Compositions comprising urolithin compounds

Abstract

The present invention provides compositions comprising medium-chain triglycerides and urolithins. The present invention also provides uses and methods related to or using the compositions, such as medicaments, dietary supplements, functional foods, and for treating and / or preventing muscle-related pathological conditions.

Description

Technical Field

[0001] This invention relates to nutritional and pharmaceutical preparations of urolithiasis and medium-chain triglycerides. Background Technology

[0002] Urolithin has potent effects on improving a variety of health conditions and has demonstrated high bioactivity both in vitro and in vivo. It has been proposed for the treatment of various conditions, including those associated with insufficient mitochondrial activity (including obesity, memory decline, decreased metabolic rate, metabolic syndrome, diabetes, cardiovascular disease, hyperlipidemia, neurodegenerative diseases, cognitive disorders, mood disorders, stress, anxiety, fatty liver disease (e.g., NAFLD or NASH), and for improving liver function and weight management. Specifically, urolithin has been shown to have beneficial effects on improving muscle function.

[0003] Low muscle mass or poor muscle performance is characteristic of many diseases and conditions. Muscle-related pathologies include myopathy, neuromuscular diseases such as Duchenne muscular dystrophy, acute sarcopenia such as muscular dystrophy, and / or cachexia, which may be associated with burns, bed rest, limb immobilization, or major chest, abdominal, neck, and / or orthopedic surgery. Age-related muscle loss is particularly common. Cachexia caused by prolonged immobility or other diseases (such as cancer) is another condition often characterized by poor muscle performance.

[0004] Good muscle performance is important for healthy individuals as well as those with illnesses (especially older adults) to live effectively at all stages of life. Furthermore, athletes are particularly focused on improving muscle performance. For example, increased muscle contraction strength, increased muscle contraction amplitude, or a shorter muscle response time between stimulus and contraction are highly beneficial to individuals, especially athletes.

[0005] In cases of severe muscular dystrophy, anabolic steroids such as methandrostenolone are administered to patients to aid in the healing process. These medications can have various side effects, so long-term use is preferred.

[0006] Urolithin compounds possess properties that make them suitable for the treatment and prevention of various conditions, including those that improve muscle function. However, urolithin in the form of a simple suspension in saline exhibits unfavorable pharmacokinetic characteristics, with a delayed second rise in blood concentration after the initial peak, making such suspensions difficult to administer.

[0007] Multiple peaks in blood concentration (two or more peaks of concentration over time) after oral administration of a compound can be due to a variety of factors, including: (i) the choice of formulation, such as excipients; (ii) the physiology of the gastrointestinal tract itself, including pH and bile composition, which are regulated by hormones and dietary factors; (iii) biochemical differences in local areas of the gastrointestinal tract, which may cause the formation of an absorption window and thus multiple peaks; and (iv) enterohepatic recirculation. When a bioactive compound is administered orally, it is preferred that the plasma concentration of the compound presents a single peak rather than a profile of multiple peaks. Compared to formulations that cause multiple peaks in blood, formulations that allow a single peak of the active compound after oral administration facilitate the optimization of the dose to be administered and the frequency of administration. Therefore, formulations that produce a single peak are desirable and facilitate the establishment of a therapeutic dose window within which the compound can exert its health benefits in mammals.

[0008] In addition to the undesirable pharmacokinetic properties of simple saline suspensions, urolithin formulations suffer from limited bioavailability in various environments. Therefore, there is a need for urolithin formulations with acceptable pharmacokinetic profiles and improved bioavailability. Summary of the Invention

[0009] This invention provides a composition comprising:

[0010] a) Medium-chain triglycerides; and

[0011] b) Compound of formula (I) or its salt:

[0012]

[0013] in:

[0014] A, B, C, and D are each independently selected from H and OH;

[0015] W, X, and Y are each independently selected from H and OH; and

[0016] Z is selected from H and OH.

[0017] Compound (I) is a member of the urolithin family; specifically, compound (I) may be urolithin A. Surprisingly, urolithin A in a combination of medium-chain triglycerides and urolithin A was found to have improved bioavailability and pharmacokinetic profiles compared to urolithin A itself in a simple saline suspension. The compositions of the present invention can thus be used to improve overall health and to manage the overall health of healthy individuals, as well as to treat and prevent various diseases and conditions, particularly those characterized by insufficient mitochondrial activity. Specifically, the compositions can be used to treat and manage healthy individuals who will benefit from improved muscle function, including those with diminished physical performance, diminished endurance, and diminished muscle function. The compositions can also be used to treat, prevent, or manage diseases and conditions characterized by low muscle mass or poor muscle performance, and to improve muscle growth and / or muscle performance. They can also be used to maintain muscle function.

[0018] The present invention further provides compositions for treating various conditions, including those related to insufficient mitochondrial activity, such as obesity, decreased metabolic rate, metabolic syndrome, diabetes, cardiovascular disease, hyperlipidemia, memory decline, neurodegenerative diseases, cognitive disorders, mood disorders, stress and anxiety disorders, fatty liver diseases (e.g., NAFLD or NASH)) and for improving liver function and weight management. Specifically, the present invention provides compositions for treating muscle-related pathological conditions. The present invention also provides a method for treating a subject with a muscle-related pathological condition, the method comprising administering an effective amount of the composition of the present invention to the subject. The present invention provides compositions for improving muscle performance. The present invention also provides a method for improving muscle performance by administering an effective amount of the composition of the present invention to a subject.

[0019] This invention further provides D 50 Sizes range from 0.5 to 50 μm and D 90 Compounds of formula (I) or salts thereof with a size in the range of 5 to 100 μm. Preferably, the D-type of the compound or salt is... 90 Sizes range from 8.2 to 16.0 μm, D 50 The size ranges from 2.8 to 5.5 μm, and D 10 The particle size ranges from 0.5 to 1.0 μm. Compounds of the present invention with these particle sizes have been found to have good dispersibility and solubility properties, as well as improved bioavailability. Attached Figure Description

[0020] Figure 1 The results of the experiment were presented in which rats were fed a formulation containing urolithin A and saline or a variety of other components (such as medium-chain triglycerides), and the level of urolithin A in the blood was assessed.

[0021] Figure 2 The results of the experiments were presented in which rats and humans were fed a formulation containing urolithin A and medium-chain triglycerides, and the levels of urolithin A in the blood were assessed.

[0022] Figure 3 The experimental results are presented in which rats were fed formulations containing urolithin A at various particle sizes and the levels of urolithin A in the blood were assessed. Detailed Implementation

[0023] As described above, the present invention provides a composition comprising medium-chain triglycerides and urolithin.

[0024] Medium-chain triglycerides typically constitute at least 1% w / w of the compositions of the present invention, for example, at least 5% w / w, for example, at least 10% w / w, for example, at least 15% w / w. Preferably, medium-chain triglycerides constitute 20% w / w or more of the compositions, for example, 25% w / w or more of the compositions by weight, for example, 30% w / w or more of the compositions by weight. For example, medium-chain triglycerides may account for 1-40% w / w, 2-40% w / w, 5-40% w / w, 10-40% w / w, 1-99% w / w, 5-99% w / w, 10-99% w / w, 20-99% w / w, 5-90% w / w, 10-90% w / w, such as 20-90% w / w, 20-80%, such as 30-80% w / w, 30-70% w / w, 30-60% w / w, 30-50% w / w, 30-40% w / w, 30-35% w / w. For example, medium-chain triglycerides may account for 40-70% w / w of the composition, such as 50-70% w / w or 55-65% w / w of the composition.

