Compositions comprising amarouciaxanthin a esters and uses thereof

Abstract

The present invention relates to a composition comprising a compound of formula (I) or a stereoisomer thereof, in particular an amarouciaxanthin A acetate; and medical and cosmetic uses thereof. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to compositions comprising amarouciaxanthin A esters and their medical and cosmetic uses. Background Art

[0002] Amarouciaxanthin A (ACX) is a naturally occurring xanthophyll that was first isolated from Amarouciumpliciferum (J Nat Prod, 1985, 48, 606-613). It is one of the major metabolites of fucoxanthin after oral administration in mice, and the presumed metabolism is that fucoxanthin (FCX) is deacetylated to fucoxanthinol and then rearranged to ACX in the liver (Drug. Metab. Dispos., 2004, 32, 205-211).

[0003] Fucoxanthin (FCX) is well known in the literature for its wide range of applications, such as antioxidants, anti-obesity, anti-diabetes, anti-cancer, etc. (Int J Mol Sci, 2013, 14, 13763-13781, Biochim Biophys Acta Mol Cell Biol Lipids, 2020, 1865, 158618). On the other hand, only recently has ACX been reported to significantly inhibit liver oxidative stress, inflammation, and fibrosis in rodent models (Biochem Biophys Res Commun, 2020, 528, 305-310), making this compound a very promising candidate.

[0004] FCX is widely distributed in brown seaweed, diatoms and dinoflagellates, and it can be obtained commercially from natural extracts. Unfortunately, since ACX or its derivatives only exist in small amounts in nature, there is no direct source to obtain it. It was previously obtained from natural extracts after cumbersome purification processes or by very long chemical synthesis with low overall yields and the risk of not being able to fully control its chiral centers (Org Lett, 2013, 15, 5310-5313).

[0005] Therefore, there is a need for ACX prodrugs that can be synthesized in good yields without isomerization of chiral centers and converted directly to ACX after administration without intermediate metabolites as occurs when FCX ​​is administered. In addition, there is a need for suitable carriers for efficient solubilization and administration of ACX prodrugs that ensure absorption and bioavailability of the ACX prodrugs. Summary of the invention

[0006] Thus, in a first aspect, the present invention relates to a composition comprising a compound of formula (I) or a stereoisomer thereof, and a carrier:

[0007]

[0008] Wherein R is selected from a linear or branched C1-C4 alkyl group, and wherein the carrier is selected from an oil or an emulsion.

[0009] In a second aspect, the present invention relates to a food, a nutritional supplement, a cosmeceutical, a cosmetic composition or a nutraceutical comprising the composition of the present invention.

[0010] In a third aspect, the present invention relates to a non-therapeutic method for improving skin health, comprising the step of administering the composition of the first aspect of the invention or the food, nutritional supplement, cosmeceutical, cosmetic composition or nutritional product of the second aspect of the invention to a patient in need of improved skin health.

[0011] The fourth aspect relates to a composition of the present invention for use in medicine, or a pharmaceutical composition comprising the composition of the present invention.

[0012] The fifth aspect relates to a composition of the present invention, which is used to treat and / or prevent a disease selected from the following: cancer, cardiovascular disease, intestinal flora imbalance, inflammatory disease, autoimmune disease, fibrosis, bacterial infection, neurological disease, hyperuricemia-related diseases, aging-related disorders, lipid-related diseases, glucocorticoid-induced muscle atrophy, bone-related diseases, eye diseases, angiogenesis-related diseases, psoriasis, eczema, atopic dermatitis and thyroid-related disorders.

[0013] A sixth aspect relates to a composition of the invention for use in the treatment and / or prevention of a disease mediated by glucocorticoid receptor activity, a aging-related disease or an aging-related disorder; or as an adjuvant for the treatment of cancer with chemotherapy, preferably chemotherapy comprising taxanes.

[0014] In a final aspect, the present invention relates to a cosmetic method for preventing and / or reducing skin aging and / or for improving the cosmetic adverse effects of aging, comprising administering to a subject in need thereof a composition according to the first aspect of the invention or a food, nutritional supplement, cosmeceutical, cosmetic composition or nutritional product according to the second aspect of the invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 Shown are plasma concentrations of amarouciaxanthin A following oral delivery of amarouciaxanthin A acetate or fucoxanthin. DETAILED DESCRIPTION

[0016] Compositions of the present invention

[0017] The authors of the present invention have observed that formulation of amarouciaxanthin A acetate in oil or in emulsion unexpectedly results in improved absorption and improved plasma levels of amarouciaxanthin when compared to the absorption and plasma levels obtained when administering a comparable formulation of fucoxanthin. Furthermore, the authors of the present invention have also observed that amarouciaxanthin A acetate exhibits improved solubility in certain lipophilic solvents when compared to fucoxanthin.

[0018] Thus, in a first aspect, the present invention relates to a composition comprising a compound of formula (I) or a stereoisomer thereof, and a carrier:

[0019]

[0020] Wherein R is selected from a linear or branched C1-C4 alkyl group, and wherein the carrier is selected from an oil or an emulsion.

[0021] The term "alkyl" refers to a linear or branched hydrocarbon chain group consisting of carbon atoms and hydrogen atoms, containing no unsaturation, having from one to four carbon atoms, and connected to the remainder of the molecule by a single bond, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl and sec-butyl. Preferably, the alkyl group is methyl.

[0022] The term "stereoisomer" refers to compounds made up of the same atoms, bonded by the same sequence of bonds, but having different three-dimensional structures that are not interchangeable.

[0023] In a preferred embodiment, more particularly, the compound of formula (I) is a compound of formula (Ia):

[0024]

[0025] wherein R is as defined previously.

[0026] In a preferred embodiment, in the compounds of formula (I), R is methyl.

[0027] In a more preferred embodiment, in the compound of formula (Ia), R is methyl, ie amarouciaxanthin A acetate.

[0028] Methods for synthesizing compounds of formula (i) or formula (ia) are disclosed in the Examples of the present application and are also described below.

[0029] The process for preparing the compound of formula (I) may comprise:

[0030] a) reacting a compound of formula (II) or (IIa) with an oxidant, preferably an oxidant selected from tetra-n-propylammonium perruthenate (TPAP) and 2-iodoacylbenzoic acid (IBX), and optionally also in the presence of an auxiliary oxidant, preferably N-methylmorpholine N-oxide (NMO), to obtain a compound of formula (III) or (IIIa),

[0031]

[0032]

[0033] b) treating the compound of formula (III) or (IIIa) with SiO2 in the presence of a base, preferably a base selected from N-methylmorpholine and triethylamine to obtain a compound of formula (I) or (Ia) wherein R is methyl, and

[0034] c) wherein if R in the compound of formula (I) or (Ia) is a linear or branched C2-C4 alkyl group, the method further comprises:

[0035] c1) converting a compound of formula (I) or (Ia) wherein R is methyl into a compound of formula (IV) or (IVa) by treating with an esterase, preferably a lipase,

[0036]

[0037] and, c2) esterifying a compound of formula (IV) or (IVa) with a carboxylic acid of formula (V) wherein R is a linear or branched C2-C4 alkyl group in the presence of a coupling agent, preferably a carbodiimide, more preferably a carbodiimide selected from dicyclohexylcarbodiimide (DDC), diisopropylcarbodiimide (DIC) and ethyl-(N',N'-dimethylamino)propylcarbodiimide (EDC) or a salt thereof, and in the presence of 4-(dimethylamino)pyridine (DMAP) to obtain a compound of formula (I) or (Ia) wherein R is selected from a linear or branched C2-C4 alkyl group:

[0038] R-COOH

[0039] (v)

[0040]

[0041] When step a) is carried out with a compound of formula (II), a compound of formula (III) is obtained in this step, a compound of formula (I) in which R is methyl is obtained in step b), a compound of formula (IV) is obtained in step c1), and a compound of formula (I) in which R is C2-C4 alkyl is obtained in step c2).

[0042] When step a) is carried out with a compound of formula (IIa), a compound of formula (IIIa) is obtained in this step, a compound of formula (Ia) wherein R is methyl is obtained in step b), a compound of formula (IVa) is obtained in step c1), and a compound of formula (Ia) wherein R is C2-C4 alkyl is obtained in step c2).

[0043] The oxidizing agent of step a) can be any suitable oxidizing agent capable of providing a compound of formula (III) or (IIIa). Some examples of oxidizing agents are tetra-n-propylammonium perruthenate (TPAP) and 2-iodobenzoic acid (IBX), preferably TPAP.

[0044] In step a) a co-oxidant may also be used. Some examples of suitable co-oxidants are N-methylmorpholine N-oxide (NMO).

[0045] Preferably, step a) is carried out using TPAP as oxidant and NMO as co-oxidant.

