii, Boswellia dioscorides, Boswellia elongata, Boswellia frereana, Boswellia nana, Boswellia neglecta, Boswellia ogadensis, Boswellia pirottae, Boswellia popoviana, Boswellia rivae, Boswellia sacra, and Boswellia socotrana.

[0393] Boswellia for use with the drug composition can comprise boswellia extract. The boswellia extract can be standardized for boswellic acid. Boswellia extracts can be standardized toDocket No.: 1022.550W01 contain one or more boswellic acids in amount of about 100%, 99% 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, or any amount intervening these amounts. In one non-limiting embodiment, the boswellia extract is standardized to about 30% boswellic acid. The boswellic acid to which the boswellic extract is standardized can be acetyl- 11-keto-beta-boswellic acid (AKBA).

[0394] (20) Boswellia for use with the invention can be boswellia gum resin. The gum resin of boswellia is a complex mixture comprising: boswellia oil fraction (BOIL) containing essential oW / boswellia volatile oil fraction (BVOIL); non-acidic boswellia low polar gum resin extract fraction (BLPRE); boswellic acids (BA); and sugars and polysaccharide fraction (BSUG). The boswellia gum resin can be standardized to contain one or more of BOIL, BVOIL, BLPRE, BA and BSUG in an amount of about 100%, 99% 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, or any amount intervening these amounts. It is contemplated that the drug composition can be formulated with boswellia in the form of BIOL, BVOIL, BLPRE, BA, BSUG, or a combination thereof. It is contemplated that the drug composition can be formulated with boswellia in the form of purified BIOL, purified BVOIL, purified BLPRE, purified BA, purified BSUG, or a combination thereof.

[0395] In a specific, non-limiting example, the composition of the invention comprises about 30% boswellia extract standardized to about 30% AKBA. In another embodiment, the composition comprises 100 mg to 10,000 mg boswellia standardized to about 5% to about 99% AKBA. In another embodiment, the composition can comprise 150 mg. boswellia standardized to about 30% AKBA.

[0396] In one embodiment, a supplement formulation can include Boswellia sp. extracts at from about 1 wt % to about 45 wt %. In other embodiments, supplement formulations can include Boswellia sp. extracts at from about 2.5 wt % to about 45 wt %, at from about 5 wt % to about 40 wt %, at from about 5 wt % to about 45 wt %, at from about 5 wt % to about 40 wt %, at from about 5 wt % to about 35 wt %, at from about 5 wt % to about 30 wt %, or at from about 5 wt % to about 25 wt %.

[0397] In certain embodiments the composition of the present invention is provided in a dose form comprising Boswellia sp. extracts provided in a range selected from: 100 to 900 mg; 150 toDocket No.: 1022.550W01850 mg; 200 to 800 mg; 250 to 800 mg; 300 to 700 mg; 400 to 700 mg; 400 to 600 mg; 450 to 550 mg; or about 500 mg.

[0398] In certain embodiments the composition is provided in a dose form wherein the Boswellia sp. extracts comprises at least 1, 2, 5, 10, 11, 12, 13, 14, 15, 20, 25, wt % or more of the claimed composition. In certain embodiments the composition is provided in a dose form wherein the composition comprises at least 10, 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500 mg or more of Boswellia sp. extracts. ix. Ginger

[0399] In one or more embodiments, the anti-inflammatory formulations and compositions of the present invention comprise ginger or ginger extract in addition to or in place of the palmitoylethanolamide. In one or more embodiments, the anti-inflammatory formulations and compositions of the present invention comprise ginger or ginger extract in place of the palmitoylethanolamide.

[0400] As used herein, the term “ginger” refers to any material obtained from the flowering plant Zingiber officinale, commonly called ginger. Ginger for use with the invention includes, but is not limited to, raw ginger, ginger oil, ginger extract, gingerols, or a combination thereof. Ginger includes, but is not limited to, ginger, ginger oil, ginger extract, gingerols, or a combination thereof, derived from the root of the ginger plant. This plant comprises volatile oils, zingerone, shogaols, and gingerols with [6]-gingerol (l-[4'-hydroxy-3'-methoxyphenyl]-5-hydroxy-3-decanone) as the major compound.

[0401] The composition can comprise, for example, about 20% to about 40% ginger. It is further understood that the percentages disclosed in this paragraph may vary, or be offset, by an amount corresponding to the amount of any bioenhancer that is added to increase the bioavailability of the ginger.

[0402] The compositions of the invention can comprise one or more ginger extract. Ginger extract may contain gingerols, including 8-gingerol, 10-gingerol, and 12-gingerol. Ginger extracts for use with the invention may be standardized to contain one or more of these gingerols in an amount of about 100%, 99% 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 80%, 70%, 60%,Docket No.: 1022.550W0150%, 40%, 30%, 20%, 10%, 5%, 2%, or any amount intervening these amounts. In a non-limiting embodiment, the ginger extract is standardized to about 5% of one or more gingerols. In another non-limiting embodiment, the ginger extract is standardized to about 20-40% of one or more gingerols.

[0403] In a specific, non-limiting example, the composition of the invention comprises about 20% ginger extract standardized to about 20% gingerols. In another embodiment, the composition comprises about 10 mg to 1,000 mg of ginger standardized to about 5% to about 99% gingerols. In another embodiment, the composition can comprise 100 mg ginger standardized to about 20% gingerols.

[0404] In certain embodiments the composition of the present invention is provided in a dose form comprising ginger extracts are provided in an amount selected from: 50 to 10000 mg; 50 to 5000 mg; 100 to 4000 mg; 100 to 3000 mg; 100 to 2000 mg; 100 to 1000 mg; 100 to 600 mg; 100 to 500 mg; or about 100 mg.

[0405] In certain embodiments the composition is provided in a dose form wherein the ginger extracts comprises at least 1, 2, 5, 10, 11, 12, 13, 14, 15, 20, 25, wt % or more of the claimed composition. In certain embodiments the composition is provided in a dose form wherein the composition comprises at least 10, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500 mg or more of ginger extracts. x. Cordyceps sp. Extract

[0406] In one or more embodiments, the anti-inflammatory formulations and compositions of the present invention comprise fungi material. In one or more embodiments, the fungi material is obtained from food-safe fdamentous fungi of the genera Rhizopus, Neurospora, Aspergillus, Trichoderma, Pleurotus, Ganoderma, Inonotus, Cordyceps, Ustilago, Tuber, Fusarium, Pennicillium, Xylaria, Trametes, or any combination thereof.

[0407] In one or more embodiments, the fungi material is obtained from food-safe fdamentous fungi of the species Aspergillus oryzae, Rhizopus oryzae, Rhizopus oligosporus, Rhizopus microsporus, Fusarium graminareum, Cordyceps militaris, Cordyceps sinensis, TuberDocket No.: 1022.550W01 rnelanosporum, Tuber magnatum, Pennicillium camemberti, Neurospor a intermedia, Neurospora sitophila, Xylaria hypoxion or any combination thereof.

[0408] In one or more embodiments, the fungi material is obtained from food-safe Cordyceps Sp. extract of the species Cordyceps militaris or Ophiocordyceps sinensis.

[0409] The composition can comprise, for example, about 2% to about 30% Cordyceps sp. In one embodiment, the composition can comprise about 4% to about 25% Cordyceps sp. In another embodiment, the composition can comprise about 10% to about 20% Cordyceps sp. In another embodiment, the composition can comprise about 12% to about 18% Cordyceps sp. It is further understood that the percentages disclosed in this paragraph may vary, or be offset, by an amount corresponding to the amount of any bioenhancer that is added to increase the bioavailability of the Cordyceps sp.

[0410] The compositions of the invention can comprise one or more Cordyceps sp. extract. Cordyceps sp. extract may contain cordycepin. As used herein, “cordycepin,” also referred to as 3'-deoxyadenosine, refers generally to a bioactive compound derived from Cordyceps militaris, and is a derivative of the nucleoside adenosine, differing from the latter by the absence of the hydroxy group in the 3' position of its ribose moiety.

