Compositions comprising urolithin compounds

Abstract

To provide compounds with beneficial effects in the enhancement of muscle function, and compositions comprising the compounds with high bioavailability.SOLUTION: The present invention provides a composition comprising urolithin represented by the following formula, controlled to a proper particle size. The composition also finds use in the treatment, prevention or treatment of diseases and conditions characterized by low muscle mass or poor muscle performance, and in the enhancement of muscle growth and / or muscle performance. It is also useful in maintaining muscle function.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to nutritional and pharmaceutical formulations of urolithins and medium chain triglycerides. [Background technology]

[0002] Urolithins have been shown to have a strong effect on improving several health disorders and to be highly biologically active in vitro and in vivo. Urolithins have been proposed as therapeutic agents for improving liver function and weight management in the treatment of various diseases, including diseases associated with insufficient mitochondrial activity, such as obesity, memory decline, reduced metabolic rate, metabolic syndrome, diabetes mellitus, cardiovascular disease, hyperlipidemia, neurodegenerative diseases, cognitive disorders, mood disorders, stress, anxiety disorders, fatty liver disease (e.g., NAFLD or NASH). Urolithins have been shown to have a particularly beneficial effect on enhancing muscle function.

[0003] Low muscle mass or poor muscle performance is a feature of many diseases and illnesses. Muscle-related pathological conditions include myopathy; neuromuscular diseases such as Duchenne muscular dystrophy; acute muscle loss (e.g., muscle contraction) and / or cachexia (e.g., associated with burns, bed rest, immobilization of limbs, or major chest, abdominal, cervical, and / or orthopedic surgery). Age-related muscle loss is a particularly prevalent condition. Cachexia resulting from prolonged immobilization or other diseases (e.g., cancer) is often characterized by poor muscle performance.

[0004] Good muscle performance is important for effective living in all stages of life, not only in healthy individuals but also in diseased individuals (especially the elderly). Also, improving muscle performance is of particular interest to athletes. For example, increasing muscle contraction strength, increasing muscle contraction amplitude, or decreasing muscle reaction time from stimulation to contraction are all beneficial for individuals, especially athletes.

[0005] In severe cases of muscle wasting, anabolic steroids such as methandrostenolone can be administered to the patient to aid in the treatment process, although such drugs are preferably avoided for long-term use as they can be associated with numerous side effects.

[0006] Urolithin compounds have properties that make them useful in the treatment and prevention of various diseases, including enhancing muscle function. However, urolithins exhibit an unfavorable pharmacokinetic profile in simple suspensions in saline, with a delayed second rise in blood levels some time after the initial peak, making such suspensions difficult to administer.

[0007] The occurrence of multiple peaks in blood fluids of orally administered compounds as well as two or more peaks in concentration over time can be attributed to several factors, including: (i) formulation (such as choice of excipients), (ii) the physiology of the gastrointestinal tract itself (such as pH and composition of bile), regulated by hormonal and dietary factors, (iii) biochemical differentiation in localized segments of the gastrointestinal tract that can result in windows for absorption and thus multiple peaks, and (iv) enterohepatic recirculation. When a bioactive compound is administered orally, it is preferable to present the plasma concentration of the compound as having a single-peak profile rather than multiple peaks. Formulations that allow a single peak of active compound following oral administration facilitate optimization of the administered dose and frequency of administration, as opposed to formulations that lead to multiple peaks in blood fluids. As a result, a formulation that produces a single peak is desirable. This formulation facilitates the establishment of a therapeutic dose window in which the compound can provide a health benefit in a mammal.

[0008] In many circumstances, not only are the pharmacokinetic properties of a simple saline suspension undesirable, but they also limit the bioavailability of the compound. Thus, a need exists for formulations of urolithins that have acceptable pharmacokinetic profiles and improved bioavailability. Summary of the Invention

[0009] The present invention relates to a) medium chain triglycerides; b) a compound of formula (I) or a salt thereof; A composition comprising:

[0010] [ka]

[0011] During the ceremony, A, B, C and D are each independently selected from H and OH; W, X and Y are each independently selected from H and OH; and The composition is provided wherein Z is selected from H and OH.

[0012] The compound of formula (I) belongs to the urolithin family. The compound of formula (I) may in particular be urolithin A. It has been found that urolithin A in a composition consisting of medium chain triglycerides and urolithin A has a surprisingly improved bioavailability and pharmacokinetic profile compared to urolithin A dissolved alone in a simple saline suspension. The composition of the present invention is therefore effective in improving and managing the overall health of healthy individuals, and in treating and preventing various diseases and conditions, particularly diseases characterized by insufficient mitochondrial activity. In particular, the composition has been found to be useful in treating and treating healthy individuals who would benefit from improved muscle function, including those with impaired physical performance, endurance, and muscle function. The composition has also been found to be useful in treating, preventing, or treating diseases and conditions characterized by low muscle mass or poor muscle performance, and for enhancing muscle growth and / or muscle performance, as well as for maintaining muscle function.

[0013] The present invention further provides compositions of the present invention for use in the treatment of various diseases, including diseases associated with insufficient mitochondrial activity, such as obesity, reduced metabolic rate, metabolic syndrome, diabetes mellitus, cardiovascular disease, hyperlipidemia, memory decline, neurodegenerative diseases, cognitive impairment, mood disorders, stress, anxiety disorders, fatty liver disease (e.g., NAFLD or NASH), and for the purpose of improving liver function and weight management. In particular, the present invention provides compositions for use in the treatment of muscle-related pathological conditions. The present invention also provides a method for treating muscle-related pathological conditions in a subject, comprising administering to the subject an effective amount of a composition of the present invention. The present invention provides compositions of the present invention for use in enhancing muscle performance. The present invention also provides a method for enhancing muscle performance by administering to a subject an effective amount of a composition of the present invention.

[0014] The present invention further comprises: 50 The size is within the range of 0.5 to 50 μm and D 90 The compound or salt thereof of formula (I) is provided, which has a size in the range of 5 to 100 μm. 90The size is within the range of 8.2 to 16.0 μm, and D 50 The size is within the range of 2.8 to 5.5 μm and D 10 Preferably, the size is in the range of 0.5 to 1.0 μm. Compounds of the invention having the above particle sizes have been found to have excellent dispersion and solubility properties and enhanced bioavailability. [Brief description of the drawings]

[0015] [Figure 1] Figure 1 shows the results of experiments in which rats were given formulations containing urolithin A and saline or various other ingredients (such as medium-chain triglycerides) and the blood levels of urolithin A were assessed. [Diagram 2] Figure 2 shows the results of an experiment in which a formulation containing urolithin A and medium-chain triglycerides was given to rats and humans and the blood concentrations of urolithin A were evaluated. [Diagram 3] Figure 3 shows the results of an experiment in which rats were given formulations containing urolithin A of various particle sizes and the blood concentrations of urolithin A were assessed. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] As described above, the present invention provides compositions comprising a medium chain triglyceride and a urolithin.

[0017] Typically the medium chain triglycerides will comprise at least 1% by weight of the composition of the invention, such as at least 5% by weight, such as at least 10% by weight, for example at least 15% by weight.Preferably the medium chain triglycerides will comprise 20% or more by weight of the composition, such as 25% or more by weight, for example 30% or more by weight. For example, the medium chain triglyceride may account for 1 to 40% by weight of the composition, 2 to 40% by weight of the composition, 5 to 40% by weight of the composition, 10 to 40% by weight of the composition, 1 to 99% by weight of the composition, 5 to 99% by weight of the composition, 10 to 99% by weight of the composition, 20 to 99% by weight of the composition, 5 to 90% by weight of the composition, 10 to 90% by weight of the composition, for example, 20 to 90% by weight of the composition, 20 to 80% by weight of the composition, for example, 30 to 80% by weight of the composition, for example, 30 to 70% by weight of the composition, for example, 30 to 60% by weight of the composition, for example, 30 to 50% by weight of the composition, for example, 30 to 40% by weight of the composition, for example, 30 to 35% by weight of the composition. For example, the medium chain triglycerides may comprise 40-70% by weight of the composition, such as 50-70% by weight of the composition, for example 55-65% by weight of the composition.