[0025] The weight ratio of medium-chain triglyceride components to urolithin is typically in the range of 0.01:1 to 100:1, for example, 0.5:1 to 100:1, 0.5:1 to 50:1, or 0.5:1 to 5:1; or for example, 1:1 to 75:1, 1:1 to 50:1, 1:1 to 20:1, 1:1 to 10:1, 1:1 to 2.5:1, 1:1 to 2:1, or 1:1 to 1.5:1. The weight ratio of medium-chain triglyceride components to urolithin can also be in the range of 0.01:1 to 10:1, for example, 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 can be provided as a single adjunct supplement to the subject’s general diet (e.g., in the form of sticks, gels or softgel capsules, hard capsules or diluted in beverages); or can be provided as part or all of a meal.

[0026] Urolithin typically constitutes 0.1 to 80% w / w of the composition of the present invention, for example, 0.1 to 60% w / w, or 0.25 to 50% w / w. For example, urolithin may constitute 0.5-50% w / w of the composition. If the composition is provided as part or all of a meal, then urolithin may constitute, for example, 0.25-5% w / w of the composition, or 0.3-3% w / w of the composition. If the composition of the present invention is provided as a single supplement to the subject's general diet, then urolithin typically constitutes 20 to 80% w / w of the composition, for example, 20 to 40% w / w, or 25 to 35% w / w of the composition of the present invention. For example, urolithin may constitute 26-34% w / w of the composition, or 28-33% w / w of the composition; for example, 29-32% w / w of the composition, or 29-31% w / w of the composition.

[0027] Medium-chain triglycerides:

[0028] Medium-chain triglycerides have the formula CH2(OR) 1 )-CH(OR 2 )-CH2(OR 3 Compounds of which R 1 R 2 and R 3 The general form is -C(=O)(CH2). nThe CH3 group is a medium-chain fatty acid group, where n is in the range of 4 to 10, for example 6 to 8. Medium-chain fatty acids are fatty acids with an aliphatic tail having 6-12 carbon atoms. The aliphatic tail is predominantly saturated. Specific medium-chain fatty acids include caproic acid (C6:0), caprylic acid (C8:0), capric acid (C10:0), and lauric acid (C12:0). Myristic acid (C14:0) may also be present in smaller amounts. The most commonly used medium-chain triglycerides are typically mixtures of caprylic and capric triglycerides and contain 95% or more of saturated fatty acids. The medium-chain triglyceride component in the composition of the present invention may be composed of a homogeneous, single type of medium-chain triglyceride compound; more generally, the medium-chain triglyceride component in the composition of the present invention is a mixture of two or more different medium-chain triglyceride compounds.

[0029] The European Pharmacopoeia describes medium-chain triglycerides as being derived from coconut (… Cocos nucifera The hard, dry components of L. / coconut endosperm or from oil palm ( Elaeis guineenis Non-volatile oil extracted from the dried endosperm of Jacq. (African oil palm). Both the European Pharmacopoeia and the USPNF specify that medium-chain triglycerides require the presence of the following specific fatty acids: hexanoic acid (C6) ≤2.0%; caprylic acid (C8) 50.0-80.0%; decanoic acid (C10) 20.0-50.0%; lauric acid (C12) ≤3.0%; and myristic acid (C14) ≤1%.

[0030] Specifically, the medium-chain triglycerides used in the compositions of the present invention comprise a mixture of triglycerides having fatty acid chains present in the following proportions: C6 ≤ 5%; C8 50-70%; C10 30-50%; and C12 ≤ 12%, for example, C6 ≤ 0.5%; C8 55-65%; C10 35-45%; and C12 ≤ 1.5%.

[0031] Medium-chain triglycerides used in the compositions of this invention may be derived from any known or other suitable source. Medium-chain triglycerides may be extracted from natural sources or synthesized from glycerol and suitable fatty acids under appropriate conditions. Non-limiting examples of commercial sources for extracting medium-chain triglycerides (or medium-chain fatty acids that can be used to synthesize medium-chain triglycerides) include coconut oil and palm oil, as well as milk fats (especially butter). Combinations of sources or types of medium-chain triglycerides may be used.

[0032] Medium-chain triglycerides used in the compositions of this invention are commercially available as liquid or solid formulations and as simple or complex combinations with sugars, vitamins, essential fatty acids, and minerals. Medium-chain triglycerides are also available in the form of oils or margarine.

[0033] Urolithin:

[0034] Urolithin is a metabolite produced by the action of ellagitannin and ellagic acid by mammals (including humans) and the gut microbiota. Ellagantannin and ellagic acid are compounds commonly found in foods such as pomegranates, nuts, and berries. Ellagantannin is minimally absorbed in the gut itself. Urolithin is a class of compounds having the representative structure (I) shown above. The structures of some particularly common urolithins are described in Table 1 below, see Structure (I).

[0035]

[0036] In practice, the synthesis of urolithiasis is convenient for commercial-scale production. The synthetic route is described, for example, in WO2014 / 004902.

[0037] Urolithin of any structure as described in structure (I) can be used in the compositions of the present invention. Particularly suitable compounds for use in the compositions of the present invention are naturally occurring urolithin. Therefore, 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 all H, and C, D, and Z are all OH, then 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 all OH, then the compound is urolithin A. Preferably, the urolithin used in the formulations of the present invention is urolithin A, urolithin B, urolithin C, or urolithin D. Most preferably, the urolithin used in the formulations of the present invention is urolithin A.

[0038]

[0039] Preferably, the urolithin used in the compositions of the present invention is micronized. Micronization allows the urolithin to disperse or dissolve more quickly. If micronized urolithin is used, then preferably the D of the urolithin is... 50 Size less than 100 μm – that is, 50% by mass of urolithin has a particle diameter of less than 100 μm. More preferably, the D of urolithin… 50 Sizes below 75 μm, for example, below 50 μm, below 25 μm, below 20 μm, or below 10 μm. More preferably, the D of urolithin... 50Within the range of 0.5-50 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. Preferably, the D of urolithin... 90 Size less than 100 μm. More preferably, the D of urolithin. 90 The size is less than 75 μm, for example less than 50 μm, for example less than 25 μm, for example less than 20 μm, for example less than 15 μm. Preferably, the D-type of urolithin... 90 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. Preferably, the D of urolithin is... 10 Within the range of 0.5-1.0 μm. Preferably, the D of urolithin... 90 In the range of 8.2 to 16.0 μm, D 50 Within the range of 2.8 to 5.5 μm, and D 10 Within the range of 0.5 to 1.0 μm. Micronization can be achieved by methods already established in the art, such as compression milling, hammer milling, universal or pin milling, or jet milling (e.g., helical jet milling or fluidized bed jet milling). Jet milling is particularly suitable.