[0046] The reaction of step a) is preferably carried out in an organic solvent such as dichloromethane, acetonitrile, acetone, methyl ethyl ketone, ethyl acetate, tetrahydrofuran or a mixture thereof, preferably dichloromethane.

[0047] The reaction of step a) is preferably carried out at a temperature in the range of 15°C to 35°C.

[0048] The amount of the oxidizing agent used in step a) is preferably 0.01 mol to 0.5 mol, more preferably 0.05 mol to 0.2 mol, per mol of the compound of formula (II) or (IIa).

[0049] When present, the amount of the auxiliary oxidant used in step a) is preferably 1.5 mol to 5 mol, more preferably 1.5 mol to 2.5 mol, per mol of the compound of formula (II) or (IIa).

[0050] Step a) is preferably carried out with the removal of water. For example, in step a) Molecular sieve.

[0051] Step a) can also be carried out without removal of water.

[0052] Preferably, step a) is performed for 0.5 hour to 5 hours.

[0053] Step a) provides a compound of formula (III) or (IIIa). When step a) is carried out with a compound of formula (II), a compound of formula (III) is obtained in this step. When step a) is carried out with a compound of formula (IIa), a compound of formula (IIIa) is obtained in this step.

[0054] The next step of the process is step b): treating the compound of formula (III) or (IIIa) with SiO2 in the presence of a base, preferably a base selected from N-methylmorpholine and triethylamine to obtain a compound of formula (I) or (Ia) wherein R is methyl.

[0055] In step a) the compound of formula (III) or (IIIa) is obtained.

[0056] The amount of SiO2 used in step b) is preferably 10 mol to 50 mol per mol of the compound of formula (II) or (IIa).

[0057] Step b) is carried out in the presence of a base. Some examples of suitable bases are N-methylmorpholine, trimethylamine, N,N-diisopropylethylamine and mixtures thereof, preferably N-methylmorpholine.

[0058] The amount of the base used in step b) is preferably 0.1 mol to 5 mol per mol of the compound of formula (II) or (IIa).

[0059] Step a) can also be carried out in the presence of NMO as co-oxidant, providing N-methylmorpholine as a by-product which is then used as base in step b).

[0060] Steps a) and b) can be performed in one pot.

[0061] The reaction of step b) is preferably carried out in an organic solvent such as dichloromethane, acetonitrile, acetone, methyl ethyl ketone, ethyl acetate, tetrahydrofuran or a mixture thereof, preferably dichloromethane.

[0062] The reaction of step b) is preferably carried out at a temperature in the range of 15°C to 35°C.

[0063] Preferably, step b) is performed for 0.5 hour to 24 hours.

[0064] Step b) provides a compound of formula (I) or (Ia) wherein R is methyl. When step b) is carried out with a compound of formula (III), a compound of formula (I) wherein R is methyl is obtained in this step. When step b) is carried out with a compound of formula (IIIa), a compound of formula (Ia) is obtained in this step.

[0065] If the target compound of the method of the present invention is a compound of formula (I) or (Ia) wherein R is methyl, step c) is not performed.

[0066] If the target compound of the method of the present invention is a compound of formula (I) or (Ia) wherein R is a linear or branched C2-C4 alkyl group, step c) is performed. Step c) includes steps c1) and c2).

[0067] Step c1) is to convert the compound of formula (I) or (Ia) wherein R is methyl into the compound of formula (IV) or (IVa) by treating with an esterase, preferably a lipase:

[0068]

[0069] In step b) the compound of formula (IV) or (IVa) is obtained.

[0070] Any esterase capable of providing compound (IV) or (IVa) from compound of formula (I) or (Ia), respectively, may be used. Some examples of esterases are lipase and cholesterol esterase, preferably lipase.

[0071] Step c1) is preferably carried out in the presence of an emulsifier (eg sodium taurocholate, sodium lauryl sulfate or a hydrate thereof).

[0072] Preferably, step c1) is performed in an aqueous solvent, preferably at a pH of 6.5 to 7.5, more preferably, step c1) is performed in a phosphate buffered saline solution (PBS).

[0073] The reaction of step c1) is preferably carried out at a temperature in the range of 30°C to 45°C.

[0074] Preferably, step c1) is performed for 2 to 24 hours.

[0075] Step c1) provides a compound of formula (IV) or (IVa). When step c1) is carried out using a compound of formula (I), a compound of formula (IV) is obtained in this step. When step c1) is carried out using a compound of formula (Ia), a compound of formula (IVa) is obtained in this step.

[0076] The next step of the process of the present invention is step c2): esterifying the compound of formula (IV) or (IVa) with a carboxylic acid of formula (V) wherein R is a linear or branched C2-C4 alkyl group in the presence of a coupling agent, preferably a carbodiimide, more preferably a carbodiimide selected from dicyclohexylcarbodiimide (DDC), diisopropylcarbodiimide (DIC) and ethyl-(N',N'-dimethylamino)propylcarbodiimide (EDC) or a salt thereof, and in the presence of 4-(dimethylamino)pyridine (DMAP) to obtain a compound of formula (I) or (Ia) wherein R is selected from a linear or branched C2-C4 alkyl group:

[0077] R-COOH

[0078] (v)

[0079]

[0080] In step c1) the compound of formula (IV) or (IVa) is obtained.

[0081] The coupling agent used in step c2) can be any suitable coupling agent known in the art for esterifying carboxylic acid with alcohol. Some examples of suitable coupling agents are carbodiimides, preferably dicyclohexylcarbodiimide (DDC), diisopropylcarbodiimide (DIC) and ethyl-(N',N'-dimethylamino)propylcarbodiimide (EDC) or its salt. The esterification reaction of step c2) is carried out in the presence of DMAP.

[0082] Preferably, 1 to 2 mol of the coupling agent is used per mol of the carboxylic acid (V) in step c2).

[0083] Preferably, 0.01 mol to 0.5 mol of DMAP are used in step c2) per mol of carboxylic acid of formula (V).

[0084] Preferably, 1 to 2 mol of compound of formula (IV) or (IVa) are used in step c2) per mol of carboxylic acid of formula (V).

[0085] Preferably, step c2) is carried out in an organic solvent such as dichloromethane, N,N-dimethylformamide or a mixture thereof.

[0086] The reaction of step c2) is preferably carried out at a temperature in the range of 0°C to 30°C.

[0087] Preferably, step c2) is performed for 1 hour to 15 hours.

[0088] Step c2) provides a compound of formula (I) or (Ia) wherein R is selected from a linear or branched C2-C4 alkyl group. When step c2) is carried out using a compound of formula (IV), a compound of formula (I) wherein R is selected from a linear or branched C2-C4 alkyl group is obtained in this step. When step c2) is carried out using a compound of formula (IVa), a compound of formula (Ia) wherein R is selected from a linear or branched C2-C4 alkyl group is obtained in this step.

[0089] In the method of the present invention:

[0090] - the oxidizing agent in step a) may be TPAP,

[0091] - step a) can be carried out in the presence of an auxiliary oxidant,

[0092] - the auxiliary oxidant in step a) may be NMO; and / or

[0093] - The base in step b) can be N-methylmorpholine.

[0094] In addition, step a) and / or b) of the process of the invention can be carried out in the presence of water, in particular with more than 0.05 mol of water per mol of compound of formula (II) or (IIa). This provides a mixture of a compound of formula (I) or (Ia) and a compound of formula (VI) or (VIa) (wherein R is selected from linear or branched C2-C4 alkyl, preferably methyl), preferably a compound of formula (VIa), preferably a compound of formula (VIa) wherein R is methyl:

[0095]

[0096] Alternatively, the compound of formula (VI) or (VIa) can be obtained by heating the compound of formula (I) or (Ia) at 60°C to 90°C in the presence of water. Step a) can be carried out in the presence of water or in the absence of water. In order to avoid the presence of water in step a), a water scavenger can be used, such as Molecular sieves. Step b) can be carried out in the presence of water or in the absence of water. In order to avoid the presence of water in step a), a dehydrating agent can be used, such as Alternatively, both steps a) and b) are carried out in the presence of water or in the absence of water. To avoid the presence of water in steps a) and b), a water removing agent may be used, such as Molecular sieve.

[0097] The term "presence of water" refers to an amount of water ranging from 0.1% to 100% by volume, preferably 100%. The amount of water is determined relative to the solvent present in the reaction medium, without taking into account water removed by any water removal agent.

[0098] Therefore, in one embodiment, the composition of the present invention comprises a compound of formula (I) or (Ia), preferably a compound of formula (Ia) (preferably wherein R is methyl), and a compound of formula (VI) or (VIa) as described above, preferably a compound of formula (VIa) (preferably wherein R is methyl).

[0099] In a specific embodiment, the amount of the compound of formula (I) or (Ia) in the composition is 10% to 99.9% by weight, preferably 40% to 99% by weight, relative to the total weight of the composition.