[0018] The weight ratio of the medium chain triglyceride component to urolithin is generally within the range of 0.01:1 to 100:1, such as 0.5:1 to 100:1, for example 0.5:1 to 50:1, such as 0.5:1 to 5:1, or for example 1:1 to 75:1, such as 1:1 to 50:1, for example 1:1 to 20:1, such as 1:1 to 10:1, for example 1:1 to 2.5:1, such as 1:1 to 2:1, for example 1:1 to 1.5:1. The weight ratio of the medium chain triglyceride component to urolithin may be in a ratio of 0.01:1 to 10:1, such as 0.1:1 to 10:1 or 0.01:1 to 5:1, for example 0.01:1 to 0.1:1. The compositions of the present invention generally have the consistency of a viscous liquid or paste and may be provided as a single dose supplement to the subject's regular diet (e.g., in the form of a bar, gel or softgel capsule, hard capsule, or diluted in a beverage) or, alternatively, as part or all of each meal.

[0019] Urolithin generally accounts for 0.1-80% by weight of the composition of the present invention, for example, 0.1-60% by weight, for example, 0.25-50% by weight. For example, urolithin may account for 0.5-50% by weight of the composition. When the composition is provided as a part or all of a meal, urolithin may account for, for example, 0.25-5% by weight of the composition, for example, 0.3-3% by weight of the composition. When the composition of the present invention is provided as a supplement for one serving of a normal meal of a subject, urolithin generally accounts for 20-80% by weight of the composition of the present invention, for example, 20-40% by weight of the composition, for example, 25-35% by weight. For example, urolithin may account for 26-34% by weight of the composition, for example, 28-33% by weight of the composition, for example, 29-32% by weight of the composition, for example, 29-31% by weight of the composition.

[0020] Medium Chain Triglycerides: Medium chain triglycerides have the formula CH 2 (OR 1 )-CH(OR 2 )-CH 2 (OR 3 ), wherein R 1 , R 2 and R 3 Generally, the formula is -C(=O)(CH 2 ) n CH 3where n is in the range of 4-10, e.g., 6-8. Medium chain fatty acids are fatty acids having an aliphatic tail of 6-12 carbon atoms. The aliphatic tail is largely saturated. Specific medium chain fatty acids include caproic acid (hexanoic acid, C6:0), caprylic acid (octanoic acid, C8:0), capric acid (decanoic acid, C10:0) and lauric acid (dodecanoic acid, C12:0). Small amounts of myristic acid (tetradecanoic acid, C14:0) may also be present. The most commonly used medium chain triglycerides generally comprise a mixture of caprylic and capric triglycerides and have a saturated fatty acid content of 95% or more. The medium chain triglyceride component in the compositions of the present invention may consist of a single homogenous medium chain triglyceride compound type; more typically, the medium chain triglyceride component in the compositions of the present invention is a mixture of two or more different medium chain triglyceride compounds.

[0021] The European Pharmacopoeia describes medium chain triglycerides as a fixed oil extracted from the hard dry fraction of the endosperm of Cocos nucifera L. (coconut palm) or the dried endosperm of Elaeis guineenis Jacq. (African oil palm). Both the European Pharmacopoeia and the USPNF have specifications for medium chain triglycerides that mandate the presence of certain fatty acids, such as 2.0% or less caproic acid (C6); 50.0-80.0% caprylic acid (C8), 20.0-50.0% capric acid (C10), 3.0% or less lauric acid (C12), and 1% or less myristic acid (C14).

[0022] In particular, the medium chain triglycerides used in the compositions of the present invention comprise a mixture of triglycerides in which the fatty acid chains are present in the following proportions: C6 5% or less, C8 50-70%, C10 30-50%, and C12 12% or less (e.g., C6 0.5% or less, C8 55-65%, C10 35-45%, and C12 1.5% or less).

[0023] The medium-chain triglycerides used in the compositions of the present invention can be derived from any known or otherwise suitable source. Medium-chain triglycerides can be extracted from natural sources or synthesized under appropriate conditions from glycerol and suitable fatty acids. Examples of commercially available sources for extracting medium-chain triglycerides (or medium-chain fatty acids that can be used to synthesize medium-chain triglycerides) include, but are not limited to, coconut oil and palm oil, and dairy fats, especially butter. A combination of sources or types of medium-chain triglycerides may also be used.

[0024] The medium chain triglycerides used in the compositions of the present invention are available commercially in liquid or solid formulations, as well as in simple or complex combinations with sugars, vitamins, essential fatty acids and minerals. Medium chain triglycerides are also available in the form of fats or margarines.

[0025] Urolithins: Urolithins are metabolic products produced by the action of the human and other mammalian gut microbiota on ellagitannins and ellagic acid, compounds commonly found in foods such as pomegranates, nuts, and berries. Ellagitannins, as such, are minimally absorbed in the intestine. Urolithins are a class of compounds, exemplary structures (I) of which are shown above. Table 1 below illustrates the structures of some of the most commonly available urolithins with reference to structure (I).

[0026] [Table 1]

[0027] Indeed, for commercial scale production, it would be advantageous if urolithins were synthesized, synthetic routes being described, for example, in WO 2014 / 004902.

[0028] Any urolithin of structure conforming to structure (I) can be used in the compositions of the invention. Particularly preferred compounds for use in the compositions of the invention are urolithins of natural origin. Thus, Z is preferably OH, and W, X and Y are preferably all H. When W, X and Y are all H, and A and B are both H, and C, D and Z are all OH, the compound is urolithin C. When W, X and Y are all H, and A, B and C are all H, and D and Z are both OH, the compound is urolithin A. The urolithin used in the formulations of the invention is preferably urolithin A, urolithin B, urolithin C or urolithin D. Most preferably, the urolithin used in the formulations of the invention is urolithin A.

[0029] [ka]

[0030] Urolithin A The urolithin used in the compositions of the invention is preferably micronized. Micronization allows for the urolithin to be dispersed or dissolved more rapidly. When micronized urolithin is used, the D 50 The size is preferably less than 100 μm, i.e., when urolithin is 50% by mass, the particle diameter size is preferably less than 100 μm. 50 More preferably, the size is less than 75 μm, such as less than 50 μm, such as less than 25 μm, such as less than 20 μm, such as less than 10 μm. 50 More preferably, the D of urolithin is within the range of 0.5 to 50 μm, for example, 0.5 to 20 μm, for example, 0.5 to 10 μm, for example, 1.0 to 10 μm, for example, 1.5 to 7.5 μm, for example, 2.8 to 5.5 μm. 90 The size is preferably less than 100 μm. 90More preferably, the size is less than 75 μm, such as less than 50 μm, such as less than 25 μm, such as less than 20 μm, such as less than 15 μm. 90 The D of urolithin is preferably within the range of 5 to 100 μm, for example, 5 to 50 μm, for example, 5 to 20 μm, for example, 7.5 to 15 μm, for example, 8.2 to 16.0 μm. 10 The D of urolithin is preferably in the range of 0.5 to 1.0 μm. 90 is in the range of 8.2 to 16.0 μm, and D 50 is in the range of 2.8 to 5.5 μm, and D 10 Preferably, the particle size is in the range of 0.5 to 1.0 μm. Micronization can be achieved by methods established in the art. For example, compression force milling, hammer milling, universal milling, pin milling, or jet milling (e.g., spiral jet milling or fluidized bed jet milling) can be used. Jet milling is particularly preferred.