[0411] Cordyceps sp. extracts for use with the invention may be standardized to contain cordycepin in an amount of about 100%, 99% 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 2%, or any amount intervening these amounts. In a non-limiting embodiment, the Cordyceps sp. extract is standardized to about 5% of cordycepin. In another non-limiting embodiment, the Cordyceps sp. extract is standardized to about 10-20% of cordycepin.

[0412] In a specific, non-limiting example, the composition of the invention comprises about 10-20% Cordyceps militaris extract standardized to about 10-20% cordycepin. In another embodiment, the composition comprises about 100 mg to 1000 mg of Cordyceps militaris standardized to about 5% to about 99% cordycepin. In another embodiment, the composition can comprise 100 mg Cordyceps militaris standardized to about 20% cordycepin.Docket No.: 1022.550W01

[0413] In certain embodiments the composition of the present invention is provided in a dose form comprising Cordyceps militaris extract are provided in an amount selected from: 50 to 10000 mg; 50 to 5000 mg; 100 to 4000 mg; 100 to 3000 mg; 100 to 2000 mg; 100 to 1000 mg; 100 to 600 mg; 100 to 500 mg; or about 100 mg.

[0414] In certain embodiments the composition is provided in a dose form wherein the Cordyceps militaris extract comprises at least 1, 2, 5, 10, 11, 12, 13, 14, 15, 16, 18, 20, 24 wt % or more of the claimed composition. In certain embodiments the composition is provided in a dose form wherein the composition comprises at least 10, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500 mg or more of Cordyceps militaris extract. xii. Vitamin C

[0415] Vitamin C, also known as L-ascorbic acid, is a water-soluble vitamin that must be provided in the human diet because it is not synthesized by the body. It is physiologically required for synthesis of many essential tissues as well as biomolecules including neurotransmitters, fat transport molecules and for catabolism of a portion of the body's cholesterol. Vitamin C is also an effective antioxidant in vivo for protecting many proteins, fats, carbohydrates and nucleic acids from damaging reactive oxygen and free radical species.

[0416] In one embodiment, vitamin C is added to compositions of the disclosure as ascorbic acid. In preferred examples, ascorbic acid may be present from 50 mg to 1000 mg in a single serving. In particularly preferred examples, ascorbic acid may be present from 250 mg to 750 mg in a single serving. In preferred examples, a serving size is about 2 to about 24 ounces.

[0417] In some embodiments, the supplement comprises an amount of vitamin C sufficient to provide at least 10, 15, 20, 25% or more of the recommended daily intake (RDI) of vitamin C.

[0418] In some embodiments, the supplement comprises at least about 200 mg vitamin C (ascorbic acid), such as at least about 300 mg, at least about 500 mg, at least about 750 mg, at least about 1000 mg, at least about 1250, at least about 1500, or at least about 2000 mg of vitamin C. In some embodiments, the supplement comprises 200mg, 500 mg, 750 mg, 1000 mg, 1250, 1500, 2000 or 3000 mg of vitamin C. In some embodiments, the compositions comprise about 200-3000 mg, from about 400-2000 mg, about 500-1000 mg of vitamin C.Docket No.: 1022.550W01Anti-Inflammatory Examples

[0419] Example 1 (liquid; aqueous): Per 10 mL serving: about 6 mg astaxanthin, about 250 mg L-citrulline, about 250 mg reduced glutathione, about 60 mg luteolin, about 600 mg PEA; citratephosphate buffer (pH 6.8), glycerin, natural flavors; optional lecithin to aid dispersion.

[0420] Example 2 (liquid; oil-continuous): Per 5 mL serving: about 6 mg astaxanthin, about 250 mg citrulline (as citrulline malate microemulsion droplets), about 250 mg reduced glutathione (liposomal), about 60 mg luteolin, about 600 mg PEA (ultramicronized); soybean oil carrier with mixed tocopherols and lecithin.

[0421] Example 3 (softgel): Per softgel: about 6 mg astaxanthin (liposomal), about 250 mg L- citrulline, about 250 mg reduced glutathione, about 60 mg luteolin, about 600 mg PEA; oil fill with MCT / soybean oil blend; viscosity adjusted for fill performance.

[0422] Example 4 (dose-range family): Per unit dose chosen from: astaxanthin 1-50 mg; citrulline 100-1000 mg; glutathione 50-800 mg; luteolin 5-100 mg; PEA 25-800 mg; luteolin:PEA ratio selected from about 1: 1 and about 1 :10.

[0423] In one or more embodiments, a subject in need of alleviation of pain and / or inflammation is administered an effective amount of any composition described herein. Endpoints may include reduced VAS pain scores, improved WOMAC indices, reduced prostaglandin E2, COX-2 expression, or systemic markers (CRP, IL-6, TNF-a). In certain embodiments, administration occurs 1-2 times daily to achieve total daily intakes within the ranges above.

[0424] Synergy can be demonstrated by (i) Chou-Talalay CI < 1.0 for a pre-specified endpoint (e g., percent inhibition ofPGE2 orNF-KB activity) across fractional doses; (ii) Bliss independence exceeding additivity in cell-based cytokine assays; and / or (iii) a statistically significant superadditive interaction in a randomized, controlled human study measuring VAS pain or inflammatory biomarkers.

[0425] Optional antioxidants (e.g., mixed tocopherols), preservatives (if aqueous), flavors, and sweeteners can be included. Packaging may include amber glass / PET bottles for liquids or blister / bottle formats for softgels; oxygen- and light-barrier considerations are applied.Docket No.: 1022.550W01

[0426] Compositions are manufactured and packaged to maintain label claim and physical attributes. For liquids: osmolality and pH remain within predefined limits; for oil fills: peroxide and anisidine values remain controlled; for liposomes: size, PDI, and encapsulation efficiency remain within specification over the labeled shelflife under ICH QI A(R2) conditions.

[0427] The disclosed combinations provide complementary anti-inflammatory mechanisms (redox buffering, NF-KB modulation, eicosanoid pathway modulation, PPAR-a engagement, endothelial support) with synergistic efficacy at lower doses of individual components, enabling improved tolerability and flexible liquid and liposomal dosage forms.

[0428] In one or more embodiments, the composition comprises about 1-50 mg astaxanthin, about 100-1000 mg L-citrulline, about 250 mg reduced glutathione, about 60 mg luteolin, and about 600 mg PEA. In other embodiments, the composition comprises about 6 mg astaxanthin, about 250 mg citrulline, about 50-800 mg glutathione, about 5-100 mg luteolin, and about 25- 800 mg PEA. In one or more embodiments, luteolin and PEA are present at about 1 : 1 or about 1 : 10 (luteolimPEA). In one or more embodiments, at least one ingredient is provided in a liposomal formulation. In one or more embodiments, the composition is a liquid and further comprises a carrier in various amounts.