[0100] In a specific embodiment, the amount of the compound of formula (VI) or (VIa) in the composition is from 1% to 60% by weight relative to the total weight of the composition.

[0101] The term "oil", "lipid" or "fat" (used indiscriminately) used herein will be defined as any of a wide range of materials that are insoluble in water and extractable with organic solvents. This wide class of compounds is well known to those skilled in the art, and as the term "lipid" used herein, it is not limited to any specific structure. It includes organic compounds with lipophilic or amphipathic properties, including but not limited to fats, fatty oils, essential oils, waxes, steroids, sterols, phospholipids, glycolipids, sulfolipids, amino lipids, chromolipids (lipochromes) and fatty acids. In the context of the present invention, oil can be solid or liquid.

[0102] "Lipophilicity" refers to those organic compounds that are dissolved in fats, oils, lipids, and non-polar solvents (e.g., organic solvents). Lipophilic compounds are slightly soluble in water or insoluble in water. Therefore, lipophilic compounds are hydrophobic. Amphiphilic lipids, also referred to herein as "amphiphilic lipids," refer to lipid molecules having both hydrophilic and hydrophobic characteristics. As described in more detail below, the hydrophobic groups of amphiphilic lipids can be long-chain hydrocarbon groups. The hydrophilic groups of amphiphilic lipids can include charged groups, such as anionic or cationic groups, or polar uncharged groups. Amphiphilic lipids can have multiple hydrophobic groups, multiple hydrophilic groups, and combinations thereof. Due to the presence of both hydrophobic groups and hydrophilic groups, amphiphilic lipids are soluble in water and, to a certain extent, soluble in non-polar organic solvents.

[0103] As used herein, "hydrophilicity" is the physical property of a molecule that is capable of hydrogen bonding with water (H2O) molecules and is soluble in water and other polar solvents. The terms "hydrophilicity" and "polarity" are used interchangeably. The hydrophilic characteristic derives from the presence of polar or charged groups such as carbohydrates, phosphates, carboxyls, sulfates, aminos, sulfhydryls, nitros, hydroxyls, and other similar groups.

[0104] In contrast, the term "hydrophobicity" is the physical property of a molecule that is repelled by large amounts of water, and may be referred to as "nonpolar" or "apolar," all of which terms may be used interchangeably with "hydrophobicity." Hydrophobicity may be imparted by the inclusion of nonpolar groups, including, but not limited to, long chain saturated and unsaturated aliphatic hydrocarbon groups and such groups substituted with one or more aromatic, alicyclic, or heterocyclic groups.

[0105] As used herein, "carrier" refers to a compound or composition capable of delivering a biologically active compound to a physiological site or cell.

[0106] The term oil refers to a single oil or a blend of oils.

[0107] The term "blended oil" refers to an oil obtained by mixing or blending any combination of oils or individual oils to obtain a desired composition. Thus, for example, oil types from different microorganisms can be mixed together to obtain a desired PUFA composition. Alternatively or in addition, the PUFA-containing oils disclosed herein can be blended with fish oils, vegetable oils, or a mixture of the two to obtain a desired composition.

[0108] Oil can be a kind of lipid or a kind of lipid.Some examples of oil include compounds and derivatives thereof containing long-chain aliphatic hydrocarbons.Lipid can be naturally occurring or synthetic (that is, designed or produced by people).However, lipid is biological material normally.Biological lipid is well known in the art, and includes for example neutral fat, phospholipid, phosphoglyceride, steroid, terpene, lyso lipid (lysolipid), glycosphingolipid, glycolipid, sulfolipid, lipid and polymerizable lipid and combination thereof with the fatty acid that ether and ester are connected.Certainly, the compound that is understood as lipid by those skilled in the art except those specifically described herein is also covered by the compositions and methods of the present invention.

[0109] In a specific embodiment, oil comprises neutral fat.Neutral fat refers to low molecular alcohol and fatty acid, also referred to as fatty acid ester (fatty acid ester, FAE) or fatty acid alkyl ester (fatty acid alkyl ester, FAAE).According to the number of fatty acid, fatty acid ester can be monoester, diester or triester.When alcohol is glycerol, then FAE is called glyceride, and similarly, according to the number of fatty acid esterified with glycerol molecule, glyceride can be monoglyceride, diglyceride or triglyceride respectively.

[0110] In a specific embodiment, lipid comprises fatty acid ester or fatty acid alkyl ester. In a preferred embodiment, lipid comprises monoester, diester and / or triester. In another specific embodiment, oil comprises a blend of fatty acid ester. In another embodiment, oil comprises a blend of glyceride. In another embodiment, oil comprises a blend of monoglyceride, diglyceride or triglyceride.

[0111] Fatty acid is typically a molecule comprising a carbon chain having an acidic portion (e.g., carboxylic acid) at the end of the chain. The carbon chain of fatty acid can be any length, as long as the lipid molecule has a transition temperature of less than about 15°C or lower. For example, fatty acid can include about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29 to about 30 or more carbon atoms, and any range that can be derived therefrom.

[0112] The transition temperature is the point at which a phospholipid membrane becomes more fluid (changes from a tightly ordered "gel" or "solid" phase to a liquid crystal phase), in which individual molecules have greater freedom of movement (see discussion in New, 1990). This parameter can be measured for a single lipid or for a composition comprising more than one lipid.

[0113] The fatty acids of FAEs, and more particularly the fatty acids of triglycerides, can be saturated, monounsaturated, and polyunsaturated, depending on the number of carbon-carbon double bonds (C=C) in the aliphatic chain. In aliphatic chains, saturated fatty acids do not contain carbon-carbon double bonds. Some examples of saturated fatty acids include, for example, palmitic acid and stearic acid. In aliphatic chains, monounsaturated fatty acids contain a single carbon-carbon double bond (C=C). Some examples of monounsaturated fatty acids include, for example, oleic acid and palmitoleic acid. In aliphatic chains, polyunsaturated fatty acids (also called PUFAs) contain at least two carbon-carbon double bonds.

[0114] Some examples of polyunsaturated fatty acids include, for example, linoleic acid (two C=C) and linolenic acid (three C=C). In addition, polyunsaturated fatty acids include ω-3 fatty acids and ω-6 fatty acids, depending on the position of the final C=C bond in the aliphatic chain. For example, linoleic acid is an ω-6 fatty acid, while linolenic acid is an ω-3 fatty acid.

[0115] Omega-3 fatty acids, also known as omega-3 oils, omega-3 fatty acids or n-3 fatty acids, are polyunsaturated fatty acids (PUFAs) characterized by the presence of a double bond three atoms away from the terminal methyl group in their chemical structure. They are widely distributed in nature, are important components of animal lipid metabolism, and they play an important role in human diet and human physiology. The three omega-3 fatty acids involved in human physiology are alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). ALA can be found in plants, while DHA and EPA are found in algae and fish. Marine algae and phytoplankton are the main sources of omega-3 fatty acids. DHA and EPA accumulate in fish that eat these algae. Common sources of vegetable oils containing ALA include walnuts, edible seeds and flaxseeds, while sources of EPA and DHA include fish and fish oils and algae oils. The term "ω-3 fatty acids" includes natural and synthetic ω-3 fatty acids, as well as pharmaceutically acceptable esters, free acids, triglycerides, derivatives, conjugates (see, e.g., U.S. Patent Application Publication No. 2004 / 0254357 to Zaloga et al. and U.S. Patent No. 6,245,811 to Horrobin et al., each of which is incorporated herein by reference), precursors, salts, and mixtures thereof. Some examples of ω-3 fatty acid oils include, but are not limited to, ω-3 polyunsaturated long-chain fatty acids, such as eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), heneicosapentaenoic acid (HPA), docosapentaenoic acid (DPA), eicosatetraenoic acid (ETA), eicosatrienoic acid (ETE), and octadecatetraenoic acid (i.e., stearidonic acid, STA); esters of ω-3 fatty acids with glycerol, such as monoglycerides, diglycerides, and triglycerides; and esters of ω-3 fatty acids with primary, secondary, and / or tertiary alcohols, such as, for example, fatty acid methyl esters and fatty acid ethyl esters. The omega-3 fatty acids, esters, triglycerides, derivatives, conjugates, precursors, salts and / or mixtures thereof according to the present disclosure can be used in their pure form and / or as a component of an oil, for example, as a marine oil (e.g., fish oil and purified fish oil concentrates), algal oil, microbial oil, and plant-based oil.