[0031] Phosphatidylcholine The composition of the present invention can advantageously comprise one or more phospholipids.The phospholipid that is particularly preferred for use in the composition of the present invention is phosphatidylcholine.The benefits of phosphatidylcholine can be at least in part due to their amphiphilic nature.

[0032] Lecithin is particularly useful as a source of phospholipids (especially phosphatidylcholine) used in the present invention, and the composition of the present invention advantageously contains lecithin. The lecithin in the composition of the present invention (if present) generally constitutes at least 0.5% by weight of the composition of the present invention, and preferably constitutes at least 1% by weight of the composition of the present invention. Lecithin preferably constitutes 10% by weight or more of the composition based on the weight of the composition, for example 20% by weight or more, for example 30% by weight or more. For example, lecithin may constitute 0.5 to 80% by weight of the composition, for example 1 to 80% by weight of the composition, for example 20 to 80% by weight, for example 40 to 80% by weight, alternatively for example 0.5 to 75% by weight, for example 1 to 40% by weight of the composition, for example 30 to 40% by weight of the composition, for example 30 to 35% by weight of the composition, for example 30 to 75% by weight of the composition. Alternatively, lecithin may comprise 0.5-5% by weight of the composition, such as 1-5% by weight of the composition, such as 1-3% by weight of the composition, such as 0.5-2% by weight of the composition, such as 1-2% by weight of the composition. The weight ratio between lecithin (if present) and urolithin is generally within the range of 0.02:1-3:1, such as 0.03:1-1.2:1, such as 1:1-1.2:1, such as 1.1:1-1.2:1.

[0033] "Lecithin" refers to any group of fatty substances produced in animal and plant tissues, such as phosphoric acid, choline, fatty acids, glycerol, glycolipids, triglycerides, and phospholipids (phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol). In particular, commercial lecithin obtained from soybeans and sunflowers contains the phospholipids phosphatidylcholine, phosphatidylinositol, phosphatidylethanolamine, and phosphatidic acid. Lecithin may be obtained by chemical extraction from lecithin raw materials in non-polar solvents such as hexane, ethanol, acetone, petroleum ether, or benzene, or by mechanical extraction. In particular, lecithin may be obtained by extraction from raw materials including soybeans, chicken eggs, milk, rapeseed, cottonseed, and sunflower. Commercial lecithin used in edible preparations is readily available.

[0034] Commercially produced lecithin that can be used in the formulations of the present invention generally contains, as major components, 33-35% soybean oil, 20-21% inositol phosphate, 19-21% phosphatidylcholine, 8-20% phosphatidylethanolamine, 5-11% other phospholipids, 5% free carbohydrates, 2-5% sterols, and 1% water.

[0035] Commercially produced lecithins that can be used in the formulations of the invention may be enriched with phosphatidylcholine, e.g. the lecithin has a minimum of 5% by weight phosphatidylcholine, e.g. the lecithin has a minimum of 10% by weight phosphatidylcholine, e.g. the lecithin has a minimum of 15% by weight phosphatidylcholine, e.g. the lecithin has a minimum of 20% by weight phosphatidylcholine, e.g. the lecithin has a minimum of 25% by weight phosphatidylcholine, e.g. the lecithin has a minimum of 30% by weight phosphatidylcholine, e.g. the lecithin has a minimum of 32% by weight phosphatidylcholine, e.g. the lecithin has a minimum of 40% by weight phosphatidylcholine.

[0036] Lecithin can be modified by one or more of the following processes to tailor its properties: alcoholic extraction of specific phospholipids to produce lecithin containing altered ratios of different phospholipids; defatted by acetone extraction to produce powdered or granulated phospholipid blends; spray drying onto proteins as carriers; spray cooling with synthetic emulsifiers such as high melting mono- and diglycerides to produce flaky or powdered products; modification by enzymatic action, especially partial hydrolysis, to produce lecithin with pronounced emulsifying behavior (phospholipases, especially phospholipase A2, are commonly used); hydrolysis of fatty acid groups by acid and alkali; and acetylation and hydroxylation of fatty acid chains and amino groups.

[0037] Form of composition: The composition of the present invention may take any suitable physical form. The composition may be in the form of a solid (e.g., a bar), a semi-solid (e.g., a soft gel, a capsule (e.g., a hard capsule) or a dragee), or a liquid (including an emulsion). In many cases, the composition of the present invention is in the form of a viscous fluid or a paste. By selecting suitable medium-chain triglycerides and excipients, the physical form of the composition can be adjusted to suit the requirements of the target product. The composition of the present invention may be a pharmaceutical composition, or the composition of the present invention may be a nutritional composition.

[0038] Softgel compositions may be available in a capsule having a shell, which may be of a conventional type (e.g., a soft gelatin-based shell), or the composition of the present invention may be contained inside a hard capsule type of shell.

[0039] Some bars may be of any suitable type, and some may contain ingredients traditionally used in snack-style bar type formulations.

[0040] Similarly, the semi-solid form may contain excipients conventional in the art. The excipients may be, for example, those that provide the desired hardness, shelf life and flavor, so that the composition has an acceptable flavor, an attractive appearance, and sufficient storage stability. The semi-solid form may be in the form of a paste.

[0041] The liquid composition may be in the form of medicine, dietary supplement, or beverage, each for oral intake.The liquid formulation may be a solution, emulsion, slurry, or other semi-liquid.Excipients may be incorporated into the liquid composition to provide, for example, shelf life, visual appearance, flavor, and mouthfeel, so that the composition has acceptable flavor, attractive appearance, and sufficient storage stability.The beverage may need to be shaken at a certain dilution level before the subject drinks it, to keep the suspension of the active ingredient uniform.

[0042] Additional ingredients in the composition of the present invention: The compositions according to the invention may contain additional ingredients in addition to urolithins and medium chain triglycerides, which may be selected from compounds that provide health benefits, such as vitamins, minerals, polyunsaturated fatty acids, and other compounds.

[0043] Specifically, vitamins such as vitamin A, vitamin C, vitamin D, vitamin E, vitamin B12, and vitamin K2 may be mentioned. As used herein, "vitamin D" refers to any of the known forms of vitamin D, and specifically includes vitamin D2 (ergocalciferol), vitamin D3 (cholecalciferol), vitamin D precursors, metabolites, and other analogs, and combinations thereof, as well as various active and inactive forms of vitamin D. For example, vitamin D3 may be marketed in a non-hydroxylated, inactive form as cholecalciferol, or in a hydroxylated, active form as calcitriol.

[0044] Creatine is said to have beneficial effects in the treatment of muscle disorders and may be included in the compositions of the present invention. β-hydroxyl-β-methylbutyrate (HMB) is said to have beneficial effects in the treatment of muscle disorders and may be included in the compositions of the present invention.

[0045] Polyunsaturated fatty acids are fatty acids that contain two or more double bonds in the main chain. This category includes many important compounds (e.g., essential fatty acids such as omega-3 and omega-6 fatty acids). Preferred are long-chain polyunsaturated fatty acids, preferably those with at least 20 carbon atoms in the molecule. Such long-chain omega-3 fatty acids include cis-11,14,17-eicosatrienoic acid (ETE) C20:3, cis-8,11,14,17-eicosatetraenoic acid (ETA) C20:4, cis-5,8,11,14,17-eicosapentaenoic acid (EPA) C20:5, cis-7,10,13,16,19-docosapentaenoic acid (DPA, clupanodonic acid) C22:5, cis-4,7,10,13,16,19-docosahexaenoic acid (DHA) C22:6, cis-9,12,15,18,21-tetracosapentaenoic acid C24:5, and cis-6,9,12,15,18,21-tetracosahexaenoic acid (Nisinic acid). Long chain omega-6 fatty acids having at least 20 carbon atoms include cis-11,14-eicosadienoic acid C20:2, cis-8,11,14-eicosatrienoic acid (dihomogammalinolenic acid) (DGLA) C20:3, cis-5,8,11,14-eicosatetraenoic acid (arachidonic acid) (AA) C20:4, cis-13,16-docosadienoic acid C22:2, cis-7,10,13,16-docosatetraenoic acid (adrenic acid) C22:4, and cis-4,7,10,13,16-docosapentaenoic acid (osbond acid) C22:5. The composition according to the present invention preferably contains EPA, DHA, or a combination of EPA and DHA, for example, from 10 to 1,000 mg per dose; for example, from 25 to 250 mg per dose.