[0429] In one or more embodiments, the composition comprises (a) a xanthophyll component selected from the group consisting of astaxanthin, astaxanthin mono- or di-esters, astaxanthin salts, astaxanthin solvates, astaxanthin hydrates, astaxanthin polymorphs, astaxanthin prodrugs, and xanthophyll analogs selected from the group consisting of zeaxanthin, lutein, canthaxanthin, P- cryptoxanthin, and mixtures thereof; (b) a urea-cycle / nitric-oxide pathway component selected from the group consisting of L-citrulline, L-citrulline salts, L-citrulline malate (1 : 1 or 2: 1), L- citrulline prodrugs, L-arginine, L-arginine salts, L-ornithine, and y-glutamyl-citrulline; (c) a thiol redox component selected from the group consisting of reduced glutathione (GSH), oxidized glutathione (GSSG), glutathione salts, glutathione solvates, glutathione hydrates, glutathione polymorphs, glutathione prodrugs selected from S-acetyl-L -glutathione and glutathione ethyl ester, y-glutamylcysteine, N-acetyl-L-cysteine and N-acetyl-L-cysteine amide; (d) a flavone component selected from the group consisting of luteolin (aglycone), luteolin salts, luteolin solvates, luteolin hydrates, luteolin polymorphs, luteolin prodrugs, luteolin glycosides selectedDocket No.: 1022.550W01 from luteolin-7-O-glucoside, luteolin-3 ',7-di-O-glucosi de, and luteolin-7-O-rutinoside, and structurally-similar flavones selected from chrysoeriol (3'-O-methyl-luteolin), diosmetin (4'-O- methyl-luteolin), and apigenin; and (e) an N-acylethanolamide component selected from the group consisting of palmitoylethanolamide (PEA), PEA salts, PEA solvates, PEA hydrates, PEA polymorphs, PEA prodrugs, micronized PEA, ultramicronized PEA, and structurally-similar N- acylethanolamides selected from oleoylethanolamide (OEA), stearoylethanolamide (SEA), and linoleoylethanolamide (LEA); wherein the mass ratio of the flavone component (d) to the N- acylethanolamide component (e) is from about 1: 1 to about 1 : 10 (luteolin:PEA basis), and wherein the composition comprises an effective and synergistic amount of components (a)-(e).

[0430] In one or more embodiments, component (a) is astaxanthin or an astaxanthin mono- or di-ester. In one or more embodiments, component (b) is L-citrulline or L-citrulline malate. In one or more embodiments, component (c) is reduced glutathione (GSH) or S-acetyl-L-glutathione. In one or more embodiments, component (d) is luteolin (aglycone) or luteolin-7-O-glucoside. In one or more embodiments, component (e) is palmitoylethanolamide (PEA) selected from non- micronized, micronized (D50 <10 pm), or ultramicronized (D50 <5 pm) PEA. In one or more embodiments, at least one of components (a)-(e) is provided in a liposomal formulation, the liposomes comprising phosphatidylcholine and cholesterol and having an average hydrodynamic diameter from about 80 nm to about 200 nm and a polydispersity index <0.3.

[0431] In one or more embodiments, the composition exhibits synergy among at least two of components as evidenced by a Combination Index (CI) < 1.0 according to the Chou-Talalay method for a prespecified anti-inflammatory endpoint selected from percent inhibition of TNF-a, IL-6, PGE2, COX-2 expression, NF-KB activity, and CRP. In one or more embodiments, the synergy is further confirmed by Bliss independence exceeding additivity or by a positive, statistically significant interaction term (p<0.05) in an analysis of variance comparing monotherapies and the combination at matched fractional doses. In one or more embodiments, the invention provides for a method of alleviating pain and / or inflammation in a subject in need thereof, comprising administering to the subject an effective amount of the composition, thereby reducing at least one of VAS pain, WOMAC score, CRP, IL-6, TNF-a, or PGE2 relative to baseline or placebo.Docket No.: 1022.550W01

[0432] In one or more embodiments, the N-acylethanolamide component comprises micronized PEA having D50 < 10 pm and D90 < 25 pm by laser diffraction. In one or more embodiments, the PEA comprises ultramicronized PEA having D50 < 5 pm, DIO > 0.5 pm, and D90 < 15 pm by laser diffraction according to ISO 13320. In one or more embodiments, the particle-size distribution is stabilized with colloidal silica or microcrystalline cellulose in the dry phase and with lecithin in liquid dispersions. In one or more embodiments, the median particle size of component (d)(luteolin aglycone or glycoside) is D90 < 25 pm. In one or more embodiments, the liposomes have a hydrodynamic diameter of 80-200 nm, a polydispersity index (PDI) < 0.25, and a zeta potential magnitude > |15| mV as determined by dynamic light scattering and electrophoretic light scattering. In one or more embodiments, the encapsulation efficiency (EE), measured after removal of unencapsulated actives by size-exclusion chromatography or tangential- flow filtration, is >40% for the thiol redox component (c) and >30% for at least one of components (a) or (d). In one or more embodiments, the liposomes comprise phosphatidylcholine and cholesterol at a molar ratio of 55:45 to 85: 15, optionally further comprising 0.5-5 mol% PEGylated lipid. In one or more embodiments, the liposomes retain >90% of initial Z-avg and PDI < 0.30 after storage for 3 months at 25 °C / 60% RH. In one or more embodiments, the liposomes are spray-dried or lyophilized with a cryo / lyo-protectant selected from trehalose, sucrose, or mannitol, and reconstitute to within ±10% of initial Z-avg.

[0433] Tables 5-7 provide a set of components that may be provided in a dry powdered form or introduced into such a liquid. The amounts provided in tables 5-7 are particularly useful to form compositions having a total final volume of about 2 to 24 fluid ounces.Docket No.: 1022.550W01

[0434] In one example, an anti-inflammatory beverage powder (luteolin : PEA = 1 : 10) is produced and used for a two-period crossover evaluation A ready-to-mix beverage powder is formulated to deliver per reconstituted serving approximately 6-20 mg luteolin and 60-200 mg palmitoylethanolamide (PEA), maintaining a luteolimPEA mass ratio of about 1 : 10. Luteolin is provided as the aglycone or a permitted mono-glycoside and is granulated with a carrier such as maltodextrin to improve dispersibility; PEA is used in micronized or ultramicronized form with a d50 of about 2-10 pm to enhance suspension uniformity. The powder further contains a foodgrade acidulant and buffer to achieve a beverage pH of about 4.0-5.5 upon reconstitution in 250- 300 mL of water, along with natural flavors and non-nutritive sweetener. Identity and assay are confirmed by validated chromatographic methods; uniformity of dosing is verified by replicate sample preparation across ten composite sachets with a target %RSD <5.0%. A randomized, double-blind, placebo-controlled, two-period crossover study is prospectively designed to evaluate anti-inflammatory endpoints. Adult participants with baseline high-sensitivity C-reactive protein (hs-CRP) above a prespecified threshold are randomized to receive active product or matchedDocket No.: 1022.550W01 placebo once daily for 14 days in Period 1, followed by a washout of 14-21 days justified by known pharmacokinetics and pharmacodynamics of the elected actives, and then crossed over for Period 2. Primary endpoints are change from baseline to end-of-period in hs-CRP; secondary endpoints include IL-6 and TNF-a. Safety, tolerability, and exploratory patient-reported outcomes are collected. The statistical analysis plan prespecifies a mixed-effects model including fixed effects for treatment, period, and sequence and a random effect for subject, with sensitivity analyses to assess carryover; multiplicity control is applied to secondary endpoints. Sample size is determined to provide adequate power for detecting a clinically meaningful change in hs-CRP while permitting estimation of effect sizes for IL-6 and TNF-a. This example is prophetic and describes contemplated formulation and clinical evaluation parameters; no human data are reported.