[0116] In some embodiments of the present disclosure, at least one of the ω-3 fatty acids of the fatty acid oil mixture has a cis configuration. Some examples include, but are not limited to, (all-Z)-9,12,15-octadecatrienoic acid (ALA), (all-Z)-6,9,12,15-octadecatrienoic acid (STA), (all-Z)-1 1,14,17-eicosatrienoic acid (ETE), (all-Z)-5,8,1 1,14,17-eicosapentaenoic acid (EPA), (all-Z)-4,7,10,13,16,19-docosahexaenoic acid (DHA), (all-Z)-8,1 1,14,17-eicosatetraenoic acid (ETA), (all-Z)-7,10,13,16,19-docosapentaenoic acid (DPA), (all-Z)-6,9,12,15,19-heneicosopentaenoic acid (HPA); (all-Z)-5,8,1 1,14-eicosatetraenoic acid, (all-Z)-4,7,10,13,16-docosapentaenoic acid (osbond acid), (all-Z)-9,12-octadecadienoic acid (linoleic acid), (all-Z)-5,8,1 1,14-eicosatetraenoic acid (AA), (all-Z)-6,9,12-octadecatrienoic acid (GLA); (Z)-9-octadecenoic acid (oleic acid), 13(Z)-docosapentaenoic acid (erucic acid), (R-(Z))-12-hydroxy-9-octadecenoic acid (ricinoleic acid).

[0117] Omega-6 fatty acids (also called ω-6 fatty acids or n-6 fatty acids) are a family of polyunsaturated fatty acids having a common final carbon-carbon double bond at the n-6 position (i.e., the sixth bond counted from the methyl end). Some examples of ω-6 fatty acids include linoleic acid (LA), gamma-linolenic acid (GLA), calendic acid, eicosadienoic acid, dihomo-gamma-linolenic acid (DGLA), arachidonic acid (AA, ARA), docosadienoic acid, adrenic acid, osbond acid, tetracosatetraenoic acid, tetracosopentaenoic acid; esters of ω-6 fatty acids with glycerol, such as monoglycerides, diglycerides, and triglycerides; and esters of ω-6 fatty acids with primary, secondary, and / or tertiary alcohols, such as fatty acid methyl esters and fatty acid ethyl esters. The omega-6 fatty acids, esters, triglycerides, derivatives, conjugates, precursors, salts and / or mixtures thereof according to the present disclosure may be used in their pure form and / or as a component of an oil.

[0118] In a specific embodiment, the oil is a vegetable oil, a microbial oil, a krill oil, or a fish oil.

[0119] In another embodiment, the oil is a blended oil comprising any of vegetable oil, microbial oil, and / or fish oil.

[0120] In another embodiment, the oil is a blend of fatty acids, the relative amount of each fatty acid can affect the overall characteristics of the oil, particularly its ability to resist oxidation and stabilize compounds suspended therein.

[0121] In certain embodiments, oil is rich in polyunsaturated or monounsaturated fatty acids.In the context of the present invention, the term "enrichment" is used to define such oil: the polyunsaturated and / or monounsaturated fatty acids greater than 20% w / w, greater than 25% w / w, 30% w / w, greater than 35% w / w, greater than 40% w / w, greater than 45% w / w, greater than 50% w / w, greater than 55% w / w, greater than 60% w / w or greater than 70% w / w of the gross weight comprising the oil.

[0122] In other embodiments, the oil may be a plant-based oil or blend of oils.

[0123] In another embodiment, the oil can be a blend of vegetable-based oils comprising greater than 25% w / w, 30% w / w, greater than 35% w / w, greater than 40% w / w, greater than 45% w / w, greater than 50% w / w, greater than 55% w / w, greater than 60% w / w, or greater than 70% w / w of polyunsaturated fatty acids, including omega-6 fatty acids and omega-3 fatty acids.

[0124] "Vegetable oil" refers to any edible oil obtained from a plant. Typically, vegetable oils are extracted from the seeds or grains of the plant. Vegetable oils are derived from some seeds, nuts, grains, and fruits. Vegetable oils consist of a complex mixture of triacylglycerols (TAGs; typically >95%) and some small amounts of diacylglycerols (typically <5%). Other minor components are tocopherols / tocotrienols (up to 900 mg kg-1) and phytosterol esters / phytosterols (up to 1%). Specialized chromatographic analysis can be used to confidently characterize vegetable oils by determining their TAG composition as well as the fatty acid composition and minor components.

[0125] The term "triacylglycerol" ("TAG") refers to a neutral lipid composed of three fatty acyl residues esterified to a glycerol molecule. TAGs can contain long-chain PUFAs and saturated fatty acids, as well as short-chain saturated and unsaturated fatty acids.

[0126] "Microorganism oil (MO)" or "microbial oil", also known as single cell oil (SCO), consists of intracellular storage lipids (triacylglycerols). It is similar to vegetable oil and is another biologically produced oil. They are produced by oleaginous microorganisms, which is a term for those bacteria, molds, algae and yeasts that can accumulate 20% to 80% of their biomass as lipids. The accumulation of lipids occurs at the end of the logarithmic phase and continues during the stationary phase until the carbon source begins to decrease with nutritional limitation. Oleaginous microorganisms are also a potential source of such fatty acids.

[0127] The most important source is some species of yeast, which are able to convert food into triglycerides and accumulate the resulting lipids when fed carbohydrates.

[0128] PUFA produced by MO through fermentation is a good and renewable source of PUFA. Some fungal species, such as Mortierella spp., including M. elongate, M. isabellina and M. alpina (Lounds et al., 2007), are considered to be good sources of PUFA. Some Phythium spp. and Phytophtora spp. can also produce ω-3 PUFA (O'Brien et al., 1993). Porphyridium cruentum (red marine algae) produces large amounts of EPA and arachidonic acid (AA). However, only a few Gram-negative marine bacteria (such as Flexibacter and Shewanella sp.) can produce PUFA (Akimoto et al., 1990).

[0129] In a specific embodiment, the lipid carrier is fish oil or a microbial oil enriched with DHA or EPA.

[0130] Fish oil is oil derived from the tissue of oily fish. Fish oil contains the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are precursors to certain eicosanoids that are known to reduce inflammation in the body and improve hypertriglyceridemia.

[0131] "Fish oil" refers to oil derived from the tissues of oily fish. Some examples of oily fish include, but are not limited to, menhaden, anchovy, herring, capelin, cod, etc. Fish oil is a typical component of feeds used in aquaculture.

[0132] "Menhaden" refers to forage fish of two marine fish genera, Brevoortia and Ethmidium, in the Clupeidae family. Recent taxonomic work using DNA comparisons has managed North American menhaden into large (Gulf menhaden and Atlantic menhaden) and small (Finescale menhaden and yellowfin menhaden) nomenclature (Anderson, JD, Fishery Bulletin, 105(3):368-378).

[0133] "Anchovies," from which anchovy meal and anchovy oil are produced, are a family of small, common saltwater forage fish (Engraulidae). There are approximately 140 species in 16 genera found in the Atlantic, Indian, and Pacific Oceans.

[0134] The term "krill" refers to a small crustacean of the order Euphausiacea and is found in all of the world's oceans. As used herein, "krill oil" refers herein to any mixture of extracted lipids derived from any part of the krill organism, which may include oils obtained directly from krill, oils derived from krill sources and further modified / processed, and combinations thereof. Krill oil is a unique marine oil containing ω-3 or n-3 fatty acids (FAs), wherein the bioactive eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are primarily present (i.e., accounting for up to 35% w / w of the FA spectrum) in phospholipids or PLs (up to 95% w / w), and the oil contains up to 60% PLs and up to 45% triglycerides.

[0135] Krill oil contains phospholipids linked to omega-3 fatty acids. For example, the krill oil may contain phospholipids containing omega-3 fatty acids in an amount of about 20% to about 60% (e.g., about 30% to about 50%) based on the weight of the krill oil. In an exemplary embodiment, the krill oil may contain triglycerides containing omega-3 fatty acids in an amount of less than about 30% (e.g., less than about 5%) based on the weight of the krill oil.

[0136] In an exemplary embodiment, the predetermined amount of phospholipids containing ω-3 fatty acids includes ω-3 fatty acids connected to the first and second positions of phospholipids instead of the third position of phospholipids. That is, the predetermined amount of phospholipids containing ω-3 fatty acids can include ω-3 fatty acids at the second position (i.e., the middle position) of phospholipids. For example, the phospholipids containing ω-3 fatty acids containing ω-3 fatty acids connected to the first and second positions of phospholipids instead of the third position of phospholipids can be present in an amount of about 70% to about 80% (e.g., about 80% to about 95%) based on the gross weight of the phospholipids containing ω-3 fatty acids.

[0137] In an exemplary embodiment, the marine crustacean oil or krill oil can be distinguished from fish oil based on at least: (1) phospholipid content, (2) content of phospholipids containing ω-3 fatty acids, (3) content of triglycerides containing ω-3 fatty acids, and / or (4) content of phospholipids containing ω-3 fatty acids that contain ω-3 fatty acids attached to the first and second positions of the phospholipids rather than the third position of the phospholipids. For example, the marine crustacean oil or krill oil can contain a higher concentration of phospholipids containing ω-3 fatty acids, a lower concentration of triglycerides containing ω-3 fatty acids, and / or a higher content of phospholipids containing ω-3 fatty acids that contain ω-3 fatty acids attached to the first and second positions of the phospholipids rather than the third position of the phospholipids.