[0046] The pharmaceutical compositions of the present invention may contain additional pharma- ceutical active compounds.

[0047] In some exemplary embodiments, compositions of the invention may include, in addition to medium chain triglycerides and urolithins, one or more additional macronutrients, typically fats or carbohydrates, or fats and carbohydrates.

[0048] Examples of suitable fats or sources thereof for use in the compositions described herein include, but are not limited to, coconut oil; fractionated coconut oil; soybean oil; corn oil; olive oil; safflower oil; high oleic safflower oil; sunflower oil; high oleic sunflower oil; palm oil and palm kernel oil; palm olein; canola oil; marine oil; cottonseed oil; polyunsaturated fatty acids (e.g., docosahexaenoic acid (DHA), arachidonic acid (ARA), eicosapentaenoic acid (EPA); and combinations thereof.

[0049] Examples of suitable carbohydrates or sources thereof for use in the compositions described herein include, but are not limited to, maltodextrin, hydrolyzed or modified starch or corn starch, glucose polymers, corn syrup, corn syrup solids, carbohydrates derived from rice, glucose, fructose, lactose, high fructose corn syrup, tapioca dextrin, isomaltulose, sucromalt, maltitol powder, glycerin, fructooligosaccharides, soy fiber, corn fiber, guar gum, konjac flour, polydextrose, honey, sugar alcohols (e.g., maltitol, erythritol, sorbitol), and combinations thereof. Particularly preferred are maltodextrin, sucrose, and fructose.

[0050] The total levels or amounts of fats and carbohydrates as well as other ingredients will vary depending on the nutritional requirements of the intended user.

[0051] Additional ingredients in the compositions of the present invention may be compounds that do not provide a health benefit to the subject, but instead improve the composition in some other way, for example with respect to flavor, texture or storage stability as described above. Thus, the compositions of the present invention may further comprise one or more compounds selected from emulsifiers, colorants, preservatives, gums, setting agents, thickeners, sweeteners and flavorings.

[0052] Suitable emulsifiers, stabilizers, colorants, preservatives, gums, stiffening agents and thickeners are well known in the art of making emulsions and other semi-liquids. Emulsifiers may include one or more of phosphatidylcholine, lecithin, polysorbates (e.g., polysorbate 60 or polysorbate 80 (Tween 60 and Tween 80) and glyceryl monostearate (GMS). Glyceryl monostearate is also known as glyceryl monostearate. Metal chelating or sequestrant agents (e.g., the sodium calcium salt of ethylenediaminetetraacetic acid (EDTA)) can also be used. Other ingredients that can be incorporated into the formulations of the present invention include polyethylene glycol, silicon dioxide, vegetable shortening and beeswax.

[0053] Stabilizers may be used in the compositions of the present invention. Many of the compositions of the present invention are stable suspensions that do not require the addition of stabilizers, a stable suspension being one that does not undergo phase separation over time. Some compositions of the present invention may be improved in stability by the inclusion of added stabilizers. Suitable stabilizers for use in the compositions of the present invention include glyceryl monostearate (GMS), silicon dioxide, and vegetable shortening. An exemplary stabilizer is GMS, and the compositions of the present invention preferably contain GMS. The properties of GMS also make it suitable as a solvent for dissolving phospholipids (such as those found in lecithin). GMS exists in two polymorphic forms. The α form is dispersible and foamy, and is useful as an emulsifier or preservative. The β form is suitable for wax substrates. The α form is converted to the β form when heated to 50°C.

[0054] GMS is classified into two distinct grades: 40-55 percent monoglyceride and 90 percent monoglyceride. The 40-55 percent monoglyceride, as specified by the European Pharmacopoeia, describes GMS as a mixture of monoacylglycerols, with monostearoylglycerol as the main component and some diglycerol and triglycerol. In particular, the 40-55 grade contains 40-55% monoacylglycerol, 30-45% diacylglycerol, and 5-15% triacylglycerol. The 99 percent grade is said to have a monoglyceride content of 90% or more. The monoglycerides in commercial GMS products are a mixture of glyceryl monostearate and glyceryl monopalmitate (in variable proportions). The European Pharmacopoeia further classifies glyceryl monostearate 40-55 into three types according to the ratio of stearic esters in the mixture. Type 1 is one in which the content of stearic acid is 40.0-60.0% and the sum of the contents of palmitic acid palmitic acid and stearic acid is not more than 90%. Type 2 is one in which the content of stearic acid is 60.0-80.0% and the sum of the contents of palmitic acid palmitic acid and stearic acid is not more than 90%. Type 3 is one in which the content of stearic acid is 90.0-99.0% and the sum of the contents of palmitic acid palmitic acid and stearic acid is not more than 96%. Any form of GMS can be used in the composition of the present invention.

[0055] The composition of the present invention is considered to be particularly beneficial in flavoring.Fruit flavor can be provided by encapsulating fruit sauce or puree in liquid or semi-liquid composition.Typical flavorings include strawberry, raspberry, blueberry, apricot, pomegranate, peach, pineapple, lemon, orange and apple.Generally, fruit flavorings often include fruit extract, fruit jam or fruit puree in any combination with sweetener, starch, stabilizer, natural and / or artificial flavor, colorant, preservative, water and citric acid or other suitable acid for adjusting pH.

[0056] dosage The effective intake amount of the composition varies depending on the mode of administration, age, weight, and general health of the subject. Factors such as the disease state, age, and body mass of the subject may be important, and the dosage regimen may be adjusted to obtain the optimal response.

[0057] The daily intake of a urolithin (e.g., urolithin A) component is typically in the range of 10 mg to 5 g / day, such as 20 mg to 2500 mg / day, such as 50 mg to 1500 mg / day, such as 100 mg to 1500 mg / day, such as 150 mg to 1500 mg / day, such as 200 mg to 1500 mg / day, such as 250 mg to 1500 mg / day, such as 50 mg to 1000 mg / day, such as 250 mg to 1000 mg / day. In one embodiment, the composition is administered in an amount to provide a dosage of urolithin in the range of about 0.2 mg / kg / day to greater than about 100 mg / kg / day. For example, the dosage of urolithin can be 0.2-100, 0.2-50, 0.2-40, 0.2-25, 0.2-10, 0.2-7.5, 0.2-5, 0.25-100, 0.25-25, 0.25-25, 0.25-10, 0.25-7.5, 0.25-5, 0.5-50, 0.5-40, 0.5-30, 0.5-25, 0.5-20, 0.5-15, 0.5-10, It can be 0.5-7.5, 0.5-5, 0.75-50, 0.75-25, 0.75-20, 0.75-15, 0.75-10, 0.75-7.5, 0.75-5, 1.0-50, 1-40, 1-25, 1-20, 1-15, 1-10, 1-7.5, 1-5, 2-50, 2-25, 2-20, 2-15, 2-10, 2-7.5, or 2-5 mg / kg / day.