[0040] Phosphatidylcholine

[0041] The compositions of the present invention may advantageously contain one or more phospholipids. Particularly preferred phospholipids for use in the compositions of the present invention are phosphatidylcholine. The advantages arising from phosphatidylcholine may be at least in part due to its amphiphilic nature.

[0042] A particularly suitable source of phospholipids (especially phosphatidylcholine) for use in this invention is lecithin, and the compositions of this invention advantageously contain lecithin. Lecithin, when present in the compositions of this invention, typically constitutes at least 0.5% w / w of the composition, preferably at least 1% w / w. Lecithin preferably constitutes 10% w / w or more of the composition, for example 20% w / w or more of the composition by weight, for example 30% w / w or more of the composition by weight. For example, lecithin may constitute 0.5-80% w / w of the composition, such as 1-80% w / w, 20-80% w / w, 40-80% w / w, or 0.5-75% w / w of the composition, such as 1-40% w / w, 30-40% w / w, 30-35% w / w, or 30-75% w / w. Alternatively, lecithin may constitute 0.5-5% w / w of the composition, such as 1-5% w / w, 1-3% w / w, 0.5-2% w / w, or 1-2% w / w. The weight ratio between lecithin (when present) and urolithiasis is typically in the range of 0.02:1 to 3:1, for example 0.03:1 to 1.2:1, for example 1:1 to 1.2:1, for example 1.1:1 to 1.2:1.

[0043] 'Lecithin' refers to any group of fatty substances present in the form of animal and plant tissues, including phosphoric acid, choline, fatty acids, glycerol, glycolipids, triglycerides, and phospholipids (such as phosphatidylcholine, phosphatidylethanolamine, and phosphatidylcyclohexanehexol). Specifically, commercial lecithin derived from soybeans and sunflowers contains phospholipids: phosphatidylcholine, phosphatidylinositol, phosphatidylethanolamine, and phosphatidic acid. Lecithin can be obtained by chemical extraction or mechanical extraction from its sources in nonpolar solvents such as hexane, ethanol, acetone, petroleum ether, or benzene. Specifically, lecithin can be extracted from sources including soybeans, eggs, milk, rapeseed, cottonseed, and sunflowers. Commercial lecithin for edible formulations is readily available.

[0044] The lecithin used in the commercial production of the formulations of this invention typically contains the following main components: 33-35% soybean oil, 20-21% inositol phospholipids, 19-21% phosphatidylcholine, 8-20% phosphatidylethanolamine, 5-11% other phospholipids, 5% free carbohydrates, 2-5% sterols and 1% water.

[0045] The lecithin used in the commercial production of the formulations of this invention may be rich in phosphatidylcholine, having a minimum of 5% w / w phosphatidylcholine in the lecithin, for example, a minimum of 10% w / w phosphatidylcholine in the lecithin, for example, a minimum of 15% w / w phosphatidylcholine in the lecithin, for example, a minimum of 20% w / w phosphatidylcholine in the lecithin, for example, a minimum of 25% w / w phosphatidylcholine in the lecithin, for example, a minimum of 30% w / w phosphatidylcholine in the lecithin, for example, a minimum of 32% w / w phosphatidylcholine in the lecithin, for example, a minimum of 40% w / w phosphatidylcholine in the lecithin.

[0046] Lecithin can also be modified to adjust its properties by one or more of the following methods: alcohol extraction of specific phospholipids to produce lecithin with different phospholipid modification ratios; acetone extraction to remove oil, yielding a powdered or granular phospholipid blend; spray drying on a protein carrier; spray cooling with synthetic emulsifiers (such as refractory monoglycerides and diglycerides) to produce flake or powder products; modification by enzymatic action (phospholipase, typically specifically phospholipase A2), specifically partial hydrolysis to produce lecithin with significant emulsifying properties; hydrolysis of fatty acid groups by acid and alkali; acetylation; and hydroxylation of fatty acid chains and amino groups.

[0047] Composition form:

[0048] The compositions of the present invention can take any suitable physical form. They can be in solid (e.g., rods), semi-solid (e.g., soft gels, capsules (e.g., hard capsules), or sugar-coated pills) or liquid (including emulsions). In many cases, the compositions of the present invention are in the form of viscous fluids or pastes. By selecting suitable medium-chain triglycerides and excipients, the physical form of the composition can be tailored to the requirements of the product in question. The compositions of the present invention can be pharmaceutical compositions. The compositions of the present invention can be nutritional compositions.

[0049] The soft gel composition can be provided in capsule form with a shell, which can be of conventional type, such as a soft gelatin shell. The compositions of the present invention can also be provided within a hard capsule-type shell.

[0050] The stick can be any suitable type, and it can contain ingredients commonly used to make dessert sticks.

[0051] The semi-solid form may also contain excipients conventional in the art. Excipients may, for example, provide desired hardness, shelf life, and flavor to give the composition an acceptable taste, an attractive appearance, and good storage stability. The semi-solid form may be in the form of a paste.

[0052] Liquid compositions may be in the form of pharmaceuticals, dietary supplements, or beverages, each intended for oral administration. Liquid formulations may be solutions, emulsions, slurries, or other semi-liquids. Excipients in the liquid composition may, for example, provide shelf life, visual appearance, taste, and mouthfeel to give the composition an acceptable taste, an attractive shape, and good storage stability. At certain dilution levels, beverages may require shaking before consumption by the subject to maintain a uniform suspension of the active ingredient.

[0053] Additional components in the compositions of this invention:

[0054] The compositions according to the invention may contain additional components other than urolithin and medium-chain triglycerides. These additional components may be compounds that provide health benefits (e.g., selected from vitamins, minerals, polyunsaturated fatty acids), and other compounds.

[0055] Among vitamins, vitamins A, C, D, E, B12, and K2 are particularly noteworthy. As used herein, “vitamin D” refers to any known form of vitamin D, and specifically includes vitamin D2 (ergocalciferol), vitamin D3 (cholecalciferol), vitamin D precursors, metabolites, and other analogs, as well as combinations thereof, and various active and inactive forms of vitamin D. For example, vitamin D3 can be provided in its unhydroxylated, inactive form as cholecalciferol, or in its hydroxylated, active form as calcitriol.

[0056] Creatine has been described as having beneficial effects in the treatment of muscle disorders. It may be included in the compositions of this invention. Methyl β-hydroxy-β-butyrate (HMB) has been described as having beneficial effects in the treatment of muscle disorders. It may be included in the compositions of this invention.

[0057] Polyunsaturated fatty acids are fatty acids containing more than one double bond in their main chain. This category includes a variety of important compounds, such as essential fatty acids, for example, ω-3 and ω-6 fatty acids. Long-chain polyunsaturated fatty acids are suitable, and preferably those having at least 20 carbon atoms in their molecule. These long-chain omega-3 fatty acids include cis-11,14,17-eicosatetrienoic acid (ETE) C20:3, cis-8,11,14,17-eicosatetraenoic acid (ETA) C20:4, cis-5,8,11,14,17-eicosatepentanoic acid (EPA) C20:5, cis-7,10,13,16,19-docosapentaenoic acid (DPA, cupanodonic acid) C22:5, cis-4,7,10,13,16,19-docosahexaenoic acid (DHA) C22:6, cis-9,12,15,18,21-docosapentaenoic acid C24:5; cis-6,9,12,15, 18,21-DOC6-nisinic acid (C24:6) Long-chain ω-6 fatty acids with at least 20 carbon atoms include cis-11,14-eicosadienoic acid (C20:2), cis-8,11,14-eicosalicylic acid (DGLA) (C20:3), cis-5,8,11,14-eicosatetraenoic acid (arachidonic acid) (AA) (C20:4), cis-13,16-docosaadienoic acid (C22:2), cis-7,10,13,16-docosatraenoic acid (adrenic acid) (C22:4), and cis-4,7,10,13,16-docosapentaenoic acid (Osbond acid) (C22:5). The compositions according to the invention preferably contain EPA, DHA or a combination thereof, for example in an amount of 10 to 1,000 mg per serving; for example in an amount of 25 to 250 mg per serving.