[0138] Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is a major structural component of the human brain, cerebral cortex, skin, and retina. In the physiological literature, it is designated 22:6(n-3). It can be synthesized from α-linolenic acid or obtained directly from maternal milk (breast milk), fatty fish, fish oil, or algae oil. The structure of DHA is a carboxylic acid (-oic acid) with a 22-carbon chain (docosa - from the ancient Greek for 22) and six (hexa-)cis double bonds (-en-); the first double bond is located at the third carbon from the ω end. [3] Its conventional name is cervonic acid (from the Latin cerebrum, meaning "brain"), its systematic name is all-cis-docosa-4,7,10,13,16,19-hexaenoic acid, and in fatty acid nomenclature, its abbreviated name is 22:6(n-3).

[0139] Eicosapentaenoic acid (EPA) is an ω-3 fatty acid. In the physiological literature, it is named 20:5 (n-3). It also has the customary name timnodonic acid. In the chemical structure, EPA is a carboxylic acid with a 20 carbon chain and 5 cis double bonds; the first double bond is located at the third carbon from the ω end. EPA is a polyunsaturated fatty acid (PUFA), which serves as a precursor of prostaglandin-3 (which inhibits platelet aggregation), thromboxane-3 and leukotriene-5 eicosanoids. EPA is a precursor and hydrolysis decomposition product of eicosapentaenoyl ethanolamide (EPEA:C22H35NO2; 20:5, n-3).

[0140] Most of the docosahexaenoic acid in multicellular organisms and fish that get their cold-water marine food comes from photosynthetic and heterotrophic microalgae, and they become more concentrated in organisms the higher they are in the food chain. DHA is also commercially produced by the following microalgae: Crypthecodinium cohnii and another species of Schizochytrium. DHA made using microalgae is vegetarian.

[0141] In some embodiments of the present disclosure, the fatty acid oil has a weight ratio of EPA:DHA of about 1:10 to about 10:1, about 1:8 to about 8:1, about 1:6 to about 6:1, about 1:5 to about 5:1, about 1:4 to about 4:1, about 1:3 to about 3:1, or about 1:2 to 2:1. In at least one embodiment, the fatty acid oil mixture has a weight ratio of EPA:DHA of about 1:2 to about 2:1. In at least one embodiment, the fatty acid oil mixture has a weight ratio of EPA:DHA of about 1:1 to about 2:1. In at least one embodiment, the fatty acid oil mixture has a weight ratio of EPA:DHA of about 1:2 to about 1:3.

[0142] The term "enriched in DHA or EPA" is used to refer to the weight percentage of DHA or EPA relative to the total weight of fatty acids of the oil, which ranges from 30 to 100%, preferably 40 to 90%, 50 to 80%, and more preferably the weight percentage of DHA or EPA is 60 to 70%.

[0143] In a specific embodiment, the carrier is a vegetable oil selected from the group consisting of sunflower oil, coconut oil, canola oil, cottonseed oil, olive oil, palm oil, rapeseed oil, safflower oil, almond oil, beech nut oil, brazil nut oil, cashew oil, hazelnut oil, macadamia oil, mongongo nut oil, pecan oil, pine nut oil, pistachio oil, walnut oil, pumpkin seed oil, grapefruit seed oil, lemon oil, orange oil, acai oil, black seed oil, black currant seed oil, borage seed oil, evening primrose oil, linseed oil, amaranth oil, apricot oil, apple seed oil, argan oil, avocado oil, babassu oil, ben oil, borneo tallow nut oil, cape chestnut oil, carob pod oil, cocklebur oil, cohune oil, cilantro seed oil, date seed oil,

[0047] The present invention relates to oils comprising the following: oils of the type described herein, which are preferably linseed oil, dika oil, grape seed oil, kapok seed oil, kenaf seed oil, lallemantia oil, mafura oil, marula oil, mustard oil, nige seed oil, okra seed oil, papaya seed oil, perilla seed oil, persimmon seed oil, pequi oil, pili nut oil, pomegranate seed oil, poppy seed oil, pracaxi oil, prune kernel oil, quinoa oil, ramtil oil, rice bran oil, royle oil, sacha inchi oil, sapote oil, seje oil, taraminra oil, tea seed oil, thistle oil, tigernut oil, tomato seed oil, wheat germ oil, peanut oil, sesame oil, soybean oil, corn oil, and mixtures thereof, preferably sunflower seed oil.

[0144] In a particular embodiment, the oil is sunflower oil.

[0145] Sunflower oil is a non-volatile oil squeezed from the seeds of sunflower (Helianthus annuus). Sunflower oil is commonly used as frying oil in food and as an emollient in cosmetic preparations. Sunflower oil is mainly composed of linoleic acid (polyunsaturated fat) and oleic acid (monounsaturated fat). Sunflower oil is mainly triglycerides. The British Pharmacopoeia lists the following profile: palmitic acid (saturated) 5%, stearic acid (saturated) 6%, oleic acid (monounsaturated ω-9) 30%, linoleic acid (polyunsaturated ω-6) 59%. Four types of sunflower oils with different concentrations of fatty acids are produced through plant breeding and industrial processing: high linoleic acid, high oleic acid, medium oleic acid, and high stearic acid and high oleic acid combination. High linoleic acid: 69% linoleic acid; high oleic acid: 82% oleic acid; medium oleic acid: 65% oleic acid; high stearic acid and high oleic acid: 18% stearic acid and 72% oleic acid. In the context of the present invention. Any one of the four types of sunflower oil or any combination thereof is contemplated as the oil vehicle for the compositions of the present invention.

[0146] In a specific embodiment, the carrier is a vegetable oil or a vegetable-based oil blend comprising saturated fatty acids (SAFA), monounsaturated fatty acids (MUFA), and polyunsaturated fatty acids (PUFA).

[0147] In another embodiment, the vegetable oil or vegetable-based oil blend comprises about 5% w / w to 95% w / w, about 10% w / w to 80% w / w, about 10% w / w to 70% w / w, about 10% w / w to 60% w / w, about 10% w / w to 50% w / w, about 10% w / w to 40% w / w, about 10% w / w to 30% w / w, about 10% w / w to 20% w / w MUFAs based on the total weight of the oil.

[0148] In another specific embodiment, the ratio of ω-6 / ω-3 fats in the vegetable oil or vegetable based oil blend is from 0.1 to 650, 1 to 650, 10 to 650, 20 to 650, 30 to 650, 40 to 650, 50 to 650, 60 to 650, 70 to 650, 80 to 650, 90 to 650, 100 to 650, 150 to 650, 200 to 650, 250 to 650, 300 to 650, 350 to 650, or 400 to 650.

[0149] In another embodiment, the vegetable oil or vegetable-based oil blend comprises about 1% w / w to 80% w / w, about 20% w / w to 70% w / w, about 30% w / w to 65% w / w, about 4% w / w to 65% w / w, or about 50% w / w to 65% w / w omega-6 fatty acids, based on the total weight of the oil.

[0150] In another embodiment, the vegetable oil or vegetable-based oil blend comprises about 0.05% w / w to 70% w / w, about 0.05% w / w to 60% w / w, about 0.05% w / w to 50% w / w, about 0.05% w / w to 40% w / w, about 0.05% w / w to 30% w / w, about 0.05% w / w to 30% w / w, about 0.05% w / w to 20% w / w, about 0.1% w / w to 10% w / w, or about 0.1% w / w to 1% w / w omega-3 fatty acids.

[0151] Fatty acids are sometimes named using numerical expressions, in which the number of carbon atoms, the number of double bonds, and the position of the double bonds are indicated in a simplified manner by combining numbers and letters of the alphabet. For example, a saturated fatty acid with 20 carbon atoms can be named C20:0, a monovalent unsaturated fatty acid with 18 carbon atoms is named C18:1, eicosapentaenoic acid is named C20:5n-3, etc. The symbol n- represents the position of the double bond counted from the terminal methyl group in the fatty acid; for example, n-3 represents that the bond between the third carbon atom and the fourth carbon atom counted from the terminal methyl group in the fatty acid is a double bond. This naming method is well known to those skilled in the art, and the fatty acids named according to this method can be easily determined by any technician in the art.