[0058] A single dose of the composition of the present invention preferably contains 10 mg to 5 g of urolithin, such as 20 mg to 2500 mg, such as 50 mg to 1500 mg, such as 250 mg to 1500 mg, such as 50 mg to 1000 mg, such as 100 mg to 1000 mg, such as 250 mg to 1000 mg. A single dose may be in the form of a snack bar. A snack bar weighing 25 to 150 g (e.g., 40 to 100 g) may contain the required amount of urolithin. A single dose of the composition may alternatively be in the form of a beverage. For example, it may be provided in a container (e.g., a pouch) of a suitable volume corresponding to a single dose (e.g., 100 to 300 ml). A beverage of 25 ml to 500 ml (e.g., 50 ml to 300 ml) may contain the required amount of urolithin. Beverages providing compositions of the invention may contain urolithins in concentrations of 0.1-50 mg / ml, 0.25-25 mg / ml, e.g., 0.5-10 mg / ml, e.g., 1-5 mg / ml. The dosage may alternatively be in the form of a semi-solid (e.g., softgel or paste) in one or more doses. A single softgel capsule may contain a single dose of urolithins, e.g., 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg or 500 mg, e.g., 250 mg.

[0059] The ratio range of the components of the present invention is as described above. The composition of the present invention may contain 10mg-15g of medium-chain triglycerides and 10-5000mg of urolithin, for example, 20-7500mg of medium-chain triglycerides and 20-2500mg of urolithin, for example, 25mg-2500mg of medium-chain triglycerides and 50-1500mg of urolithin, for example, 50mg-4500mg of medium-chain triglycerides and 50-1500mg of urolithin, for example, 250-4500mg of medium-chain triglycerides and 250-1500mg of urolithin, for example, 50-3000mg of medium-chain triglycerides and 50-1000mg of urolithin, for example, 250-3000mg of medium-chain triglycerides and 250-1000mg of urolithin. It is preferable that the composition further contains lecithin. The composition also preferably further contains an additional stabilizer, such as glyceryl monostearate.

[0060] A typical composition is shown in Table 1.

[0061] [Table 2]

[0062] The composition of the present invention contains urolithin and medium-chain triglyceride. The composition of the present invention may contain, for example, 20-85% by weight of medium-chain triglyceride and 15-70% by weight of urolithin, for example, 40-80% by weight of medium-chain triglyceride and 20-60% by weight of urolithin, for example, 50-70% by weight of medium-chain triglyceride and 30-50% by weight of urolithin, for example, 60-75% by weight of medium-chain triglyceride and 25-40% by weight of urolithin.

[0063] The composition of the present invention preferably contains urolithin, medium-chain triglyceride, and an emulsifier (e.g., phosphatidylcholine such as lecithin). For example, the composition of the present invention may contain 10-80% by weight of medium-chain triglyceride, 5-70% by weight of urolithin, and 0.5-65% by weight of lecithin. The composition of the present invention may contain 20-70% by weight of medium-chain triglyceride, 15-70% by weight of urolithin, and 0.5-50% by weight of lecithin, for example, 25-50% by weight of medium-chain triglyceride, 20-50% by weight of urolithin, and 20-50% by weight of lecithin, for example, 30-40% by weight of medium-chain triglyceride, 25-35% by weight of urolithin, and 30-40% by weight of lecithin. Alternatively, a composition of the invention comprising a urolithin, a medium chain triglyceride, and a lecithin may contain, for example, 60-75% by weight of medium chain triglyceride, 25-40% by weight of urolithin, and 0.5-5% by weight of lecithin.

[0064] A more preferred composition of the present invention may contain urolithin, medium-chain triglyceride, an emulsifier such as lecithin, and a stabilizer such as GMS. For example, the composition of the present invention may contain 25-75% by weight of medium-chain triglyceride, 20-50% by weight of urolithin, 0.5-50% by weight of lecithin, and 0.5-5% by weight of GMS, for example, 30-40% by weight of medium-chain triglyceride, 25-35% by weight of urolithin, 30-40% by weight of lecithin, and 0.5-3% by weight of GMS. Alternatively, a composition of the present invention containing urolithin, medium-chain triglyceride, lecithin, and GMS may contain, for example, 60-75% by weight of medium-chain triglyceride, 25-40% by weight of urolithin, 0.5-5% by weight of lecithin, and 0.5-3% by weight of GMS.

[0065] Further compositions of the invention may contain urolithin, medium chain triglycerides, emulsifiers such as lecithin and / or Tween (polysorbate), and stabilizers such as GMS. For example, the compositions of the invention may contain 25-75% by weight of medium chain triglycerides, 20-50% by weight of urolithin, 0.5-50% by weight of lecithin, 0.5-5% by weight of GMS, and 1-10% by weight of Tween 60, for example, 60-75% by weight of medium chain triglycerides, 25-40% by weight of urolithin, 0.5-5% by weight of lecithin, 0.5-3% by weight of GMS, and 1-5% by weight of Tween 60.

[0066] Treatment: The composition of the present invention may be administered as a single therapeutic agent or, more generally, as a series of therapeutic agents. In one embodiment, the subject takes a dose before or after exercise. For subjects who are unable to exercise, the dose of the composition may be administered, for example, once, twice or three times a day, or twice, three times, four times, five times or six times a week. In other embodiments, the subject may take the present invention regardless of their ability or need to exercise. It will also be understood that the effective dosage of the compound may increase or decrease over the course of a particular treatment.

[0067] Medicinal and non-medical treatments: The composition of the present invention may be suitable for use as a pharmaceutical. The composition may be used as a dietary supplement, functional food, or medical food. Thus, the composition of the present invention is useful for treating various diseases, as well as health disorders that are not considered to be diseases. In particular, diseased and non-disease health disorders may be characterized by a lack of mitochondrial activity. The composition has been found to be useful for treating both disease and pathology, and also for managing normal physiological functions in healthy individuals with diseases characterized by poor physical performance, impaired endurance and muscle function. The composition of the present invention may improve physical performance in disease sufferers, including young and elderly individuals. The composition of the present invention may improve physical performance, such as short-term or long-term performance, in healthy individuals, including athletes, sedentary individuals, sedentary individuals, and elderly individuals. This improvement in performance can be measured in terms of the time spent walking or running a certain distance (e.g., improved performance during a 6-minute walk test (MWT), reduced time to run a certain distance, improved International Physical Activity Questionnaire IPAQ score, increased number of chair rises in a certain time, or by another test designed to measure physical performance.

[0068] The compositions of the present invention further provide improved endurance performance. Endurance performance is generally defined as strength <80% VO 2 It refers to the time to fatigue when exercising at a constant workload at max. The compositions of the present invention can improve endurance capacity in diseased individuals, including young and elderly. The compositions of the present invention can improve endurance capacity in healthy individuals, including athletes, sedentary individuals, sedentary individuals, and elderly individuals. The present invention provides a method for delaying the time to fatigue while performing a particular activity (e.g., fitness training, walking, running, swimming, or cycling). This improvement in endurance capacity can be assessed by objective measures (e.g., speed, oxygen consumption, or heart rate) or can be a self-reported measure (e.g., using a validated questionnaire).

[0069] The present invention further provides a composition for improving, maintaining or reducing the impairment of muscle function. The composition of the present invention can improve, maintain or reduce the impairment of muscle function in disease sufferers, including young and elderly people. The composition of the present invention can improve, maintain or reduce the impairment of muscle function in healthy people, including athletes, sedentary people, sedentary people and elderly people. For example, the composition of the present invention can increase muscle strength, as evidenced by, for example, increased ability to lift heavy objects or improved performance of physical activities such as exercise, such as increased hand grip strength. The composition of the present invention can also improve muscle structure, for example, by increasing or maintaining muscle mass in normal muscle function, reduced muscle function or impaired muscle function conditions.

[0070] The present invention further provides compositions that improve a person's perceived physical performance or endurance capacity, as determined using self-report questionnaires, for example, by reducing perceived exertion or effort during exercise or activity.