[0435] In certain embodiments, optional co-actives are selected from bounded, mechanism- linked groups and combined only across distinct groups. Group A (N-acylethanolamides) consists of palmitoylethanolamide (PEA), oleoylethanolamide (OEA), and docosahexaenoylethanolamide (also referred to in some literature as “DEA” or synaptamide). Group B (flavonoids) consists of luteolin and quercetin, and their mono-glycosides wherein n<l (e.g., luteolin-7-O-glucoside or quercetin-3-O-glucoside), with di- or higher glycosides excluded. Group C (cholinergic donors) consists of citicoline (CDP-choline) and L-a-glycerylphosphorylcholine (a-GPC). Group D (adenosinergic / xanthine modulators) consists of paraxanthine. Group E (nitric-oxide precursors) consists of L-citrulline and L-arginine. Group F (redox / anti-oxidative modulators) consists of reduced L-glutathione and astaxanthin. The compositions include actives independently selected such that at least two and no more than four distinct groups are present in a given formula, with no more than one species elected from any single group, and with the combined active-ingredient content constituting, by dosage form, about 5-40% w / w of an orodispersible film, about 1-10% w / w of a beverage or ready -to-mix powder, or about 10-60% w / w of a capsule or tablet. Unless expressly stated otherwise, each selected species may be used as a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or polymorph. In representative embodiments directed to energy support, the elected species are citicoline or a-GPC from Group C in combination with paraxanthine from Group D, optionally further combined with one species from Group B or Group F; in representative embodiments directed to anti-inflammatory support, the elected species are PEA or OEA from Group A in combination with luteolin or quercetin (or a mono-glycosideDocket No.: 1022.550W01 thereof) from Group B, optionally further combined with L-citrulline from Group E and / or reduced L-glutathione or astaxanthin from Group F. Pairwise mass ratios are bounded as follows to preserve the intended mechanisms of action: citicoline: paraxanthine from about 4: 1 to about 1 :4; luteolin:PEA from about 1 : 1 to about 1 : 10; and luteolimOEA from about 1 :1 to about 1 :8. In certain “consisting essentially of’ embodiments, the composition consists essentially of elected species from the foregoing Groups A-F and excipients suitable for the dosage form, and is substantially free of caffeine, theophylline, and theobromine (each <1 mg per unit dose), such that the presence of excluded xanthines does not materially alter the composition’s energy or antiinflammatory performance as measured by pre-specified endpoints.

[0436] Unit Dosage Forms

[0437] The compositions of the disclosure may take the form of a unit dosage form in the form of an oral film comprising an active pharmaceutical ingredient (API) and a film-forming polymer. The term “unit dosage form” refers to physically discrete units suitable as unitary dosage for subjects undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect. The term “oral film” as used herein refers to sublingual, buccal and orodispersible films (ODF), as well as any other films placed into the oral cavity aiming at local or systemic effects.

[0438] In one embodiment, the unit dosage form is for buccal administration. In one embodiment, the film is a mucoadhesive film. The term “buccal administration” as used herein refers to administration to the space in the oral cavity that is outside the teeth when the jaws are closed, such as for example the inside of the cheek or under the upper lips. In one embodiment, the film has a relatively high dissolution rate for the rapid delivery of API into systemic circulation.

[0439] To avoid slow in vivo the dissolution rate, it may be favorable if the API is dissolved in the film, i.e. not suspended. In addition, the film should not be too thick, but yet thick enough to accommodate the intended dose of the API. Further, the unit dosage form should be stable for storage. Such storage stability does not just comprise chemical stability, but also physical stability, e g., that the API, if intended to be dissolved in the film, should not precipitate during storage.Docket No.: 1022.550W01

[0440] In one aspect, the present invention relates to a unit dosage form in the form of an oral film comprising: a) at least 20 wt % synergistic composition described herein; and b) 35 to 70 wt % film-forming polymer.

[0441] In a preferred embodiment, the unit dosage form of the present invention has a relatively high dissolution rate. The term “relatively high dissolution rate” as used herein means that at least 85% of the API has been dissolved within 10 minutes in the USP Dissolution Apparatus 2-Paddle.

[0442] In one embodiment, the concentration of API in the film is at least 10 wt %, such as at least 15 wt %, such as at least 20 wt %, such as at least 25 wt %, such as at least 30 wt %. In one embodiment, the concentration of API in the film is no more than 80 wt %, such as no more than 70 wt %, such as no more than 60 wt %, such as no more than 50 wt %, such as no more than 40 wt %. In one embodiment, the concentration of API in the film is in the range of 10 to 60 wt %, such as in the range of 15 to 40 wt %, such as in the range of 15 to 25 wt % or such as in the range of 30 to 60 wt %, for example in the range of 20 to 40 wt %, such as in the range of 25 to 35 wt %, such as in the range of 30 to 35 wt %.

[0443] Film-Forming Polymers

[0444] The unit dosage form of the present invention comprises one or more film-forming polymers. In one embodiment, the film-forming polymer is selected from the group consisting of HPMC, alginate, acrylate, PVP, gum, carrageenan, chitosan, collagen, gelatin, hyaluronic acid, maltodextrin, pectin, polylactic acid, polylactic acid derivatives / copolymers thereof, pullulan, scleroglucan, starch, starch derivatives, polysaccharides, dendritic polymers, polyethylene glycol, polyethylene oxide and polyvinyl alcohol.

[0445] In one embodiment, the film-forming polymer is hypromellose (HPMC). The term “hypromellose” as used herein refers to hydroxypropyl methylcellulose, CAS number 9004-65-3, E number E464. HPMC is a partly O-methylated and O-(2-hydroxypropylated) cellulose and is available in several grades that differ in molecular weight as well as in the extent of substitution, and therefore also differ in viscosity. HPMC types may be classified based on the extent of substitution, and thus given a four digit number. The first two digits refer to the percentage (w / w) of the methoxy, while the second two digits refer to the percentage of the hydroxypropoxy-groupsDocket No.: 1022.550W01 in the dried substance. In one embodiment, the HPMC is HPMC of substitution type 2910 (also known as “E”).

[0446] In one embodiment, the HPMC is HPMC Pharmacoat 603. In one embodiment, the HPMC is HPMC Metolose 60SH-50. In one embodiment, the film-forming polymer is a mixture of HPMC Pharmacoat 603 and HPMC Metolose 60SH-50. In one embodiment, the unit dosage form comprises HPMC Pharmacoat 603 and HPMC Metolose 60SH-50 in the ratio of 70:30 to 30:70, such as 60:40, such as 50:50, such as 40:60.

[0447] In one embodiment, the film-forming polymer is alginate selected from the group consisting of sodium alginate, potassium alginate, ammonium alginate, calcium alginate, propylene glycol alginate, alginic acid and mixtures thereof. In one embodiment, the alginate is sodium alginate, potassium alginate or ammonium alginate, or a mixture thereof. In one embodiment, one or more of these alginate salts comprises from 25 to 35 wt % by weight of a-D- mannuronate and / or from 65 to 75 wt % by weight of a-L-guluronate, and a mean molecular weight of from 30,000 g / mol to 90,000 g / mol.

[0448] In one embodiment, the film-forming polymer is acrylate selected from acrylic polymers and co-polymers thereof; polyacrylic acids, polymethacrylates and co-polymers thereof (such as Eudragit E PO); and polyvinyl alcohol -polyethylene glycol graft-copolymers (for example Kollicoat, such as Kollicoat IR, which is a polymer consisting essentially of 75% polyvinyl alcohol units and 25% polyethylene glycol units) In one embodiment, the film-forming polymer is gum selected from the group consisting of acacia gum, guar gum, tragacanth gum, xanthan gum and diutan gum.

[0449] In one embodiment, the unit dosage form comprises at least 35 wt % film-forming polymer, such as at least 45 wt %, such as at least 50 wt %, such as at least 55 wt %, such as at least 60 wt %, such as at least 65 wt % film-forming polymer.

[0450] In one embodiment, the unit dosage form comprises no more than 80 wt % film-forming polymer, such as no more than 70 wt % such as no more than 65 wt %, such as no more than 60 wt %, such as no more than 55 wt %, such as no more than 50 wt %, such as no more than 45 wt % film-forming polymer.Docket No.: 1022.550W01

[0451] In one embodiment, the unit dosage form comprises 35 to 70 wt % film-forming polymer, such as 45 to 70 wt %, such as 50 to 60 wt %, such as 55 to 65 wt % film-forming polymer. In one embodiment, the unit dosage form comprises 35 to 70 wt % HPMC, such as 45 to 70 wt %, such as 50 to 65 wt %, such as 55 to 60 wt % HPMC.