[0152] In another specific embodiment, oil comprises highly unsaturated fatty acids or its alkyl ester.The term highly unsaturated fatty acids used herein means the fatty acid with 18 or more carbon atoms and 3 or more double bonds.For example, highly unsaturated fatty acids can be the fatty acid with 20 or more carbon atoms and 3 or more or even 4 or more double bonds, or the fatty acid with 20 or more carbon atoms and 5 or more double bonds.Exemplary highly unsaturated fatty acids include linolenic acid (18:3n-3), linolenic acid (18:3n-6), dihomolinolenic acid (20:3n-6), arachidonic acid (20:4n-6), eicosapentaenoic acid (C20:5n-3), docosapentaenoic acid (22:5n-6) and docosahexaenoic acid (22:6n-3).

[0153] The composition containing highly unsaturated fatty acid or its alkyl ester used herein means a fatty acid composition containing highly unsaturated fatty acid or a fatty acid alkyl ester composition containing the alkyl ester of highly unsaturated fatty acid. Here, the fatty acid composition is a composition containing fatty acid as a main component, and the fatty acid alkyl ester composition is a composition containing the alkyl ester of fatty acid as a main component.

[0154] In the present invention, if highly unsaturated fatty acids are obtained as the main distillate after enrichment by distillation, their alkyl esters are not particularly limited. Highly unsaturated fatty acids can be eicosapentaenoic acid, docosahexaenoic acid, dihomolinolenic acid, arachidonic acid or a combination thereof. In some preferred embodiments, highly unsaturated fatty acids can be eicosapentaenoic acid, docosahexaenoic acid or a combination thereof. In some more preferred embodiments, highly unsaturated fatty acids can be eicosapentaenoic acid.

[0155] In certain embodiments, oil is rich in polyunsaturated or monounsaturated fatty acids and / or alkyl esters.In the context of the present invention, term "enriching" is used to define such oil, and described oil comprises polyunsaturated and / or monounsaturated fatty acids and / or alkyl esters greater than 20%w / w, greater than 25%w / w, 30%w / w, greater than 35%w / w, greater than 40%w / w, greater than 45%w / w, greater than 50%w / w, greater than 55%w / w, greater than 60%w / w of the total weight of the oil.

[0156] In a particular embodiment, the oil is enriched in polyunsaturated fatty acids and / or omega-3 fatty acids, the term enriched as defined above.

[0157] Another class of lipids includes phospholipids. Therefore, in another embodiment, oil includes phospholipids. Phospholipids generally include glycerol or sphingosine moieties, ionic phosphate groups and one or more fatty acids producing amphipathic compounds. The type of phospholipids includes, for example, phosphoglycerides and sphingomyelin (sphingophospholipid) (e.g., sphingomyelin (sphingomyelin)), in which the phosphate group is connected to the first carbon of the glycerol of diglyceride in the phosphoglyceride, and in which the phosphate group is esterified to sphingosine amino alcohol. For example, in some embodiments, the lipid molecule is dilaurylphosphatidylcholine, which is a phospholipid comprising two completely saturated fatty acid moieties.

[0158] Of course, phospholipids may contain additional chemical groups, such as, for example, alcohols linked to the phosphate groups.One of ordinary skill in the art will be familiar with the broad class of agents known as phospholipids, and the chemical groups that can be linked to the phospholipids.

[0159] Those of ordinary skill in the art will be familiar with the many other classes of lipids that are known to exist.

[0160] Lipid can be obtained from natural origin, commercial source or chemical synthesis, as known to those of ordinary skill in the art.For example, phospholipid can be from natural source, for example egg phosphatidylcholine or soybean phosphatidylcholine, brain phosphatidic acid, brain phosphatidylinositol or plant phosphatidylinositol, heart cardiolipin and plant phosphatidylethanolamine or bacterial phosphatidylethanolamine.In another example, the lipid that is suitable for use according to the present invention can be obtained from commercial source.

[0161] Some examples of other fatty acid or fatty acid alkyl ester compositions or mixtures thereof (fatty acid oil mixtures) encompassed by the present disclosure include, but are not limited to, Ph. Eur. Omega-3 Ethyl Esters 90 and purified marine oils, such as Ph. Eur. Omega-3 acid triglycerides, Ph. Eur. Omega-3 acid ethyl esters 60, Ph. Eur. Omega-3 acid enriched fish oil monographs and / or fatty acids defined in, for example, the USP fish oil monograph.

[0162] Some commercial examples of fatty acid oil mixtures containing different fatty acids suitable for the present disclosure include, but are not limited to: Incromega TM Omega-3 marine oil concentrates, such as

[0163] Incromega TM TG7010 SR,Incromega TM E7010 SR,Incromega TM TG6015,Incromega TM EPA500TG SR,Incromega TM E400200 SR,Incromega TM E4010,Incromega TM DHA700TG SR,Incromega TM DHA700E SR,Incromega TM DHA500TG SR,Incromega TM TG3322 SR,Incromega TM E3322 SR,Incromega TM TG3322,Incromega TM E3322,Incromega TMTrio TG / EE(Croda International PLC, Yorkshire, England); EPAX2050TG, EPAX5500EE, EPAX5500TG, EPAX5000EE, EPAX5000TG, EPAX6000EE, EPAX60 00TG,EPAX6000FA,EPAX6500EE,EPAX6500TG,EPAX4510TG,EPAX1050TG,EPAX6015TG / EE,EPAX4020TG,and EPAX4020EE

[0164] (EPAX is a wholly owned subsidiary of the Norwegian company Austevoll Seafood ASA); Final drug products K85EE and AGP 103 (PronovaBioPharma Norge AS); EPA / DHA fish oil concentrate (Ocean Nutrition Canada); DHAFNO "functional nutritional oil" and DHACL "clear liquid" (Lonza); Superba TM Krill oil (Aker); omega-3 products containing DHA produced by Martek; Neptune krill oil (Neptune); cod liver oil products and anti-reflux fish oil concentrate (TG) produced by Mollers; Lysi omega-3 fish oil; Seven Seas Cod liver oil blend (Seven Seas); Fri Flyt omega-3 (Vesteralens); and Epadel (Mochida). These commercial embodiments provide a variety of omega-3 fatty acids, combinations, and other components that are the result of an interesterification process or preparation method to obtain omega-3 fatty acids from a variety of sources (e.g., marine, algae, microbial, and plant-based sources).

[0165] Some examples of synthetic oils include, without limitation, Maisine, Labrafac Lipophilic 1349, Labrafac MC60, and Plurol Oleique.

[0166] Lipid can be crude oil or refined oil. The term crude oil used herein means the oil of a mixture of lipids such as extracted from an organism. The term refined oil used herein means the oil obtained from crude oil by carrying out at least one fat / oil refining step selected from the following: a degumming step, a deacidification step, a decolorization step, and a deodorization step that make off-target substances (such as phospholipids and sterols) be removed from crude oil. Those skilled in the art can distinguish crude oil from refined oil by conventional analysis.

[0167] Compositions comprising the compounds of the invention may be dissolved or dispersed in oil to provide solutions or dispersions. One of ordinary skill in the art will be familiar with a range of techniques that can be used to disperse or solubilize drugs in oils. For example, the compounds of the invention may be dispersed in a solution containing lipids, dissolved with lipids, emulsified with lipids, mixed with lipids, combined with lipids, covalently bonded with lipids, contained in lipids as suspensoids, contained in micelles or liposomes or compounded with micelles or liposomes, or otherwise associated with lipids or lipid structures by any means known to one of ordinary skill in the art.

[0168] Thus, according to the above, the composition may be a solution or a dispersion. Likewise, the oil may also comprise micelles, microemulsions, macroemulsions and liposomes.

[0169] In some embodiments, the carrier of the delivery system encapsulates the compound of the invention. The terms "encapsulate" and "embed" are used interchangeably herein and refer to the incorporation of a substance or molecule (e.g., a biologically active compound) into or associated with an oil. For example, in those embodiments in which the oil is a liposome, the substance or molecule may be associated with a lipid bilayer. The compound may also be encapsulated in a micelle, microemulsion, or macroemulsion.

[0170] The term "micelle" refers to a colloidal aggregate of amphiphilic molecules formed at a well-defined concentration known as the critical micelle concentration. The micelle is oriented with the non-polar portion of the lipid molecules inside the micelle and the polar portion on the outer surface, exposed to water. The typical number of aggregated molecules in a micelle (aggregate number) is about 50 to about 100.

[0171] Liposome is a self-assembled substantially spherical vesicle comprising a lipid bilayer surrounding an aqueous interior or core, wherein the lipid bilayer comprises an amphiphilic lipid having a hydrophilic head group and a hydrophobic tail, wherein the hydrophilic head group of the amphiphilic lipid molecule is oriented toward the aqueous solution, and the hydrophobic tail is oriented toward the interior of the bilayer. Therefore, the lipid bilayer structure comprises two relative monolayers, which are referred to as "inner leaflet" and "outer leaflet", wherein the hydrophobic tail is shielded from contact with the surrounding medium. "Inner leaflet" is a monolayer in which the hydrophilic head group is oriented toward the aqueous core of the liposome. "Outer leaflet" is a monolayer comprising amphiphilic lipids in which the hydrophilic head group is oriented toward the outer surface of the liposome. The diameter of the liposome is generally about 25nm to about 1 μm. The term "liposome" encompasses multilayer liposomes consisting of two to hundreds of concentric lipid bilayers alternating with an aqueous layer and unilamellar vesicles consisting of a single lipid bilayer.