[0071] The present invention further provides compositions of the present invention for use in the treatment of various diseases, including diseases associated with insufficient mitochondrial activity, such as obesity, reduced metabolic rate, metabolic syndrome, diabetes mellitus, cardiovascular disease, hyperlipidemia, memory loss, neurodegenerative diseases, cognitive impairment, mood disorders, stress, anxiety disorders, fatty liver disease (e.g., NAFLD and NASH), for the purpose of improving liver function and weight control. In particular, the compositions of the present invention have been found to be useful in the treatment of muscle-related pathological conditions. Thus, the present invention provides compositions of the present invention useful for treating muscle-related pathological conditions. The present invention also provides a method of treating muscle-related pathological conditions in a subject, comprising administering to the subject an effective amount of the composition of the present invention. Muscle-related diseases include both diseases that affect normally healthy people and diseases that affect people with pathological conditions. Such muscle conditions found in healthy or diseased individuals include musculoskeletal diseases or disorders; cachexia; muscle wasting; age-related muscle decline; pre-weakness; frailty; myopathy; neuromuscular diseases such as Duchenne muscular dystrophy and other dystrophies; age-related sarcopenia; acute sarcopenia; muscle contraction and / or cachexia (e.g., muscle contraction and / or cachexia associated with burns, bed rest, immobilization of limbs, or major surgery including thoracic, abdominal and / or orthopedic surgery); and muscle degenerative diseases.

[0072] Examples of age-related conditions that can be treated with the compositions of the present invention include sarcopenia and muscle wasting.

[0073] Myopathy may also result from, for example, Duchenne muscular dystrophy syndrome. It has been reported in WO 2014 / 111580 that the mean diameter of myotubes in vitro was increased by Urolithin B (but not Urolithin A). No effect was observed with the use of Urolithin A.

[0074] Non-pharmaceutical treatments: The composition of the present invention is useful for enhancing muscle performance. Therefore, the present invention provides the composition of the present invention, which is used for the purpose of enhancing muscle performance. The present invention also provides a method for enhancing muscle performance by administering an effective amount of the composition of the present invention to a subject. The administration can be self-administration. The enhancement of muscle performance can be one or more of the following: improvement of muscle function, muscle strength, muscle endurance, and muscle recovery.

[0075] Thus, the compositions of the present invention can be used in methods of improving physical endurance (e.g., the ability to perform physical tasks such as exercise, physical labor, sporting activities), preventing or delaying physical fatigue, enhancing work capacity and endurance, and enhancing cardiac and cardiovascular function.

[0076] Improving muscle function may be particularly beneficial in elderly subjects whose muscle function has been weakened as a result of age-related diseases.For example, subjects who can benefit from improving muscle function may experience muscle function weakening, which may lead to pre-frailty and frailty later.Such subjects do not necessarily experience muscle wasting in addition to muscle function deterioration.Some subjects, such as those suffering from sarcopenia, experience both muscle wasting and muscle function deterioration.The composition of the present invention may be used to enhance muscle performance, which is achieved by administering the composition of the present invention to subjects who are frail or pre-frail.

[0077] Muscle performance can be the ability of an athlete to use muscles when participating in sports activities, i.e., athletic ability. Enhancement of athletic ability, strength, speed and endurance is measured by increasing muscle contraction strength, increasing muscle contraction amplitude, or shortening muscle reaction time from stimulus to contraction. An athlete refers to a person who participates in athletics at any level, such as a bodybuilder, a cyclist, or a long-distance runner, in an attempt to achieve improved levels of strength, speed or endurance in performance. Enhancement of athletic ability is manifested by the ability to overcome muscle fatigue and the ability to sustain activity for a longer period of time to enhance training effects. EXAMPLES

[0078] The present invention is illustrated by the following examples.

[0079] compound Urolithin A was prepared as follows. Urolithin A (4) was prepared in two steps starting from 2-bromo-5-methoxybenzoic acid 1 and resorcinol 2. The pure compound was obtained as a pale yellow powder.

[0080] [ka]

[0081] Step 1: A mixture of 2-bromo-5-methoxybenzoic acid 1 (27.6 g; 119 mmol; 1.0 equiv.), resorcinol 2 (26.3 g; 239 mmol; 2.0 equiv.), and sodium hydroxide (10.5 g; 263 mmol; 2.2 equiv.) in water (120 mL) was heated under reflux for 1 h. Then, a 5% aqueous solution of copper sulfate (3.88 g of CuSO 4 5H 2 A solution of 2,4-dichlorophenyl ether (O; 15.5 mmol; 0.1 equiv.) in 50 mL of water was added and the mixture was refluxed for an additional 30 min. The mixture was cooled to room temperature and the solid was filtered through a Büchner funnel. The residue was washed with cold water to give a light red solid, which was triturated in hot MeOH. The suspension was allowed to stand overnight at 4° C. and the resulting precipitate was filtered and washed with cold MeOH to give the title compound 3 as a light brown solid.

[0082] Step 2: A suspension of 3 (10.0 g; 41 mmol; 1.0 equiv.) in dry dichloromethane (100 mL) was added to a 1 M solution of boron tribromide in dry dichloromethane (11.93 mL of pure BBr 3A solution of 110 mL of anhydrous dichloromethane (124 mmol; 3.0 equiv.) was added dropwise at 0° C. The mixture was left at 0° C. for 1 h and then warmed to room temperature. The solution was stirred at that temperature for 17 h. Then, sufficient ice was added to the mixture. The yellow precipitate was filtered and washed with cold water to give a yellow solid. This was heated to reflux in acetic acid for 3 h. The hot solution was quickly filtered and the precipitate was washed with acetic acid followed by diethyl ether to give the title compound 4 as a yellow solid. 1 H and 13 C NMR was consistent with the structure of 4.

[0083] Example 1: Bioavailability Study of Urolithin A Formulated with or without Medium Chain Triglycerides Male Sprague-Dawley rats were fasted overnight and then orally gavaged with a saline suspension of Urolithin A without further excipients or with Urolithin Formulation A with various further excipients at a dose corresponding to 60 mg / kg / day. The Urolithins used in the formulations had a particle size distribution D 90 is 9μm~15μm, and D 50 The actual particle size was 2μm to 9μm. 90 11.5, D 50 is 3.9 and D 10 The components (wt%) of the formulation used are shown in Table 2 below.

[0084] [Table 3]

[0085] Medium chain triglycerides were obtained from Cremer Oleo GmbH & Co KG under the product name CremerCOOR MCT 60 / 40 EP, containing 0.5% or less C6, 55-65% C8, 35-45% C10, and 1.5% or less C12.

[0086] Lecithin was obtained from Cargill, Inc. under the product name Epikuron® 135 FIP containing a minimum of 32% phosphatidylcholine.

[0087] Glyceryl monostearate was obtained from Cremer Oleo GmbH & Co KG under the product name IMWITOR® 900 (F) P, containing 40.0-50.0% monoacylglycerol, 30.0-45.0% diacylglycerol, and 5.0-15.0% triacylglycerol.

[0088] Blood was collected from the rats via jugular vein cannulation at different time points to quantify Urolithin A in plasma and determine the pharmacokinetic profile in each of the different formulations. Each formulation was replicated in a total of six rats. Figure 1 shows the resulting pharmacokinetic profile for each formulation used. The collected data is summarized in Table 3 below.

[0089] [Table 4]

[0090] A suspension of urolithin A in saline showed a double-peak curve and a T max The T value was significantly delayed and the peak plasma concentration was reduced at 4 hours. In contrast, each of the vehicle-containing formulations 65-68 showed a significant reduction in the T value at 4 hours. max The single-peak pharmacokinetic profile of Formulations 65-68 is much more preferable for oral administration than the double peak exhibited by the saline suspension, as it facilitates optimization of dosing and dosing frequency.