[0452] The mechanical properties of the film must allow for a continuous coating process and converting process, the latter of which can be rather high speed and requires strength and plasticity of the polymer-based film. One way to achieve a satisfactory plasticity is to add one or more plasticizers. In general, the optimal type and concentration of plasticizer(s) depends on various factors, such as the type and concentration of polymer(s). The type and concentration of API, as well as its state also have an impact when selecting optimal type and concentration of plasticizer(s), at least if the substance constitutes a significant fraction of the finished film e g. more than 10 wt%.

[0453] Preferably, the unit dosage form of the present invention comprises an API, a filmforming polymer and one or more plasticizer(s). Plasticizers might be defined as small low molecular weight, non-volatile compounds added to polymers to reduce brittleness, impart flexibility, and enhance toughness for films.

[0454] In one embodiment, the unit dosage form comprises an API, one or more film-forming polymers, a pigment but no other additives or excipients. In one embodiment, the unit dosage form comprises 15 to 35 wt % API and 35 to 70 wt % film-forming polymer, such as 20 to 35 wt % API and 45 to 70 wt % film-forming polymer.

[0455] In one embodiment, the unit dosage form comprises 15 to 35 wt % API, 35 to 70 wt % film-forming polymer and 3 to 35 wt % plasticizer.

[0456] The amounts of the various components of the unit dosage form or the film are sometimes given as wt %. In such cases, the sum of the wt % of the components does not exceed 100 wt %.

[0457] Key features for oral films are that they are thin, e.g. 50-150 pm in order to achieve relatively high dissolution rate and being flexible, and that they have a feasible area that fits into the oral cavity surfaces, e.g. <5 cm2, yet large enough for convenient handling e.g. >2 cm2.Docket No.: 1022.550W01

[0458] In one embodiment, the oral film is 30 to 150 m thick, such as 50 to 120 pm thick, such as 70 to 110 pm thick. The thickness of an oral film is often measured and defined by coat weight, rather than being measured as an actual thickness and presented in pm. Coat weight is the weight of the dry film per unit area, and is often measured and presented as g / m2. If the density of the dry film is 1 g / cm3, the numerical values of thickness in pm will equal that of coat weight in g / m2. In one embodiment, the film is homogenous.

[0459] As for excipients other than the film-forming polymer (which may be HPMC, PVA, alginate or a wide range of others), several excipients can be imagined: plasticizers (e g. glycerol), fillers, colorants, flavors, disintegration agents, solubilizing agents, etc.

[0460] In one example, nanoscale liposomes encapsulating one or more actives selected from luteolin, palmitoylethanolamide, and citicoline are prepared by thin-film hydration followed by stepwise extrusion. A lipid phase comprising hydrogenated soy phosphatidylcholine and cholesterol at a molar ratio of about 7:3 is dissolved with the lipophilic actives (e.g., luteolin and / or PEA) in a volatile organic solvent system and rotary-evaporated to form a uniform thin fdm. The film is hydrated with an aqueous buffer containing hydrophilic actives (e.g., citicoline) as applicable at about 35-45 °C under gentle agitation to produce multilamellar vesicles, which are then subjected to serial extrusion through polycarbonate membranes to achieve a target Z-average diameter of about 100-160 nm with a polydispersity index (PDI) of not more than 0.25-0.30. Unencapsulated actives are removed by size-exclusion chromatography or ultracentrifugation. Dynamic light scattering provides Z-average and PDI; zeta potential is measured by electrophoretic light scattering with a target magnitude of at least about 20 mV in absolute value to support colloidal stability. Encapsulation efficiency is quantified pre-lyophilization by disrupting aliquots and assaying total versus free drug to calculate %EE. Batches are lyophilized with a disaccharide cryoprotectant at about 5-10% (w / w) relative to lipid and stored in moisture- protective containers. Upon reconstitution to the original volume with buffered diluent, nanoscale metrics are reassessed; reconstitution acceptance specifies that Z-average remains within about ±20 nm of the pre-lyophilization value, PDI remains <0.30, and encapsulation efficiency loss does not exceed about 10% absolute versus pre-lyophilization. Where applicable, accelerated and longterm stability studies monitor particle size distribution, zeta potential, assay, degradation products, and reconstitution behavior at predefined intervals. This example is prophetic and outlines aDocket No.: 1022.550W01 contemplated manufacturing and characterization plan for nanoscale liposomes without reporting experimental data.

[0461] Nutritional Supplements

[0462] The compositions of the disclosure may take the form of dietary supplements or may themselves be used in combination with dietary supplements, also referred to herein as food supplement. Nutritional supplements may be found in many forms such as tablets, capsules, soft gels, gel caps, liquids, or powders. Some dietary supplements can help ensure an adequate dietary intake of essential nutrients; others may help reduce risk of disease.

[0463] The compositions of the disclosure may take the form of a food product. Here, the term “food” is used in a broad sense and covers food and drink for humans as well as food and drink for animals (i.e. a feed). Preferably, the food product is suitable for, and designed for, human consumption. The food may be in the form of a liquid, solid or suspension, depending on the use and / or the mode of application and / or the mode of administration.

[0464] When in the form of a food product, the composition may comprise or be used in conjunction with one or more of: a nutritionally acceptable carrier, a nutritionally acceptable diluent, a nutritionally acceptable excipient, a nutritionally acceptable adjuvant, a nutritionally active ingredient.

[0465] By way of example, the compositions of the disclosure may take the form of one of the following: A fruit juice; a beverage comprising whey protein: a health or herbal tea, a cocoa drink, a coffee drink, a yoghurt and / or a drinking yoghurt, a cheese, an ice cream, a desserts, a confectionery, a biscuit, a cake, cake mix or cake filling, a snack food, a fruit filling, a cake or doughnut icing, an instant bakery filling cream, a filling for cookies, a ready-to-use bakery filling, a reduced calorie filling, an adult nutritional beverage, an acidified soy / juice beverage, a nutritional or health bar, a beverage powder, an energy drink, a sublingual, a gummy, a calcium fortified soy milk, or a calcium fortified coffee beverage.

[0466] Compositions of the present disclosure may take the form of a food ingredient and / or feed ingredient. As used herein the term “food ingredient” or “feed ingredient” includes a composition which is or can be added to functional foods or foodstuffs as a nutritional and / orDocket No.: 1022.550W01 health supplement for humans and animals. The food ingredient may be in the form of a liquid, suspension or solid, depending on the use and / or the mode of application and / or the mode of administration. Compositions of the disclosure may take the form of functional foods. As used herein, the term “functional food” means food which is capable of providing not only a nutritional effect but is also capable of delivering a further beneficial effect to the consumer. Although there is no legal definition of a functional food, most of the parties with an interest in this area agree that they are foods marketed as having specific health effects beyond basic nutritional effects.

[0467] In some examples, the composition can further include one or more carbohydrates (e g., d-ribose), folic acid, malic acid, vitamin B6, vitamin B 12, vitamin D3, magnesium oxide, calcium, inulin, chicory root extract, cherry extract, or a combination thereof. In some examples, the composition can further include a pharmaceutically acceptable carrier. In one example, the composition can further include coatings, isotonic agents, absorption delaying agents, binders, adhesives, lubricants, disintegrants, coloring agents, flavoring agents, sweetening agents, absorbents, detergents, emulsifying agents, antioxidants, vitamins, minerals, proteins, fats, carbohydrates, or a combination thereof. In one example, the composition can further include a sweetener, a preservative, a flavoring, or a combination thereof. In some examples, the formulation can include a polymers for sustained release of a given compound.

[0468] In some embodiments, the carbohydrates consist of one or more of alginic acid, alginate, propylene glycol alginate, inulin, arabinogalactan, lignosulfonate, carrageenan, furcelleran, pullulan, glucomannan, gellan gum, gum arabic, gum ghatti, guar gum, gum karaya, tara gum, tragacanth, xanthan gum, carboxymethylcellulose, hydroxyethyl cellulose, ethylhydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, modified starch, dextrin, polydextrose, pectin, beta-glucan, lactobionic acid, lactobionate, isomalt, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, sucrose, lactose, maltose, trehalose, maltitol, glucose, fructose, galactose, arabinose, ribose, xylose, allulose, sorbose, tagatose, fucose, mannose, and hydrogenated starch hydrolysate. In some embodiments, the carbohydrates comprise stevia or allulose.