[0172] Liposomes contain one or more lipids. The lipids can be neutral, anionic or cationic lipids at physiological pH.

[0173] As used herein, the term "emulsion" refers to a mixture of two immiscible liquids in which one liquid forms a continuous phase and droplets of the other liquid are dispersed as a discontinuous phase in the continuous phase.

[0174] As stated above, an "emulsion" is a heterogeneous system composed of at least two immiscible liquids or phases in the presence of an active surface agent such as a surfactant or emulgent (emulsifier).

[0175] In the context of the present invention, the term emulsion encompasses microemulsions and macroemulsions.

[0176] Microemulsions as described herein are essentially swollen micelles, but not all micellar solutions can swell to form microemulsions. Microemulsions are thermodynamically stable, spontaneously formed, and contain extremely small particles. The droplets in a microemulsion are typically about 10 nm to about 100 nm in diameter. In contrast, the term macroemulsion refers to droplets with a diameter greater than about 100 nm.

[0177] Macroemulsions (also commonly referred to as emulsions) are thermodynamically unstable systems in which the particle size is 1 to 100 μm (order of magnitude), and most generally they do not form spontaneously. Emulsions consist of droplets of a dispersed phase in a continuous phase. Macroemulsions scatter light effectively and therefore appear milky because their droplets are larger than the wavelength of light. Simple emulsions are classified as water-in-oil (W / O) or oil-in-water (O / W) depending on the phase that constitutes the dispersed phase. From both a fundamental and a technical perspective, an important aspect of preparing emulsions is to obtain the desired droplet size and narrow size distribution. Surfactants (as primary emulsifiers) are used to reduce the interfacial tension between the two phases and induce emulsion stability over a useful time. Emulsions can be stabilized in other ways with other emulsifiers (e.g., polymers, solid particles, or proteins).

[0178] In a preferred embodiment, the emulsion is an oil-in-water (O / W) emulsion. In an O / W emulsion, droplets of oil are dispersed in an aqueous phase. In the context of the present invention, the major oil component of the emulsion is a compound of the present invention. According to certain embodiments, the oil emulsion of the present invention is an oil-in-water emulsion with an average droplet size of less than 1.0 micron. According to certain typical embodiments, the average droplet size of the emulsion is about 30nm to 500nm.

[0179] Oil-in-water emulsions (O / W) are dispersions of oil droplets or colloidal particles in an aqueous medium, wherein the colloidal particles have an oily core surrounded by an interfacial film of an emulsifier and a surface acting agent or surfactant. According to the teachings of the present invention, the major component of the oil component of the emulsion is a compound of the present invention.

[0180] In another embodiment, the emulsion is a multiple emulsion.In another embodiment, the emulsion is an O / W / O emulsion.

[0181] According to the present invention, O / W / O emulsions are multiple emulsions in which the aqueous phase (hydrophilicity) separates the internal oil phase from the external oil phase. The internal phase and the external phase may be the same or may not be the same. Multiple emulsions are complex polydisperse systems in which both an oil-in-water emulsion and a water-in-oil emulsion (stabilized by a lipophilic surfactant and a hydrophilic surfactant, respectively) exist simultaneously. The ratio of these surfactants is important in obtaining stable multiple emulsions. Multiple emulsions are also referred to as emulsions of emulsions or double or triple emulsions because the internal phase itself contains dispersed globules that are miscible with the continuous phase. These are also referred to as liquid membrane systems because two miscible phases are separated by an immiscible phase (liquid membrane), which acts as a thin semipermeable membrane through which a solute must diffuse to pass from one phase to another.

[0182] Any emulsifier and / or surfactant that does not interfere with the activity of the compounds of the invention and the biocompatibility characteristics of the emulsion may be used in accordance with the teachings of the present invention. In addition, surfactants that can dissolve the oil in micelles are also suitable for the delivery system.

[0183] "Surfactant" refers to an amphiphilic compound generally recognized in the art as having surface active properties. Surfactants generally include anionic compounds, cationic compounds, nonionic compounds and zwitterionic compounds. As further used herein, an emulsifier is equivalent to a surfactant.

[0184] For example, a surfactant can reduce the surface tension of a liquid or the surface tension between two liquids. For example, a surfactant according to the present disclosure can reduce the surface tension between a fatty acid oil mixture and an aqueous solution.

[0185] Chemically speaking, a surfactant is a molecule having at least one hydrophilic portion and at least one hydrophobic (i.e., lipophilic) portion. Surfactant properties can be reflected in the hydrophilic-lipophilic balance (HLB) value of a surfactant, where the HLB value is a measure of the degree of hydrophilicity of a surfactant relative to its lipophilicity. HLB values ​​are typically between 0 and 20, where an HLB value of 0 indicates a high hydrophilic character and an HLB value of 20 indicates a high lipophilic character. Surfactants are typically used in combination with other surfactants, where the HLB values ​​are additive. The HLB value of a surfactant mixture can be calculated as follows:

[0186] HLBA (fraction of surfactant A) + HLBB (fraction of surfactant B) = HLBA + B mixture

[0187] Surfactants are generally classified as ionic surfactants, such as anionic surfactants or cationic surfactants and nonionic surfactants. If a surfactant contains two oppositely charged groups, the surfactant is called a zwitterionic surfactant. Other types of surfactants include, for example, phospholipids.

[0188] In at least one embodiment of the present disclosure, the composition comprises at least one surfactant selected from the group consisting of nonionic surfactants, anionic surfactants, cationic surfactants, and zwitterionic surfactants.

[0189] In a preferred embodiment, the surfactant is selected from polysorbates, sorbitan esters, PEO-PPO block copolymers, POE alkyl ethers, POE castor oil, POE hydrogenated castor oil, POE stearate, POE vitamin E, sucrose esters, alkyl polyglucosides, polyglycolized glycerides, polyether alcohols, phospholipids, alkyl sulfates.

[0190] Further non-limiting examples of surfactants suitable for the present disclosure are mentioned below.

[0191] According to the present disclosure, other exemplary nonionic surfactants include, but are not limited to, diacetyl monoglyceride, diethylene glycol monopalmitostearate, ethylene glycol monopalmitostearate, glyceryl behenate, glyceryl distearate, glyceryl monolinoleate, glyceryl monooleate, glyceryl monostearate, polyethylene glycol cetearyl ethers (e.g., cetomacrogol 1000 and polyoxyl 20 cetearyl ether), polyethylene glycol 15 hydroxystearate, polyethylene glycol lauryl ethers (e.g., laureth 4 and lauroyl alcohol 400), polyethylene glycol monomethyl ether, polyethylene glycol oleyl ethers (e.g., polyoxyl 10 oleyl ether), polyethylene glycol stearates (e.g., polyoxyl 40 stearate), menfegol, mono- and diglycerides, nonoxinol (e.g., nonoxynol-9, nonoxynol-10 and nonoxynol-1 1), octoxinol (e.g., octoxinol 9 and octoxinol 10), polyoxamer (e.g., polyoxalene), poloxamer 188, poloxamer 407, polyoxyethylene castor oil (e.g., polyoxyethylene 35 castor oil), polyoxyethylene hydrogenated castor oil (e.g., polyoxyethylene 40 hydrogenated castor oil), propylene glycol diacetate, propylene glycol laurate (e.g., propylene glycol dilaurate and propylene glycol monolaurate). Other examples include propylene glycol monopalmitostearate, Quillaja salsa bark, sorbitan esters, and sucrose esters.

[0192] Anionic surfactants suitable for the present disclosure include, for example, perfluorocarboxylates and sulfonates, alkyl sulfates (eg, sodium dodecyl sulfate and ammonium lauryl sulfate), ether sulfates (eg, sodium lauryl ether sulfate), and alkylbenzene sulfonates.

[0193] Cationic surfactants suitable for the present disclosure include, for example, quaternary ammonium compounds such as benzalkonium chloride, cetylpyridinium chloride Benzethonium chloride and cetyltrimethylammonium bromide or other trimethylalkylammonium salts.

[0194] Zwitterionic surfactants include, but are not limited to, for example, lauryl betaine, cocoamphoglycolate, and cocamidopropyl betaine.