[0091] In addition, as shown in Table 3 and Figure 1, when Urolithin A was formulated with medium-chain triglycerides (formulations 65 and 66), maxAs shown by the increased C and AUC values, the bioavailability is enhanced over the formulations that do not contain medium chain triglycerides (formulations 67 and 68). Formulation 66, which contains a combination of both medium chain triglycerides and lecithin, has a C max and AUC are significantly higher. This formulation has a higher bioavailability of Urolithin A than the formulation containing only lecithin and no medium-chain triglycerides (formulation 67). The addition of Tween 60 to the lecithin formulation (formulation 68) does not improve bioavailability. Formulation 65 differs significantly from formulation 68, which uses lecithin, in that it uses medium-chain triglycerides instead of lecithin. max The bioavailability (ng / ml) of formulation 65 using medium chain triglycerides increased from 1.606 for formulation 68 to 3.177 for formulation 65 using medium chain triglycerides, an increase of approximately 98%. Additionally, the AUC of formulation 65 was 28.77 compared to 15.7 for formulation 68. This demonstrates an 83% increase in bioavailability when medium chain triglycerides are substituted for lecithin.

[0092] Thus, the pharmacokinetic profiles of both formulations 65 and 66 according to the invention, which yield only a single peak in blood concentrations, are advantageous compared to unformulated urolithin dissolved in saline alone and demonstrate enhanced bioavailability, making them useful for oral administration of urolithins.

[0093] Example 2: Comparison of the pharmacokinetic profiles of Urolithin A in formulation 66 in both rats and humans The pharmacokinetic profile of Urolithin A in formulation 66 in humans was compared to that observed in rats. An equivalent dose of Urolithin A, quantified by the rat to human surface area ratio, was delivered in humans. A pharmacokinetic study was conducted in rats using formulation 66 at a dose of 60 mg / kg / d. Following FDA guidance on dose conversion based on body surface area, this dose was divided by a conversion factor of 6.2 to calculate the human equivalent dose. The resulting human equivalent dose (for humans) was 9.68 mg / kg / d. Assuming an average adult weight of 60-70 kg, the daily dose of Urolithin A would be 580-680 mg. Humans were administered a softgel delivering a similar equivalent dose of 500 mg / day of Urolithin A per day. In both cases, the Urolithin A used in the formulations had a particle size distribution D 90 = 8μm~20μm, D 50 = 2μm~8μm, and D 10 =0.5μm~2μm.

[0094] The pharmacokinetic profile of formulation 66 was determined in male Sprague-Dawley rats administered Urolithin A in formulation 66 by oral gavage at a dose corresponding to 60 mg / kg / day after an overnight fast. The components (wt%) of the formulation used are shown in Table 4 below.

[0095] [Table 5]

[0096] Medium chain triglycerides were obtained from Cremer Oleo GmbH & Co KG under the product name CremerCOOR MCT 60 / 40 EP, containing 0.5% or less C6, 55-65% C8, 35-45% C10, and 1.5% or less C12. Lecithin was obtained from Cargill, Inc. under the product name Epikuron® 135 FIP, containing a minimum of 32% phosphatidylcholine.

[0097] Glyceryl monostearate was obtained from Cremer Oleo GmbH & Co KG under the product name IMWITOR® 900 (F) P, containing 40.0-50.0% monoacylglycerol, 30.0-45.0% diacylglycerol, and 5.0-15.0% triacylglycerol.

[0098] At different time points, blood was collected from the rats via jugular vein cannulation to quantify Urolithin A in plasma and determine its pharmacokinetic profile. The formulation study was repeated in a total of six rats. The resulting pharmacokinetic profile was expressed as the relative C max Normalized to =1.

[0099] To compare the pharmacokinetic profile observed in rats at a dose of 60 mg / kg / d with that in humans, softgel capsules, each containing 250 mg of Urolithin A in formulation 66, were prepared by standard methods.

[0100] To determine whether the pharmacokinetic profile of Urolithin A delivered by softgels containing Formulation 66 was similar to that observed in rats, six healthy subjects (three adult males and three females) were administered 500 mg of Urolithin A delivered in two softgels. Subjects were fasted overnight and administered two softgels at time 0 (T0h). Each of these softgels contained 250 mg of Urolithin A in Formulation 66 and water.

[0101] [Table 6]

[0102] Blood was sampled at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24 and 36 hours. At each time point, 6 mL of blood sample was introduced into a K2-EDTA coated tube. The blood sample was inverted to thoroughly mix with the anticoagulant. Within 30 minutes after blood was collected, each blood sample was centrifuged at 1500g for 10 minutes at 4°C, and the top layer of human plasma was transferred to a pre-labeled polypropylene tube within 30 minutes after centrifugation. At each time point, the concentration of Urolithin A in the plasma samples was quantified and its pharmacokinetic profile was determined. Figure 2 shows the resulting pharmacokinetic profile for Formulation 66 in both rat and human samples. To compare these profiles, the calculated maximum blood concentration (i.e., C max ) to a value of 1.

[0103] As seen in Figure 2, Urolithin A delivered to humans via softgel exhibited a similar pharmacokinetic profile as observed in rats, with a sharp single peak. max was 4 h in rodents and 6 h in humans. This shift in the curves is likely due to differences in the administration of Formulation 66 (by simple gavage in rodents and via softgel in humans). The inventors also observed sustained blood levels of Urolithin A in humans, which was not predicted from the rodent data and further highlights the utility of medium-chain triglycerides for oral delivery of Urolithin A in humans.

[0104] This indicates that medium-chain triglyceride-containing formulation 66 is useful for delivery of Urolithin A in humans and other mammals. These results demonstrate that Urolithin A, when formulated in MCT-containing formulation 66, exhibits an attractive bioavailability profile in both humans and rats, as well as a favorable pharmacokinetic profile, making it useful for oral administration of urolithins.

[0105] Example 3: Effect of particle size on the bioavailability of Urolithin A The particle size of Urolithin A was reduced using an MC50 Spiral Jetmill with filtered nitrogen at a controlled feed rate of 240 g / hr, venturi pressure of 12 bar, and mill pressure of 12 bar. The various particle size distributions of Urolithin A were quantified using a Malvern Particle Size Analyzer (Malvern Instruments, UK). Three samples were thoroughly evaluated. The particle size distribution of Urolithin A sample #1 was D 10 1.03μm, D 50 is 53.4μm, and D 90 The particle size of Urolithin A sample #2 was D 10 0.272μm, D 50 is 2.17μm, and D 90 The particle size of Urolithin A sample #3 was D 10 0.597μm, D 50 is 5.67μm, and D 90 was 40.1 μm.

[0106] [Table 7]

[0107] To demonstrate the effect of a specific particle size distribution on bioavailability, male Sprague-Dawley rats were fasted overnight and then administered by oral gavage either Urolithin A sample #1, sample #2, or sample #3 suspended in a mixture of 15% DMSO and 85% of an aqueous solution of 0.5% methylcellulose and 0.25% Tween 80 at a dose corresponding to 25 mg / kg / day.

[0108] [Table 8]

[0109] The gavage solution was prepared by diluting 35 mg of Urolithin A powder with 7 ml of 15% DMSO, 0.5% methylcellulose / 0.25% Tween 80 in water to give a fine suspension of 5 mg / ml. DMSO was from BDH, methylcellulose was from Sigma, and Tween 80 was from Sigma-Aldrich.

[0110] At different time points, blood was collected from the rats via jugular vein cannulation to quantify Urolithin A in plasma and determine the pharmacokinetic profiles of Sample #1, Sample #2 and Sample #3 after oral gavage. The study was repeated on three rats per sample. Figure 3 shows the resulting pharmacokinetic profiles of Urolithin Sample #1 and Sample #2. The collected data are summarized in Table 8 below.

[0111] [Table 9]

[0112] Urolithin A is a particle size D 90 When the particle size was reduced to less than 50 μm, an increase in bioavailability was observed. In sample #2, the C max There was a 116% relative increase (2.16-fold increase) in AUC and a 28% increase in AUC in sample #1. There was a 26% relative increase in AUC in sample #2.