[0058] The pharmaceutical compositions of the present invention may include additional pharmaceutically active compounds.

[0059] In some exemplary embodiments, in addition to medium-chain triglycerides and urolithiasis, the compositions of the present invention may contain one or more additional macronutrients, typically fats or carbohydrates, or fats and carbohydrates.

[0060] Non-limiting examples of suitable fats or sources thereof for use in the compositions described herein include 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 oil extract; rapeseed oil; seafood oil; cottonseed oil; polyunsaturated fatty acids such as docosahexaenoic acid (DHA), eicosapentaenoic acid (ARA), eicosapentaenoic acid (EPA); and combinations thereof.

[0061] Non-limiting examples of suitable carbohydrates or sources thereof for use in the compositions described herein may include maltodextrin, hydrolyzed or modified starch or corn starch, glucose polymers, corn syrup, corn syrup solids, rice-derived carbohydrates, glucose, fructose, lactose, high-fructose corn syrup, tapioca dextrin, isomaltulose, sucromalt, maltitol powder, glycerol, fructooligosaccharides, soybean fiber, corn fiber, guar gum, konjac flour, polydextrose, honey, sugar alcohols (e.g., maltitol, erythritol, sorbitol), and combinations thereof. Maltodextrin, sucrose, and fructose are particularly preferred.

[0062] The total concentration or amount of fat, carbohydrates, and other components varies depending on the nutritional needs of the intended user.

[0063] Additional components in the compositions of the present invention may be compounds that do not provide health benefits to the subject, but instead improve the composition in some other way, such as its taste, texture, or shelf life as mentioned above. The compositions of the present invention may therefore further contain one or more compounds selected from: emulsifiers, colorants, preservatives, gums, hardeners, thickeners, sweeteners, and flavorings.

[0064] Suitable emulsifiers, stabilizers, colorants, preservatives, gums, hardeners, and thickeners are well known in the field of manufacturing emulsions and other semi-liquids. Emulsifiers may include one or more of the following: phosphatidylcholine, lecithin, polysorbates (such as polysorbate 60 or polysorbate 80 (Tween-60 and Tween-80)), and glyceryl monostearate (GMS). Glycerol monostearate is also known as glycerylmonostearate. Metal chelating agents or clamping agents, such as sodium and calcium salts of ethylenediaminetetraacetic acid (EDTA), may also be used. Other components that may be included in the formulations of this invention include polyethylene glycol, silica, vegetable shortening, and beeswax.

[0065] Stabilizers can 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 is a suspension that does not undergo phase separation over time. For a particular composition of the present invention, stability can be improved by including an added stabilizer. Suitable stabilizers for the compositions of the present invention include glyceryl monostearate (GMS), silica, and vegetable shortening. An exemplary stabilizer is GMS, and preferred compositions of the present invention contain GMS. Its properties also make GMS a good solvent for phospholipids, such as those found in lecithin, for example. GMS exists in two polymorphs: the α-form is dispersible and foamy, suitable as an emulsifier or preservative. The P-form is suitable for wax matrices. The α-form transforms into the P-form upon heating at 50°C.

[0066] GMS is classified into two different grades: 40-55% monoglycerides and 90% monoglycerides. The 40-55% monoglyceride grade, as defined by the European Pharmacopoeia, describes GMS as a mixture of monoacylglycerols (primarily glyceryl stearate) with certain amounts of diglycerides and triglycerides. Specifically, the 40-55 grade contains 40-55% monoacylglycerols, 30-45% diacylglycerols, and 5-15% triglycerides. The 99% grade contains not less than 90% monoglycerides. In commercial GMS products, the monoglycerides are a mixture of glyceryl monostearate and glyceryl monopalmitate in variable proportions. The European Pharmacopoeia further classifies 40-55% glyceryl monostearate into three types based on the proportion of stearate in the mixture. Type 1 contains 40.0-60.0% stearic acid, and the sum of palmitic acid and stearic acid is <90%. Type 2 contains 60.0-80.0% stearic acid, and the sum of palmitic acid and stearic acid is <90%. Type 3 contains 90.0-99.0% stearic acid, and the sum of palmitic acid and stearic acid is <96%. Any form of GMS can be used in the compositions of this invention.

[0067] Flavoring agents can be particularly beneficial in the compositions of this invention. In liquid or semi-liquid compositions, fruit flavors can be provided by including jams or purees. Typical flavoring agents include strawberry, raspberry, blueberry, apricot, pomegranate, peach, pineapple, lemon, orange, and apple. Generally, fruit flavoring agents comprise fruit extracts, fruit preserves, or purees, combined with any sweetener, starch, stabilizer, natural and / or artificial flavoring agents, coloring agents, preservatives, water, and citric acid or other suitable acids to control the pH.

[0068] Dosage

[0069] The effective amount of the composition to be administered will vary depending on the subject's method of administration, age, weight, and general health condition. Factors such as the subject's disease state, age, and weight may be significant, and the dosing regimen may be adjusted to provide the best response.

[0070] The daily intake of the urolithin (e.g., urolithin A) component is typically in the range of 10 mg to 5 g per day, for example, 20 mg to 2500 mg per day, for example, 50 mg to 1500 mg per day, for example, 100 mg to 1500 mg per day, for example, 150 mg to 1500 mg per day, for example, 200 mg to 1500 mg per day, for example, 250 mg to 1500 mg per day, for example, 50 mg to 1000 mg per day, for example, 250 mg to 1000 mg per day. In one embodiment, the composition is administered in an amount providing a urolithin dose in the range of 0.2 mg / kg / day to greater than about 100 mg / kg / day. For example, the dosage of urolithiasis precipitate can be 0.2 to 100, 0.2 to 50, 0.2 to 40, 0.2 to 25, 0.2 to 10, 0.2 to 7.5, 0.2 to 5, 0.25 to 100, 0.25 to 25, 0.25 to 25, 0.25 to 10, 0.25 to 7.5, 0.25 to 5, 0.5 to 50, 0.5 to 40, 0.5 to 30, 0.5 to 25, 0.5 to 20, 0.5 to 15, 0.5 10, 0.5 to 7.5, 0.5 to 5, 0.75 to 50, 0.75 to 25, 0.75 to 20, 0.75 to 15, 0.75 to 10, 0.75 to 7.5, 0.75 to 5, 1.0 to 50, 1 to 40, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 7.5, 1 to 5, 2 to 50, 2 to 25, 2 to 20, 2 to 15, 2 to 10, 2 to 7.5 or 2 to 5 mg / kg / day.