[0469] In another example, the formulation can include emulsifiers. In one example, the emulsifier can add stability to the final product. Examples of suitable emulsifiers include, but areDocket No.: 1022.550W01 not limited to, lecithin (e.g., from egg or soy), or mono- and di-glycerides. Other emulsifiers are readily apparent to the skilled artisan and selection of suitable emulsifier(s) will depend, in part, upon the formulation and final product.

[0470] In yet another example, the formulation can include a preservative. In one example, the preservatives such as potassium sorbate, sodium sorbate, potassium benzoate, sodium benzoate, or calcium di sodium EDTA are used.

[0471] In a further example, the nutritional supplement can contain natural or artificial sweeteners, e.g., glucose, sucrose, fructose, saccharides, cyclamates, aspartame, sucralose, aspartame, acesulfame K, or sorbitol.

[0472] In one example, the composition can be in the form of an oral dosage formulation. In another example, the oral dosage formulation can be a capsule, a tablet, a soft gel, a lozenge, a sachet, a powder, a beverage, a syrup, a suspension, or a food. In another example, the compositions can be formulated into a food or drink, and provided, for example, as a snack bar, a cereal, a drink, a gum, or in any other easily ingested form. In one example, the composition can be incorporated into a liquid beverage such as water, milk, juice, or soda. In another example, the composition can be formulated into a nutritional beverage. The nutritional beverage can be in a premixed formulation or can be a powdered mix in that can be added to a beverage. In another example, the powder mix in can be in the form of granules. In one example, the composition can be dried and made readily soluble in water.

[0473] In yet another example, the oral dosage form can be in a solution or a suspension in an aqueous liquid or non-aqueous liquid, such as ethanol, glycerol, vegetable oil, salt solutions, or hydroxymethyl cellulose; or in the form of an oil-in-water emulsion or a water-in-oil emulsion, or a combination thereof. In examples where the oral dosage form includes oils, the oils can be edible oils, such as e.g. cottonseed oil, sesame oil, coconut oil, or peanut oil. In some examples, the composition can include suitable dispersing or suspending agents for aqueous suspensions include synthetic or natural gums such as tragacanth, alginate, gum arabic, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose, and polyvinylpyrrolidone.Docket No.: 1022.550W01

[0474] In another example, the composition can be formulated into a food product. In one example, the food product can be a pudding, confections, (i.e., candy), ice cream, frozen confections and novelties, or non-baked extruded food products such as bars. In one example, the composition can be a powder that is added to non-baked goods. For, example a nutritional bar can be manufactured by adding the powder to the dry ingredients and then incorporating the dry and wet. The wet and dry ingredients can be mixed until the dough phase is reached. The dough can then be put into an extruder and extruded; the extruded dough can be cut into appropriate lengths; and the product can be cooled.

[0475] Flavors, coloring agents, spices, nuts, and the like can be incorporated into the product. Flavorings can be in the form of flavored extracts, volatile oils, chocolate flavorings (e.g., non- caffeinated cocoa or chocolate, chocolate substitutes such as carob), peanut butter flavoring, cookie crumbs, crisp rice, vanilla, or any commercially available flavoring. Flavorings can be protected with mixed tocopherols. Examples of useful flavorings include but are not limited to pure anise extract, imitation banana extract, imitation cherry extract, chocolate extract, pure lemon extract, pure orange extract, pure peppermint extract, imitation pineapple extract, imitation rum extract, imitation strawberry extract, or pure vanilla extract; or volatile oils, such as balm oil, bay oil, bergamot oil, cedarwood oil, cherry oil, walnut oil, cinnamon oil, clove oil, or peppermint oil; peanut butter, chocolate flavoring, vanilla cookie crumb, butterscotch, or toffee. In one example, the nutritional supplement contains berry or other fruit flavor. The food compositions may further be coated, for example with a yogurt coating if it is as a bar.

[0476] Within additional aspects of the invention, combinatorial formulations and coordinate administration methods are provided which employ an effective amount of the compositions, and one or more additional active agent(s) that is / are combinatorially formulated or coordinately administered.

[0477] Such secondary or additional agents for use within the formulations and methods of the present invention include, but are not limited to, adaptogens, amino acids and amino acid derivatives, anti-inflammatory agents, anti-nausea agents, analgesics, antioxidants, aphrodisiacs, detoxifying agents, dietary supplements, herbal supplements, calming agents, herbs and plant extracts, flavorings, essential nutrients, coenzymes, electrolytes, energy boosters, essential traceDocket No.: 1022.550W01 elements, flavonoids, hormones, immune boosters, neurotransmitters, essential fatty acids, memory enhancers, vitamins and minerals, protein, sedatives, stimulants and nutritional supplements for use within the formulations and methods described herein.

[0478] Such combinations may be administered either combinatorially or coordinately as disclosed herein to effectively optimize health and performance; prevent illness; decrease recovery times from exertion, illness, and injury; increase energy levels; improve exercise performance; improve hydration; prevent muscle damage after exercise; and increase stamina during exercise.

[0479] Adaptogen agents for use within the formulations and methods herein include, but are not limited to, ashwagandha, eleutherococcus senticosus, reishi, astragalus, licorice root, panax quinquefolius, panax ginseng and schi sandra berries.

[0480] Antioxidants included in the formulations provided herein may be in the form of nutritional supplements such as, but not limited to, vitamin A; vitamin C; vitamin E; erythorbic acid; beta-carotene; carotenes; lutein; manganese; lycopene; melatonin; or coenzyme Q10; xanthine oxidase inhibitors, including, but not limited to, allopurinol and folic acid; NADPH oxidase inhibitors, including, but not limited to, adenosine; calcium channel blockers; superoxide dismutases; catalases; albumin; inhibitors of iron redox cycling, including, but not limited to deferoxamine, apotransferin and ceruloplasmin; beta carotene; ascorbates; myricetin-3-O- galactoside, quercitin-3-O-galactoside; alpha tocopherol; and benzaldehyde derivatives, such as those described in U.S. patent application Ser. No. 12 / 418,342, incorporated by reference herein in its entirety. In some embodiments, antioxidants may be present in plant extracts which may also be combined with the nitric oxide increasing formulations. Plant extracts may come from plant sources such as, but not limited to, apricot, acai fruit, acerola, apple, blueberry, blackberry, black currant, carrots, cherry, chokeberry, cranberry, elderberry, green tea, goji berry, grape seed, mangosteen, maqui berry, milk thistle, pomegranate seed, prune, raspberry, red grape, rooibos, rosehips, strawberry, seabuckthorn, white grape, whole grape, yumberry and acerola fruit.

[0481] Vitamin, mineral and nutritional supplements for use herein may be in a variety of forms including, but not limited to, vitamin B complex, folic acid, niacin, niacinamide, pantothenic acid, pyridoxine HC1, vitamin B2, folate, biotin, vitamin C, vitamin D, vitamin D3, vitamin E, vitamin K, cyanocobalamin, inositol, thiamine, thiamine mononitrate, calcium pantothenate, mixedDocket No.: 1022.550W01 tocophyerols, d-alpha tocopheryl acetate, magnesium, calcium, calcium carbonate, calcium chelate, calcium di-phosphate, calcium phosphate, iron, magnesium carbonate, magnesium citrate, magnesium oxide, magnesium phosphate, manganese chelate, manganese sulfate, potassium, potassium chelate, potassium chloride, sodium, zinc, vanadyl sulphate, chromium, chromium chloride, chromium picolinate, and chromium polynicotinate.