[0113] These results are consistent with the particle size D of the Urolithin A formulation. 90 If the particle size is less than 50 μm, the particle size D 90 The results demonstrate that the particle size D of Urolithin A formulations consistently exhibits higher bioavailability than Urolithin A formulations with particle sizes >300 μm. 90 It is particularly advantageous if the diameter is less than 20 μm, which allows a significant increase in the peak blood concentration of urolithin A, max was observed to be more than two-fold higher.

[0114] Preferred embodiments of the present invention will be described below in detail. EMBODIMENT 1 a) medium chain triglycerides; b) a compound of formula (I) or a salt thereof A composition comprising: [ka] wherein A, B, C and D are each independently selected from H and OH; W, X and Y are each independently selected from H and OH; and The composition wherein Z is selected from H and OH. EMBODIMENT 2 The composition of embodiment 1, wherein said compound of formula (I) is urolithin A. EMBODIMENT 3 The compound of formula (I) has a D 50 size, and D in the range of 5–100 μm 90 3. The composition of embodiment 1 or 2, having a size of EMBODIMENT 4 4. The composition of any one of embodiments 1 to 3, wherein the medium chain triglyceride comprises 20-99% by weight of the composition. EMBODIMENT 5 The composition of embodiment 4, wherein the medium chain triglycerides comprise 20-60% by weight of the composition. EMBODIMENT 6 5. The composition of embodiment 4, wherein the medium chain triglycerides comprise 30-80% by weight of the composition. EMBODIMENT 7 7. The composition of any of the preceding embodiments, wherein the weight ratio of the medium chain triglyceride component to the urolithin is in the range of 0.5:1 to 3:1. EMBODIMENT 8 8. The composition of any one of the preceding embodiments, wherein the medium chain triglycerides comprise caprylic acid and / or capric acid. EMBODIMENT 9 The composition of embodiment 8, wherein the medium chain triglycerides are derived from a source selected from coconut oil, palm oil and dairy fat. EMBODIMENT 10 10. The composition of any one of embodiments 1 to 9, further comprising an emulsifier. EMBODIMENT 11 The composition of embodiment 10, wherein the emulsifier is a source of phosphatidylcholine. EMBODIMENT 12 The composition of embodiment 11, wherein said source of phosphatidylcholine is lecithin. EMBODIMENT 13 13. The composition of embodiment 12, wherein the lecithin comprises 0.5-80% by weight of the composition. EMBODIMENT 14 14. The composition of embodiment 13, wherein the lecithin comprises 1-40% by weight of the composition. EMBODIMENT 15 15. The composition of any one of the preceding embodiments, further comprising a stabilizer. EMBODIMENT 16 The composition of embodiment 15, wherein the stabilizer is glyceryl monostearate. EMBODIMENT 17 The composition of any one of the preceding embodiments, wherein the composition is in the form of a solid (e.g., a bar), a semi-solid (e.g., a softgel, a capsule (e.g., a hard capsule) or a dragee), or a liquid (including an emulsion). EMBODIMENT 18 The composition of embodiment 17, wherein the composition is in the form of a softgel. EMBODIMENT 19 19. The composition according to any one of embodiments 1 to 18 for use as a medicine, a dietary supplement, a functional food or a medical food. EMBODIMENT 20 20. The composition of embodiment 19 for use as a medicament. EMBODIMENT 21 The composition according to embodiment 20, for use as a medicament for the treatment and / or prevention of a muscle-related pathological condition. EMBODIMENT 22 A method for treating a muscle-related pathological condition, comprising administering the composition according to any one of embodiments 1 to 18 to a subject in need thereof. EMBODIMENT 23 The composition for use according to embodiment 21 or the method according to embodiment 22, wherein the muscle-related pathological condition is selected from a musculoskeletal disease or disorder; muscle wasting; myopathy; neuromuscular diseases such as Duchenne muscular dystrophy and other dystrophies; sarcopenia (e.g. acute sarcopenia); muscle contractions and / or cachexia. EMBODIMENT 24 The composition for use or the method according to embodiment 23, wherein the muscle-related pathological condition is sarcopenia (e.g. acute sarcopenia). EMBODIMENT 25 A method for enhancing muscle performance comprising administering to a subject an effective amount of the composition of any one of embodiments 1-18. EMBODIMENT 26 The method of enhancing muscle performance of embodiment 25, wherein said subject suffers from age-related muscle function decline, age-related sarcopenia, age-related muscle wasting, physical fatigue, muscle fatigue, and / or is frail or pre-frail. EMBODIMENT 27 The method of embodiment 26, wherein the subject is frail or pre-frail. EMBODIMENT 28 A compound of formula (I) or a salt thereof, [ka] wherein A, B, C and D are each independently selected from H and OH; W, X and Y are each independently selected from H and OH; and Z is selected from H and OH; And the compound or salt is in the range of 0.5 to 50 μm. 50 and D within the range of 5 to 100 μm 90 or a salt thereof, wherein the compound of formula (I) has a size of EMBODIMENT 29 The compound has a diameter of 8.2 to 16.0 μm.90 size, D in the range of 2.8-5.5μm 50 and D in the range of 0.5 to 1.0 μm. 10 28. The compound or salt of embodiment 27, having a size:

Claims

1. A compound of formula (I) or a salt thereof, 【Chemistry 1】 (In the formula, A, B, C and D are each independently selected from H and OH; W, X and Y are each independently selected from H and OH; and Z is selected from H and OH. D in the range of 0.5 to 50 μm ５０ and D in the range of 5 to 100 μm. ９０ The compound or a salt thereof, wherein the compound has a size of

2. The above D ５０ The compound or salt thereof according to claim 1, wherein the size of said compound or salt is within the range of 0.5 to 50 μm.

3. The above D ５０ The compound or salt thereof according to claim 1, wherein the size of said compound or salt is within the range of 1.0 to 10 μm.

4. The above D ９０ The compound or salt thereof according to claim 1, wherein the size of said compound or salt is within the range of 5 to 50 μm.

5. The above D ９０ The compound or salt thereof according to claim 1, wherein the size of said compound or salt is within the range of 7.5 to 15 μm.

6. D in the range of 0.5 to 1.0 μm １０ 2. The compound of claim 1 or a salt thereof, having a size of:

7. D in the range of 8.2 to 16.0 μm ９０ size, D in the range of 2.8 to 5.5 μm ５０ and D in the range of 0.5 to 1.0 μm １０ 2. The compound of claim 1 or a salt thereof, having a size of:

8. The compound or salt thereof according to any one of claims 1 to 7, wherein the compound of formula (I) is selected from urolithin A, urolithin B, urolithin C and urolithin D.

9. The compound or salt thereof according to any one of claims 1 to 7, wherein the compound of formula (I) is urolithin A.

10. A composition comprising the compound according to any one of claims 1 to 9 or a salt thereof.

11. A composition according to any one of claims 1 to 10 for use as a medicine, a dietary supplement, a functional food or a medical food.

12. 20. The composition of claim 19 for use as a medicine.

13. 11. The composition of claim 10 for use in improving, maintaining or reducing impairment of muscle function.

14. 11. The composition of claim 10 for use in improving physical performance or endurance.

15. 11. The composition of claim 10 for use in enhancing muscle performance.

16. 16. The composition of claim 15, administered to a subject suffering from age-related decline in muscle function, age-related sarcopenia, age-related muscle wasting, physical fatigue, muscle fatigue, and / or who is frail or pre-frail.

17. The composition of claim 16, wherein the subject is frail or pre-frail.

18. The composition of claim 15, wherein the muscle performance is athletic performance.

19. 11. The composition of claim 10 for use as a medicament for the treatment and / or prevention of muscle-related pathological conditions.

20. 20. The composition for use according to claim 19, wherein the muscle-related pathological condition is selected from a musculoskeletal disease or disorder; muscle wasting; myopathy; neuromuscular diseases such as Duchenne muscular dystrophy and other dystrophies; sarcopenia (e.g. acute sarcopenia); muscle contractions and / or cachexia.

Images