[0071] The unit dose composition of the present invention preferably contains 10 mg to 5 g of urolithin, for example 20 mg to 2500 mg, for example 50 mg to 1500 mg, for example 250 mg to 1500 mg, for example 50 mg to 1000 mg, for example 100 mg to 1000 mg, for example 250 mg to 1000 mg. The unit 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 necessary amount of urolithin. The unit dose composition may also be in the form of a beverage, for example, provided in a container (e.g., a sachet) suitable for 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 necessary amount of urolithin. Beverages providing the compositions of the present invention may contain urolithin at concentrations of 0.1 to 50 mg per ml, 0.25 to 25 mg per ml, for example 0.5 to 10 mg per ml, or for example 1 to 5 mg per ml. The unit dose may be in one or more semi-solid dosage forms, such as soft gels or pastes. A single soft gel capsule may contain, for example, 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, for example 250 mg of urolithin.

[0072] The component ratios of the compositions of the present invention are within the ranges described above. The compositions of the present invention may contain 10 mg to 15 g of medium-chain triglycerides and 10 to 5000 mg of urolithin; for example, 20 to 7500 mg of medium-chain triglycerides and 20 to 2500 mg of urolithin; for example, 25 mg to 2500 mg of medium-chain triglycerides and 50 to 1500 mg of urolithin; for example, 50 mg to 4500 mg of medium-chain triglycerides and 50 to 1500 mg of urolithin; for example, 250 to 4500 mg of medium-chain triglycerides and 250 to 1500 mg of urolithin; for example, 50 to 3000 mg of medium-chain triglycerides and 50 to 1000 mg of urolithin; for example, 250 to 3000 mg of medium-chain triglycerides and 250 to 1000 mg of urolithin. The compositions preferably additionally contain lecithin. The composition also preferably contains additional stabilizers, such as glyceryl monostearate.

[0073] Representative compositions are shown in Table 1:

[0074] Table 1: Representative Blend A:

[0075] .

[0076] The compositions of this invention contain urolithin and medium-chain triglycerides. The compositions of this invention may contain, for example, 20-85% w / w medium-chain triglycerides and 15-70% w / w urolithin, for example, 40-80% w / w medium-chain triglycerides and 20-60% w / w urolithin, for example, 50-70% w / w medium-chain triglycerides and 30-50% w / w urolithin, for example, 60-75% w / w medium-chain triglycerides and 25-40% w / w urolithin.

[0077] Preferred compositions of the present invention comprise urolithin, medium-chain triglycerides, and an emulsifier (such as phosphatidylcholine, for example, lecithin). For example, the compositions of the present invention may contain 10-80% w / w medium-chain triglycerides, 5-70% w / w urolithin, and 0.5-65% w / w lecithin; the compositions of the present invention may contain 20-70% w / w medium-chain triglycerides, 15-70% w / w urolithin, and 0.5-50% w / w lecithin; for example, 25-50% w / w medium-chain triglycerides, 20-50% w / w urolithin, and 20-50% w / w lecithin; for example, 30-40% w / w medium-chain triglycerides, 25-35% w / w urolithin, and 30-40% w / w lecithin. Alternatively, the composition of the present invention comprising urolithin, medium-chain triglycerides and lecithin may contain, for example, 60-75% w / w medium-chain triglycerides, 25-40% w / w urolithin and 0.5-5% w / w lecithin.

[0078] Other preferred compositions of the present invention may contain urolithin, medium-chain triglycerides, emulsifiers (such as lecithin), and stabilizers (such as GMS). For example, the compositions of the present invention may contain 25-75% w / w medium-chain triglycerides, 20-50% w / w urolithin, 0.5-50% w / w lecithin, and 0.5-5% w / w GMS; for example, 30-40% w / w medium-chain triglycerides, 25-35% w / w urolithin, 30-40% w / w lecithin, and 0.5-3% w / w GMS. Alternatively, compositions of the present invention containing urolithin, medium-chain triglycerides, lecithin, and GMS may contain, for example, 60-75% w / w medium-chain triglycerides, 25-40% w / w urolithin, 0.5-5% w / w lecithin, and 0.5-3% w / w GMS.

[0079] Other compositions of the present invention may contain urolithin, medium-chain triglycerides, emulsifiers (such as lecithin and / or Tween (polysorbate)), and stabilizers (such as GMS). For example, compositions of the present invention may contain 25-75% w / w medium-chain triglycerides, 20-50% w / w urolithin, 0.5-50% w / w lecithin, 0.5-5% w / w GMS, and 1-10% w / w Tween-60, such as 60-75% w / w medium-chain triglycerides, 25-40% w / w urolithin, 0.5-5% w / w lecithin, 0.5-3% w / w GMS, and 1-5% w / w Tween-60.

[0080] treat:

[0081] The compositions of the present invention can be used as a single treatment or more generally as a series of treatments. In one instance, a subject takes a dose before or after exercise. For subjects unable to exercise, a dose of the composition may be taken, for example, once, twice, or three times daily, or once, twice, three times, four times, five times, or six times weekly. In another instance, the intervention may be performed by the subject independently of the subject's ability or need for exercise. It should also be understood that the effective dose of the compound may be increased or decreased within a specific course of treatment.

[0082] Drug and non-drug treatments:

[0083] The compositions of this invention can be used as pharmaceuticals. They can be used as dietary supplements or as functional foods. Therefore, the compositions of this invention can be used to treat various diseases and health conditions not considered diseases. Specifically, disease and non-disease health conditions may be characterized by insufficient mitochondrial activity. The compositions can be used to treat diseases and disease states. The compositions can be used to manage the normal physiological functions of healthy individuals with conditions characterized by poor physical performance, decreased endurance, and weakened muscle function. The compositions of this invention can improve the physical performance of individuals with diseases (including young and old individuals). The compositions of this invention can improve physical performance, such as the short-term or long-term performance of healthy individuals (including athletes, non-athletes, sedentary individuals, and older adults). This improvement in performance can be measured by the time taken to walk or run a certain distance (e.g., improved performance during a 6-minute walk test (MWT), improved time to run a certain distance, improved IPAQ scores according to the International Physical Activity Questionnaire, an increase in the number of sit-stands over a certain period, or another test designed to measure physical performance.

[0084] The compositions of this invention further provide an improvement in endurance. Endurance refers to the time to fatigue during exercise at a constant workload (typically at <80% of maximum VO2 intensity). The compositions of this invention can improve the endurance of individuals with illnesses (including young and older individuals). The compositions of this invention can improve the endurance of healthy individuals (including athletes, non-athletes, sedentary individuals, and older adults). This invention provides a method for extending the time to fatigue during specific activities (e.g., fitness training, walking, running, swimming, or cycling). This improvement in endurance can be assessed using objective measurements (e.g., speed, oxygen consumption, or heart rate), or it can be a self-reported measurement (e.g., using a validated questionnaire).