[0482] Amino acids, amino acid precursors and derivatives as used within the formulations herein may be branched or straight chain amino acids. Exemplary amino acids, precursors and derivatives which may be used in the formulations and methods described herein include, but are not limited to, 5-HTTP, arginine, beta alanine, carnitine fumarate, citrulline malate, glutamine peptide, glycine, 1-alanine, 1-arginine, 1-arginine hydrochloride, 1-histidine, 1-methionine, 1-lysine HC1, 1 -phenyl alanine, leucine ethyl ester, 1-glutamine, 1-isoleucine, 1-theanine, 1-tyrosine, phenylalanine, taurine, tri-methyl glycine, tryptophan, tyrosine, 1-carnitine, 1-carnosine, glutamine alpha ketoglutarate and alpha-L-poly lactate.

[0483] Electrolytes used with the formulations herein include, but are not limited to, sodium chloride, sodium acetate, acidic sodium citrate, acidic sodium phosphate, sodium chloride, sodium bicarbonate, sodium bromide, sodium citrate, sodium lactate, sodium molybdate, sodium phosphate, anhydrous sodium sulphate, sodium sulphate, sodium tartrate, sodium benzoate, sodium selenite, and other sodium salts and mixtures thereof; potassium chloride, potassium acetate, potassium bicarbonate, potassium bromide, potassium citrate, potassium-D-gluconate, monobasic potassium phosphate, potassium tartrate, potassium sorbate, potassium iodide, and other potassium salts and mixtures thereof; magnesium carbonate, magnesium citrate, magnesium oxide, magnesium phosphate, as well as other magnesium salts and mixtures thereof; calcium chloride, calcium carbonate, calcium chelate, calcium di-phosphate, calcium lactate, calcium phosphate tribasic and other calcium salts and mixtures thereof. Such electrolytes may be included in the formulations described herein in proportions and amounts suitable to replenish salts lost during exercise or illness or otherwise depleted.

[0484] Anti-inflammatory agents for use within the formulations and methods herein include, but are not limited to, extracts from plants such as maqui berry, milk thistle, skull cap, red raspberry, red sour cherry, green tea and hops.Docket No.: 1022.550W01

[0485] Other agents which may be used in the compositions and methods described herein include anti-nausea agents including, but not limited to, extracts from peppermint, ginger and chamomile.

[0486] A further agent which may be used in the compositions and methods described herein includes analgesic agents such as, but not limited to, white willow bark.

[0487] The formulations and methods described herein may additionally include herbal supplements and extracts with beneficial properties including, but not limited to, passionflower, horny goat weed, skullcap, milk thistle, Echinacea, dandelion leaf St. John's wort, green tea, black tea, chamomile or peppermint, or an extract thereof.

[0488] The formulations and methods described herein may further include plants with beneficial properties including, but not limited to, guarana seeds, acerola berries, coconut water, yerba mate, acai berry, ginseng root, panax ginseng root, ginkgo biloba, white willow bark, acacia, ashwagandha, chokeberry, elderberry, cranberry, maqui berry, blueberry, pomegranate, rooibos, goji berry, elder berry, valerian, seabuckthorn, yumberry, blackberry, astragalus, damiana, and ginger.

[0489] Energy boosters that may increase performance and are contemplated for use within the methods and formulations described herein include, but are not limited to, creatine ethyl ester, creatine monohydrate, magnesium creatine chelate, creatine hydrochloride, creatine nitrate, creatine monohydrate and royal jelly.

[0490] Useful flavonoids within the compositions and methods of the present invention are present in chamomile extract, cocoa powder, red grape, black tea, and white tea, ginkgo biloba, berries, parsley, and green tea some or all of which may be included in the compositions and methods described herein.

[0491] Useful sedatives for use within the compositions and methods described herein include, but are not limited to, lavender, lemon balm, lemongrass, linden, oatstraw, St. John's wart, valerian root, kava kava, hops and passionflower.Docket No.: 1022.550W01

[0492] Stimulants for use within the methods and compositions described herein include, but are not limited to, caffeine, citicoline, d-glucuronolactone, guarana extract, ginseng, concentrated green tea, green coffee beans, glucuronolactone, guarana, panax ginseng, panax quinquefolius, Siberian ginseng, and theobromine.

[0493] Additional agents which may be included in the formulations and methods described herein are immune boosters including, but not limited to, Echinacea and astragalus root.

[0494] Flavoring agents for use with the compositions and methods described herein include, but are not limited to fruit juice, vegetable juice, milk solids, fruit flavors, herbal flavor and mixtures thereof. The fruit juice can be any citrus juice, non-citrus juice, or mixture thereof, which is known for use in dilute juice beverages. The juice can be derived from, but not limited to, apple, cranberry, pear, peach, plum, apricot, nectarine, grape, guava, cherry, currant, raspberry, gooseberry, elderberry, blackberry, blueberry, strawberry, lemon, lime, mandarin, orange, tomato, lettuce, dandelion, rhubarb, pineapple, coconut, pomegranate, kiwi, mango, papaya, banana, watermelon, passion fruit, tangerine, and cantaloupe. The vegetable juice can be any vegetable juice generally consumed including but not limited to, celery, spinach, cabbage, watercress, carrot, beet, spirulina, sweet potato, kale, romaine, collard greens, endive, escarole, bok Choy, fennel, parsley, wheat grass, or cucumber. Such fruit and vegetable juices may or may not have additional beneficial properties such as antioxidants and / or flavonoids.

[0495] Formulations and methods herein may additionally include a protein source. Protein sources include, but are not limited to, milk solids, calcium caseinate, whey protein concentrate, whey protein isolate, whey protein hydrolysate, soy protein, casein hydrolysate, rice protein, wheat protein, com protein, partially hydrolyzed whey protein, or ultra-filtered whey protein.

[0496] Formulations and methods herein may further include one or more sweeteners or other carbohydrate source. Such sweeteners include, but are not limited to, acesulfame potassium, allulose, aspartame, cane sugar, com syrup, crystalline fructose, dextrose, D-ribose, fructose, glucose, glucose-fructose syrup, high fructose corn syrup, high fructose liquid sugar, honey, maltodextrin, sorbitol, stevia, sucralose, sucrose, sugar, trehalose, truvia or xylitol.Docket No.: 1022.550W01

[0497] Yet additional formulations are provided for powders that further comprise that comprise a fortifying agent as a carrier. The carrier may be any solid or semisolid compound that is suitable for use in ingestible compositions and is compatible with the other ingredients in the composition. Preferred solid or semisolid carriers include water soluble or water suspendible macronutrients. Suitable carriers include, but are not limited to, carbohydrates and proteins. Exemplary carbohydrate carriers include simple sugars (e.g., glucose, fructose, or sucrose); complex sugars (e.g., maltodextrins, fructo-oligosaccharides, or inulin); starches (e.g., com starch modified corn starch, potato starch, or rice starch); cellulosics (e.g., powdered cellulose, microcrystalline cellulose, or hemicellulose), sugar alcohols (e.g., xylitol, mannitol, sorbitol, or maltitol); and combinations thereof. Exemplary protein carriers include milk proteins (e.g., casein, caseinate, or whey); animal proteins (e.g., beef, poultry, or fish); vegetable proteins (e.g., bean, pea, or potato); cereal proteins (e.g., rice or wheat), and combinations thereof. A preferred example of a suitable carrier is nonfat dry milk powder, which comprises a combination of simple sugars (e.g., lactose) and proteins (e.g., casein and whey).

[0498] The carrier may also be in the form of an aqueous solution, emulsion, or suspension comprising a compound that is suitable for use in ingestible compositions and is compatible with the other ingredients in the composition. Preferred liquid carriers comprise water and water soluble or water suspendible macronutrients. Suitable liquid carriers include, but are not limited to, liquids comprising carbohydrates or proteins. Exemplary liquid carriers include fluid whole milk, fluid skim milk, fluid condensed milk, fluid evaporated milk, aqueous starch slurries, liquid sugar solutions, corn syrups, diluted corn syrups, honey, diluted honey, and combinations thereof. A preferred example of a suitable liquid carrier is fluid skim milk, which comprises a combination of simple sugars (e.g., lactose) and proteins (e.g., casein and whey).