[0085] The present invention further provides compositions for improving, maintaining, or reducing muscle function loss. The compositions of the present invention can improve, maintain, or reduce muscle function loss in individuals with disease (including young and old individuals). The compositions of the present invention can improve, maintain, or reduce muscle function loss in healthy individuals (including athletes, non-athletes, sedentary individuals, and older adults). For example, the compositions of the present invention can increase muscle strength, as demonstrated by engaging in physical activity (such as exercise, e.g., increased weightlifting capacity or increased hand grip strength). Furthermore, the compositions of the present invention can improve muscle structure, for example, by increasing or maintaining muscle mass in cases of normal muscle function, reduced muscle function, or impaired muscle function.

[0086] The present invention further provides compositions for improving physical performance or endurance as perceived by an individual. For example, by reducing perceived movement or effort during exercise or by activity levels as determined using a self-report questionnaire.

[0087] The present invention further provides compositions for treating a variety of conditions, including those related to insufficient mitochondrial activity, such as obesity, decreased metabolic rate, metabolic syndrome, diabetes, cardiovascular disease, hyperlipidemia, memory decline, neurodegenerative diseases, cognitive disorders, mood disorders, stress and anxiety disorders, fatty liver diseases (e.g., NAFLD or NASH)) and for improving liver function and weight management. Specifically, the compositions of the present invention can be used to treat muscle-related pathological conditions. Therefore, the present invention provides compositions of the present invention for treating muscle-related pathological conditions. The present invention also provides a method of treating a subject with a muscle-related pathological condition, the method comprising administering an effective amount of the composition of the present invention to the subject. Muscle-related pathological conditions include conditions that generally affect healthy individuals as well as pathological conditions. These types of muscle conditions are found in healthy individuals or those affected by conditions including: musculoskeletal disorders or conditions; cachexia; muscle atrophy; myopathy; age-related decline in muscle function; pre-deterioration; weakness; myopathy; neuromuscular diseases such as Duchenne muscular dystrophy and other malnutritions; age-related sarcopenia; acute sarcopenia; muscle atrophy and / or cachexia, such as muscle atrophy and / or cachexia associated with burns, bed rest, limb immobilization, or major surgery (including thoracic, abdominal, and / or orthopedic surgery); and degenerative muscle diseases.

[0088] Examples of age-related conditions that can be treated with the compositions of the present invention include sarcopenia and muscle atrophy.

[0089] Myopathy can also be caused by muscular dystrophy syndromes (such as Duchenne's disease), and urolithin B (not urolithin A) has been reported in WO2014 / 111580 to increase the mean diameter of myotubes in vitro. No effect was found with urolithin A.

[0090] Non-pharmacological treatment:

[0091] The compositions of this invention can be used to improve muscle performance. Therefore, this invention provides compositions for improving muscle performance. This invention also provides a method for improving muscle performance by administering an effective amount of the compositions of this invention to a subject. Administerment can be self-administered. Enhanced muscle performance can be one or more improvements in muscle function, increased muscle strength, improved muscle endurance, and improved muscle recovery.

[0092] The compositions of the present invention can therefore be used to improve physical endurance (e.g., the ability to perform physical tasks such as exercise, manual labor, sports activities), inhibit or delay physical fatigue, enhance work capacity and endurance, reduce muscle fatigue, and enhance cardiac and cardiovascular function.

[0093] Improved muscle function can be particularly beneficial in older subjects with age-related muscle weakness due to age-related conditions. For example, subjects who may benefit from improved muscle function may be experiencing muscle decline, which subsequently leads to pre-frailty and frailty. These subjects do not necessarily experience muscle loss in addition to their muscle decline. Some subjects do experience muscle atrophy and muscle decline, such as those with sarcopenia. The compositions of the present invention can be used to improve muscle performance by administering them to subjects who are frail or in the pre-frailty stage.

[0094] Muscle performance can be considered athletic performance, that is, the ability of an athlete's muscles to perform during athletic activities. Enhanced athletic performance, strength, speed, and endurance are measured by increased muscle contraction intensity, increased muscle contraction amplitude, or shortened muscle response time between stimulus and contraction. An athlete is an individual who participates in sports at any level and strives to improve their strength, speed, or endurance during those activities; for example, bodybuilders, cyclists, long-distance runners, and short-distance runners. Improved athletic performance is reflected in the ability to overcome muscle fatigue, maintain activity for longer periods, and train more effectively.

[0095] Example

[0096] The following examples illustrate the present invention.

[0097] compound

[0098] Urolithin A is prepared as follows:

[0099] Urolithin A (4) was prepared in two steps using 2-bromo-5-methoxybenzoic acid 1 and resorcinol 2 as starting materials. A pure compound in the form of a pale yellow powder was obtained.

[0100]

[0101] Step 1:

[0102] A mixture of 2-bromo-5-methoxybenzoic acid 1 (27.6 g; 119 mmol; 1.0 equivalent), resorcinol 2 (26.3 g; 239 mmol; 2.0 equivalent), and sodium hydroxide (10.5 g; 263 mmol; 2.2 equivalent) in water (120 mL) was heated under reflux for 1 hour. Then, a 5% aqueous solution of copper sulfate (3.88 g CuSO4·5H2O in 50 mL water; 15.5 mmol; 0.1 equivalent) was added, and the mixture was refluxed again for 30 minutes. The mixture was cooled to room temperature, and the solid was filtered through a Büchner filter. The residue was washed with cold water to give a light red solid, which was ground in hot MeOH. The suspension was allowed to stand overnight at 4 °C. The resulting precipitate was filtered and washed with cold MeOH to give the title compound 3 as a light brown solid.

[0103] Step 2:

[0104] At 0 °C, a 1 M solution of boron tribromide in anhydrous dichloromethane (11.93 mL of pure BBr3 in 110 mL of anhydrous dichloromethane; 124 mmol; 3.0 equivalent) was added dropwise to a suspension of 3 (10.0 g; 41 mmol; 1.0 equivalent) in 100 mL of anhydrous dichloromethane. The mixture was allowed to stand at 0 °C for 1 hour, and then warmed to room temperature. The solution was stirred at said temperature for 17 hours. Ice was then added to the mixture thoroughly. The yellow precipitate was filtered and washed with cold water to give a yellow solid, which was heated to reflux in acetic acid for 3 hours. The hot solution was quickly filtered and the precipitate was washed successively with acetic acid and diethyl ether to give title compound 4 as a yellow solid. 1 H and 13 C NMR conforms to the structure of 4.

[0105] Example 1: Bioavailability study of urolithin A formulated with or without medium-chain triglycerides.

[0106] Following an overnight fast, male Sprague-Dawley rats were orally administered via tube feeding at a dose corresponding to 60 mg / kg / day of either a saline suspension of urolithin A without other excipients or other formulations of urolithin A with different excipients. The urolithin used in the formulations was micronized, with a particle size distribution of D. 90 = 9 μm to 15 μm and D 50 =2 μm to 9 μm. Actual particle size is D 90 = 11.5, D 50 = 3.9 and D 10 = 0.7 μm. The components used, expressed as % w / w of the formulation, are shown in Table 2 below.

[0107] Table 2: Formulations used in bioavailability studies.

[0108]

[0109] Medium-chain triglycerides are obtained from Cremer Oleo and Co KG under the product name CremerCOOR MCT 60 / 40 EP, and contain C6 ≤ 0.5%; C8 55-65%; C10 35-45%; and C12 ≤ 1.5%.