[0499] The carrier may be in the fortifying powder at about 10 wt % to about 88 wt %, as a percentage of the weight of the fortifying powder. The carrier may be in the fortifying powder at about 20 wt % to about 85 wt %, including about 30 wt % to about 82 wt %, about 440 wt % to about 80 wt %, about 50 wt % to about 78 wt %, about 52 wt % to about 75 wt %, about 55 wt % to about 72 wt %, about 58 wt % to about 70 wt %, about 60 wt % to about 68 wt %, about 62 wt % to about 66 wt %, and about 63 wt % to about 65 wt %, as a percentage of the weight of the fortifying powder. The carrier may be in the fortifying powder at about 40 wt %, at about 43 wtDocket No.: 1022.550W01%, at about 46 wt %, at about 49 wt %, at about 50 wt %, at about 53 wt %, at about 56 wt %, at about 59 wt %, at about 60 wt %, at about 64 wt %, at about 67 wt %, at about 70 wt %, at about 73 wt %, at about 75 wt %, at about 77 wt %, at about 80 wt %, at about 84 wt %, at about 86 wt %, and at about 88 wt %, as a percentage of the weight of the fortifying powder.

[0500] The carrier may be added to the fortifying powder at different stages during the preparation of the fortifying powder. In a preferred embodiment, the carrier is dissolved or suspended in an aqueous solution or suspension. This aqueous liquid comprising the carrier is mixed with the mixture of the MDG oil, lipophilic nutrient, and phospholipid.

[0501] The products within the scope of this invention may take a variety of forms. For example, the product may be manufactured and sold as a ready-to-drink beverage for immediate consumption by a mammalian subject. The compositions described herein may be preferred in concentrate or powder form to be reconstituted for use by a mammalian subject by the addition of water. Such reconstitution is made with the requisite amounts of water to ensure that the beverage to be consumed contains the active components in the proportions previously noted. In some embodiments, liquid formulations as described herein may be sold as part of a kit. The kits of the present invention comprise one or more compositions of the present invention together with the, information which informs a user of the kit, by words, pictures, and / or the like, that use of the kit will provide one or more general health and / or general physiological benefits including, but not limited to, health and performance optimizing, illness preventing, energy level increasing, hydration increasing, recovery time decreasing, muscle protecting and stamina increasing benefits and which informs the user of the method of monitoring their low levels of nitric oxide levels.

[0502] In the detailed description of exemplary embodiments of the disclosure, specific exemplary embodiments in which the disclosure may be practiced are described in sufficient detail to enable those skilled in the art to practice the disclosed embodiments. For example, specific details such as specific method orders, structures, elements, and connections have been presented herein. However, it is to be understood that the specific details presented need not be utilized to practice embodiments of the present disclosure. It is also to be understood that other embodiments may be utilized and that logical, architectural, programmatic, mechanical, electrical and other changes may be made without departing from general scope of the disclosure. The followingDocket No.: 1022.550W01 detailed description is, therefore, not to be taken in a limiting sense, and the scope of the present disclosure is defined by the appended claims and equivalents thereof.

[0503] References within the specification to “one embodiment,” “an embodiment,” “embodiments”, or “one or more embodiments” are intended to indicate that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present disclosure. The appearance of such phrases in various places within the specification are not necessarily all referring to the same embodiment, nor are separate or alternative embodiments mutually exclusive of other embodiments. Further, various features are described which may be exhibited by some embodiments and not by others. Similarly, various requirements are described which may be requirements for some embodiments but not other embodiments.

[0504] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure. As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms “comprises” and / or “comprising,” when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof.

[0505] The description of the present disclosure has been presented for purposes of illustration and description but is not intended to be exhaustive or limited to the disclosure in the form disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope of the disclosure. The described embodiments were chosen and described in order to best explain the principles of the disclosure and the practical application, and to enable others of ordinary skill in the art to understand the disclosure for various embodiments with various modifications as are suited to the particular use contemplated.

Claims

1. Docket No.: 1022.550W01CLAIMSWhat is claimed is:

1. A composition comprising citicoline and paraxanthine in a mass ratio of 4: 1 to 1 :4, wherein a unit dose comprises 50-500 mg of citicoline and 50-500 mg of paraxanthine, and wherein at least one of citicoline or paraxanthine is liposomally encapsulated with an average hydrodynamic diameter of 80-200 nm and a poly dispersity index (PDI) of less than 0.3 as measured by dynamic light scattering.

2. The composition of claim 1, wherein the mass ratio of citicoline to paraxanthine is about 1 : 1.

3. The composition of claim 2, wherein the unit dose comprises about 200-300 mg of citicoline and about 200-300 mg of paraxanthine.

4. The composition of any one of claims 1-3, wherein the liposomes have an encapsulation efficiency of at least 70% for the encapsulated active.

5. The composition of claim 1, wherein the liposomes comprise phosphatidylcholine and cholesterol at a mass ratio of 6: 1 to 2: 1.

6. The composition of claim 1, further comprising spray-dried liposomal microparticles having a volume-median particle size of 25-55 pm that, upon reconstitution in aqueous media, yield liposomes of 80-200 nm with PDI <0.3.

7. The composition of claim 1, wherein the composition is formulated as an oral disintegrating film comprising 30-55 wt% film-forming polymer, 5-20 wt% plasticizer, 15-40 wt% of the citicoline / paraxanthine active phase (independently based on the total film mass), 2-8 wt% residual moisture, and 0-10 wt% additional excipients.

8. The composition of claim 1, wherein the composition is formulated as a hard-shell capsule comprising the active phase and pharmaceutically acceptable excipients.

9. The composition of claim 1, wherein the composition is provided in unit doses configured to deliver a total daily intake of 200-900 mg citicoline and 200-900 mg paraxanthine.

10. A method of improving energy, mental focus, and physical performance in a human subject in need thereof, comprising buccally administering to the subject an effective amount of the composition of claim 1.Docket No.: 1022.550W0111 . The method of claim 13, wherein performance improvement is quantified by an improvement in psychomotor vigilance task (PVT) median reaction time relative to baseline.

12. A composition comprising, per unit dose, astaxanthin in an amount of 2-10 mg, L-citrulline in an amount of 200-400 mg, glutathione in an amount of 200-400 mg, luteolin in an amount of 20-60 mg, and palmitoylethanolamide in an amount of 200-600 mg.

13. The composition of claim 12, wherein the mass ratio of luteolin to palmitoylethanolamide is about 1 : 1.

14. The composition of claim 12, further comprising spray-dried liposomal microparticles that reconstitute to liposomes of 80-200 nm with PDI <0.3.

15. The composition of claim 12, wherein administration results in a synergistic reduction in one or more inflammatory biomarkers relative to administration of any individual active alone, as determined by a combination index (CI) of less than 1.

16. A method of alleviating pain and / or inflammation in a human subject in need thereof, comprising administering to the subject an effective amount of the composition of claim 12.

17. The method of claim 16, wherein the subject demonstrates a reduction in at least one biomarker selected from IL-6, TNF-a, CRP, and PGE2, or an improvement in a validated pain score relative to placebo.

18. An orodispersible film comprising: (a) citicoline and paraxanthine in a mass ratio of 4: 1 to 1:4, wherein a unit dose delivers 100-500 mg of each; (b) a film-forming polymer selected from pullulan, hydroxypropyl methylcellulose, or polyvinyl alcohol at 30-55 wt%; and (c) a plasticizer at 5-20 wt%; wherein the film has a total active ingredient mass of <500 mg and, when tested in 900 mL simulated saliva buffer at 50 rpm, releases >85% of citicoline and >85% of paraxanthine within 10 minutes.

Images