[0110] Lecithin, obtained from Cargill, Inc. under the product name Epikuron® 135 F IP, contains a minimum of 32% phosphatidylcholine.

[0111] Glyceryl monostearate is available from Cremer Oleo and Co KG under the product name IMWITOR® 900 (F) P, and contains 40.0-50.0% monoacylglycerol, 30.0-45.0% diacylglycerol and 5.0-15.0% triacylglycerol.

[0112] Blood was collected from rats at different time points using a jugular vein cannula, and plasma urolithin A levels were quantified to determine its pharmacokinetic profiles in different formulations. The studies for each formulation were replicated on a total of six rats. Figure 1 The pharmacokinetic profiles of each formulation used are presented. The collected data are summarized in Table 3 below.

[0113] Table 3: Results of the bioavailability study

[0114] .

[0115] Urolithin A suspension in saline exhibits a bimodal curve with a significantly delayed T value at 24 h. 最大值 The values, and a smaller peak in blood content at 4 h. In contrast, formulations 65-68 containing excipients showed only a single peak, with T... 最大值 The duration is 4 h. The single-peak pharmacokinetic characteristic curve (65-68) is far more advantageous for oral administration than the bipeak curve shown by the saline suspension formulation, because it facilitates the optimization of dosing and frequency.

[0116] As shown in Table 3 and Figure 1 As demonstrated, when formulated with medium-chain triglycerides (formulations 65 and 66), urolithin A is also more bioavailable than formulations that do not contain medium-chain triglycerides (formulations 67 and 68), such as through higher C... 最大值As shown by the AUC values, formulation 66, containing both medium-chain triglycerides and lecithin, exhibits significantly higher C... 最大值 And AUC, and this formulation of urolithiasis A is more bioavailable than the formulation containing only lecithin without medium-chain triglycerides (formulation 67), and the addition of Tween 60 to the lecithin formulation does not improve bioavailability (formulation 68). The main difference between formulations 65 and 68 is the substitution of medium-chain triglycerides with lecithin. The use of medium-chain triglycerides results in C 最大值 The concentration (ng / ml) increased from 1.606 in formulation 68 to 3.177 in formulation 65, or an increase of approximately 98%. Furthermore, formulation 65 exhibited an AUC of 28.77, compared to a 15.7 AUC in formulation 68, indicating an 83% increase in bioavailability when medium-chain triglycerides were used to replace lecithin.

[0117] Compared to undiluted urolithin in saline solution, formulations 65 and 66 according to the invention therefore exhibit more favorable pharmacokinetic profiles, containing only a single peak in blood concentration, and improved bioavailability, making them suitable for oral administration of urolithin.

[0118] Example 2: Comparison of pharmacokinetic characteristics of urolithin A in formulation 66 in rats and humans.

[0119] The pharmacokinetic profiles of urolithin A in formulation 66 in humans were compared with those observed in rats. Equivalent doses of urolithin A (determined as a surface area ratio between rats and humans) were delivered in humans. Pharmacokinetic studies were conducted in rats using formulation 66 at a dose of 60 mg / kg / day. The human equivalent dose (following FDA guidance on dose conversion based on surface ratio) was determined by dividing this dose by a conversion factor of 6.2, yielding a human equivalent dose of 9.68 mg / kg / day. Assuming an average adult weight of 60 to 70 kg, this would yield a daily dose of urolithin A between 580 and 680 mg. A similar equivalent dose of urolithin A delivered in a soft gel was administered to humans at 500 mg / day. In both cases, the particle size distribution of urolithin A used in the formulation was D. 90 = 8 μm to 20 μm and D 50 = 2 μm to 8 μm and D 10 = 0.5 μm to 2 μm.

[0120] The pharmacokinetic characteristics of formulation 66 were determined in male Sprague-Dawley rats administered urolithin A in formulation 66 via oral feeding after an overnight fast. The components used, expressed as % w / w of the formulation, are shown in Table 4 below.

[0121] Table 4: Compounds used in bioavailability studies.

[0122]

[0123] Medium-chain triglycerides, obtained under the product name CremerCOOR MCT 60 / 40 EP from Cremer Oleo and Co KG, contain C6 ≤ 0.5%; C8 55-65%; C10 35-45%; and C12 ≤ 1.5%. Lecithin, obtained under the product name Epikuron® 135 F IP from Cargill, Inc., contains a minimum of 32% phosphatidylcholine.

[0124] Glyceryl monostearate is available from Cremer Oleo and Co KG under the product name IMWITOR® 900 (F) P, and contains 40.0-50.0% monoacylglycerol, 30.0-45.0% diacylglycerol and 5.0-15.0% triacylglycerol.

[0125] Blood was collected from rats at different time points using jugular cannulation, and plasma urolithin A levels were quantified to determine its pharmacokinetic profile. The formulation was studied in a total of six rats. Figure 2 The display is standardized to relative C 最大值 The pharmacokinetic characteristic curve obtained when the value is 1.

[0126] The pharmacokinetic profiles in humans were compared with those observed in rats at a dose of 60 mg / kg / d. Soft gel capsules containing 250 mg of urolithin A from formulation 66 were prepared using standard methods.

[0127] To determine whether the pharmacokinetic profile of urolithin A delivered by a softgel containing formulation 66 was similar to that observed in rats, six healthy individuals (3 male and 3 female adults) were administered 500 mg of urolithin A delivered in two softgels. Individuals fasted overnight and were orally administered two softgels, each containing 250 mg of formulation 66, with water at 0h.

[0128] Table 5: Design of biological usability studies.

[0129]

[0130] Blood samples were collected at the following time points: before administration, and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, and 36 hours. At each time point, 6 mL of blood was drawn into a K2-EDTA-coated tube. The blood sample was inverted to ensure complete mixing with the anticoagulant. Within 30 minutes of blood collection, each blood sample was centrifuged at 1500 g for 10 minutes at 4°C. Within 30 minutes of centrifugation, the supernatant of human plasma was transferred to pre-labeled polypropylene tubes, and the urolithin A content of the plasma samples at each time point was quantified to determine its pharmacokinetic profile. Figure 2 The pharmacokinetic profiles of formulation 66 are shown for both rat and human samples. To compare these profiles, the maximum concentration or Cg found in the blood is used. 最大值 Set to value 1.

[0131] As in Figure 2 The urolithin A delivered to humans via a soft gel, as observed in rats, exhibited a pharmacokinetic profile similar to that observed in rats, with a single, rapid peak. The Tg in rats... 最大值 The administration time was 4 h (for rodents) and 6 h (for humans). This shift in the curve may be due to differences in the administration of formulation 66, whether via simple tube feeding in rodents or via a soft gel in humans. Furthermore, the persistent levels of urolithin A in the blood observed in humans, which were not anticipated from rodent data, further highlight the practicality of medium-chain triglycerides in the oral delivery of urolithin to humans.

[0132] This demonstrates that formulation 66, containing medium-chain triglycerides (MCTs), can be used for the delivery of urolithin A in humans and other mammals. These results show that urolithin A, when formulated in formulation 66 containing MCTs, exhibits an attractive bioavailability profile and favorable pharmacokinetic profiles in both humans and rats, making it suitable for oral administration of urolithin.

[0133] Example 3: The effect of particle size on the bioavailability of urolithin A

[0134] The particle size of urolithin A was reduced in a controlled manner using an MC50 Spiral Jetmill, filtered nitrogen, a feed rate of 240 g / hr, a Venturi pressure of 12 bar, and a milling pressure of 12 bar. The different particle size distributions of urolithin A were determined using a Malvern particle size analyzer (Malvern Instruments, UK). Three samples were evaluated in detail. The particle size distribution of urolithin A sample #1 is shown in Figure D. 10 It is 1.03 μm, D50 It is 53.4 μm and D 90 The particle size of urolithin A sample #2 is 365 μm. 10 0.272 μm, D 50 It is 2.17 μm and D 90 The particle size of urolithin A sample #3 is 6.84 μm. 10 0.597 μm, D 50 It is 5.67 μm and D 90 It is 40.1 μm.

[0135] Table 6: Particle size determination of urolithin A before and after micronization

[0136] .

[0137] To demonstrate the effect of a specific particle size distribution on bioavailability, male Sprague-Dawley rats were fasted overnight and then administered urolithin A in samples #1, #2, or #3, which were suspended in 15% DMSO, 85% (0.5% methylcellulose in water, 0.25% Tween 80), via oral tube feeding at a dose corresponding to 25 mg / kg / day.

[0138] Table 7: Design of biological usability studies.

[0139]

[0140] The solution for tube feeding was prepared as follows: 35 mg of urolithiasis A powder was diluted in 7 ml of 15% DMSO, 0.5% methylcellulose / 0.25% Tween 80 in water to obtain a fine suspension of 5 mg / ml. DMSO was obtained from BDH, methylcellulose from Sigma, and Tween 80 from Sigma-Aldrich.

[0141] Blood was collected from rats at different time points using a jugular cannula, and plasma urolithin A levels were quantified to determine pharmacokinetic profiles after oral administration of samples #1, #2, and #3. The study was replicated for each sample on three rats. Figure 3 The pharmacokinetic profiles of urolithiasis samples #1 and #2 are shown. The collected data are summarized in Table 8 below.

[0142] Table 8: Results of bioavailability studies of urolithin A with different particle sizes

[0143] .

[0144] When the particle size is reduced to D90 Below 50 μm, urolithin A exhibits improved bioavailability. For sample #2, there is a 116% increase in C compared to sample #1. 最大值 The relative increase was 2.16 times and the AUC increased by 28%. For sample #3, there was a relative increase of 26% in AUC.

[0145] These results demonstrate that, with a particle size of D 90 Compared to urolithiasis A formulations with a particle size >300 μm, the particle size is D. 90 Urolithiasis A formulations with a particle size <50 μm consistently exhibited high bioavailability. Furthermore, it was observed that particle sizes of D... 90 Urolithin A formulations with a thickness of <20 μm are particularly advantageous and can achieve significantly higher peak blood urolithin A levels, such as those obtained with C. 最大值 Greater than double.

Claims

1. A composition comprising: a) 30-40% w / w medium-chain triglycerides; b) lecithin, wherein the lecithin constitutes 30 to 40% w / w of the composition; and c) Urolithin A: Or its salt.

2. The composition claimed in claim 1, comprising: a) 30-40% w / w medium-chain triglycerides; b) 30-40% w / w lecithin, and c) Urolithiasis A or its salt; The weight ratio between the medium-chain triglyceride component and urolithin A is in the range of 0.5:1 to 3:

1.

3. The composition claimed in claim 1 or 2, wherein the urolithin A has a D 50 Sizes range from 0.5 to 50 μm and D 90 The size ranges from 5 to 100 μm.

4. The composition claimed in claim 1 or 2, wherein the D of urolithin A is... 50 Sizes range from 0.5 to 20 μm and D 90 The size ranges from 5 to 50 μm.

5. The composition claimed in claim 1 or 2, wherein the D of urolithin A is... 50 Size less than 50 μm and D 90 Size less than 75 μm.

6. The composition claimed in claim 1 or 2, wherein the D of urolithin A is... 50 Size less than 25 μm and D 90 Size less than 50 μm.

7. The composition claimed in claim 1 or 2, wherein the urolithin A has a D 50 Size less than 10 μm and D 90 Size less than 20 μm.

8. The composition claimed in claim 1 or 2, wherein the D of urolithin A is... 50 Size less than 10 μm and D 90 Size less than 15 μm.

9. The composition claimed in claim 1 or 2, wherein the D of urolithin A is... 10 Within the range of 0.5 μm to 1.0 μm, D 50 Within the range of 2.8 μm to 5.5 μm and D 90 Within the range of 8.2 μm to 16.0 μm.

10. The composition claimed in claim 1 or 2, wherein the D of urolithin A is... 50 The size is 10 μm and D 90 The size is 20 μm.

11. The composition claimed in claim 1 or 2, wherein the medium-chain triglyceride comprises: (i) 30-35% w / w of the composition.

12. The composition claimed in claim 1 or 2, wherein the medium-chain triglyceride comprises caprylic acid and / or capric acid, and / or the medium-chain triglyceride is derived from a source selected from coconut oil, palm oil and dairy fat.

13. The composition claimed in claim 1 or 2, wherein the lecithin comprises: (i) 30-35% w / w of the composition.

14. The composition claimed in claim 1 or 2, further comprising a stabilizer.

15. The composition claimed in claim 14, wherein the stabilizer is glyceryl monostearate.

16. The composition claimed in claim 1 or 2, wherein the composition is in solid, semi-solid or liquid form.

17. The composition claimed in claim 1 or 2, wherein the composition is in the form of a stick, soft gel, capsule or emulsion.

18. The composition claimed in claim 17, wherein the composition is a soft gel.

19. Use of the composition claimed in any one of claims 1 to 18 in the preparation of a medicament for the treatment and / or prevention of muscle-related pathological conditions, wherein said muscle-related pathological conditions are muscle atrophy, neuromuscular diseases, sarcopenia, and / or cachexia.

20. The use claimed in claim 19, wherein the neuromuscular disease is selected from Duchenne muscular dystrophy and other malnutritions.

21. The use claimed in claim 19, wherein the sarcopenia is acute sarcopenia.

22. The non-medical use of the composition claimed in any one of claims 1 to 18 as a dietary supplement or functional food, wherein the dietary supplement or functional food is used to improve physical endurance, inhibit or delay physical fatigue, or reduce muscle fatigue.

23. The composition claimed in any one of claims 1 to 18 for non-medical use in improving physical endurance.

24. The composition claimed in any one of claims 1 to 18 for non-medical use in inhibiting or delaying physical fatigue, enhancing work capacity and endurance, and reducing muscle fatigue.

25. Use of the composition claimed in any one of claims 1 to 18 in the preparation of medicaments for obesity, decreased metabolic rate, metabolic syndrome, diabetes, cardiovascular disease, hyperlipidemia, memory decline, neurodegenerative diseases, cognitive disorders, mood disorders, fatty liver disease, for improving liver function, and for weight management.

26. The use claimed in claim 25, wherein the fatty liver disease is selected from NAFLD and NASH.

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