[0195] In some embodiments of the present disclosure, surfactant may include phospholipids, derivatives thereof, or analogs thereof. Such surfactants may be, for example, selected from natural, synthetic and semisynthetic phospholipids, derivatives thereof, and analogs thereof. Some exemplary phospholipid surfactants include phosphatidylcholine with saturated, unsaturated and / or polyunsaturated lipids, such as dioleoylphosphatidylcholine, dipentadecanoylphosphatidylcholine, dilauroylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, dieicosapentaenoic acid (EPA) choline, didocosahexaenoic acid (DHA) choline, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, and phosphatidylinositol. Other exemplary phospholipid surfactants include soybean lecithin, egg lecithin, dioleylphosphatidylcholine, distearoylphosphatidylglycerol, PEGylated phospholipids, and dimyristoylphosphatidylcholine.

[0196] According to certain embodiments, the emulsifier is selected from one or more of the following: polyoxyethylene polyoxypropylene copolymer (trade name: poloxamer TM ), transesterification product of natural vegetable oil triglyceride and polyalkylene polyol (trade name: Labrafil M 2125 TM 、Labrafil M 1944CS TM Labrasol TM ), fatty acid glycerides (trade name: Plurol TM oleique), polyoxyethylene 40 hydrogenated castor oil (trade name: polyethylene glycol alkyl ether (trade name: Brij TM ), polyoxyethylene sorbitan triglyceride (trade name: Tween TM), sorbitan fatty acid esters (trade name: SpanCremophor RH 40), vitamin E polyethylene glycol succinate (vitamin E polyethylene glycol succinate), lecithin, sodium lauryl sulfate and bile acid and its derivatives.

[0197] Without wishing to be bound by any particular theory or mechanism of action, the higher efficacy observed for the oil-in-water emulsions of the compounds of the invention may be attributed to the improved bioavailability of the emulsified oil. The improved bioavailability may be the result of increased solubility of the active ingredient, improved stability during passage through the gastrointestinal tract, improved gastrointestinal absorption, improved cellular uptake, or a combination thereof.

[0198] According to certain typical embodiments, the compositions of the present invention are formulated as oil diluents, dispersions or emulsions for oral or parenteral administration. However, other forms of administration, including transdermal administration, are also within the scope of the present invention.

[0199] For oral administration, an effective amount of the composition can be administered in a form selected from, but not limited to, a solid state, a semi-solid state or a liquid state. Some specific examples include tablets, capsules, powders, granules, solutions, suspensions and syrups.

[0200] In terms of convenience and compliance of the subject, it is highly desirable to administer the composition of the present invention as its salt or ester in a solid dosage form. Capsules for delivery into the gastrointestinal tract are known in the art and include capsules for oral or rectal administration. Generally speaking, capsules are designed to dissolve in the aqueous environment of the gastrointestinal tract.

[0201] In a particular embodiment, the emulsion is a microemulsion.

[0202] In another embodiment, the emulsion is a self-emulsifying system.

[0203] Self-emulsifying systems are defined as isotropic mixtures of oil, surfactant and cosolvent. Self-emulsifying formulations are easily distributed in the gastrointestinal tract. The aqueous contents of the stomach and the digestive movement of the intestine provide the required environment and enough agitation for the spontaneous formation of the emulsion. Therefore, the preparation of the composition as a self-emulsifying system makes it possible to avoid the use of aqueous phase and its preparation as a capsule for oral delivery.

[0204] Compared with other drug delivery systems (such as solid dispersions, liposomes and nanoparticles), ease of manufacture and scale-up is another important advantage of self-emulsifying systems. Self-emulsifying systems require very simple and economical manufacturing facilities, such as a simple mixer with an agitator and a volumetric liquid filling device for large-scale manufacturing.

[0205] According to some typical embodiments, the self-emulsifying system comprises a compound of the present invention and at least one emulsifier, surfactant, or combination thereof.

[0206] In the context of the present invention, the term "self-emulsifying system" includes "self-microemulsifying drug delivery system" (self-microemulsifying drug delivery system, SMEDDS) or "self-emulsifying drug delivery system" (self-emulsifying drug delivery system, SEDDS). SMEDDS and SEDDS refer to compositions containing the active agent defined herein that is closely mixed with a pharmaceutically acceptable excipient, so that when diluted with an aqueous medium (e.g., water) or diluted in gastric juice, the system can dissolve the active agent to a desired concentration and produce a colloidal structure by spontaneously forming a microemulsion. The colloidal structure can be a solid or liquid particle, comprising droplets and nanoparticles. In SEDDS or SMEDDS systems, the type of the microemulsion produced will be clear or turbid, depending on the type of drug load and surfactant used.

[0207] SEDDS is an isotropic mixture of oil, hydrophobic surfactant and sometimes cosolvent, which rapidly produces fine o / w emulsions after digestive movement or gentle agitation encountered in the gastrointestinal tract. SMEDDS is an isotropic mixture of oil, hydrophilic surfactant and cosolvent, which rapidly forms O / W microemulsions after dilution in aqueous medium experienced in the gastrointestinal tract with gentle agitation. The basic difference between SEDDS and SMEDDS is that SEDDS usually produces opaque emulsions with droplet sizes higher than 300nm, while SMEDDS forms transparent microemulsions with droplet sizes less than 250nm. In addition, the oil concentration in SMEDDS is less than 20%, compared with 40% to 80% in SEDDS.

[0208] In one embodiment, SEDDS is prepared using a surfactant of HLB 512. In another embodiment, SMEDDS is prepared using a surfactant of HLB 412.

[0209] The formulation method for oral administration is known to those skilled in the art. For example, in order to prepare the composition into tablets, capsules, powders, granules, solutions or suspensions, the compounds of the present invention combined with oil or the emulsions comprising emulsions or the self-emulsifying compositions described above are preferably mixed with binders, disintegrants and / or lubricants. If necessary, the resulting composition can be mixed with diluents, buffers, infiltrating agents, preservatives, penetration enhancers and / or flavoring agents using known methods. Some examples of binders include crystalline cellulose, cellulose derivatives, corn starch and gelatin. Some examples of disintegrants include corn starch, potato starch and sodium carboxymethyl cellulose. Some examples of lubricants include talc and magnesium stearate. In addition, additives such as lactose and mannitol can also be used.

[0210] In the case of oily compositions, the composition according to the invention may also contain at least one customary excipient or additive, such as a cosolvent, such as an alcohol, for example, or an antioxidant.

[0211] The co-solvent, such as, for example, an alcohol, may be present in the composition, for example, in a ratio of 0% to 5%, in particular 1% to 5% (v / v) of the total volume of the composition.

[0212] In a particular embodiment, the composition further comprises an antioxidant.

[0213] "Antioxidants" are simply described as compounds (e.g., enzymes, organic molecules) that slow the rate of oxidation reactions or can counteract the damaging effects of oxygen. Although the term is technically applied to molecules that react with oxygen, it is generally applied to any molecule that blocks free radicals (i.e., molecules with unpaired electrons, such as hydroxyl radicals, lipid oxygen or peroxyl radicals, singlet oxygen, and peroxynitrite formed from nitrogen oxide (NO)). Free radicals are natural byproducts of cellular processes in organisms or are produced by exposure to environmental factors. In cellular organisms, free radicals can cause cell and tissue damage, which can ultimately lead to disease. Antioxidants neutralize free radicals by donating an electron of their own to the free radicals, because the radicalized antioxidant molecules are more stable as free radicals than the original free radicals.

[0214] The antioxidant can be selected from compounds commonly used in the art, for example: hydroxylated substances such as citric acid and its derivatives, in particular sodium citrate, calcium citrate or potassium citrate; ascorbic acid and its derivatives, in particular isoascorbic acid, sodium ascorbate or calcium ascorbate; thiol derivatives, such as cysteine, acetylcysteine, dithiothreitol; ethylenically unsaturated substances, such as sorbic acid, etc.

[0215] In a specific embodiment, the antioxidant is selected from alpha-tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), citric acid, calcium disodium edetate / disodium edetate, fumaric acid, malic acid, propyl gallate, tert-butylhydroquinone (TBHQ), hydroquinone, monothioglycerol, sodium bisulfite, sodium metabisulfite, sodium sulfite, or a combination thereof.

[0216] The antioxidant may be present in the composition, for example, at a ratio of 0.005% to 1% (w / v), 0.01% to 0.5% (w / v), 0.025% to 0.25% (w / v), 0.05% to 0.2% (w / v), 0.1% to 0.2% (w / v).

[0217] Preferred antioxidants are selected from ascorbic acid and its derivatives.

[0218] In another embodiment, when the carrier is an emulsion, it additionally comprises a co-surfactant.

[0219] Thus, as described above, when the carrier is an emulsion, it already contains a surfactant, and therefore, according to this embodiment, the emulsion will contain a first surfactant and a second surfactant or co-surfactant, the first surfactant and the second surfactant being different from each other. As described above, surfactants are often used in combination with other surfactants, wherein the HLB values ​​are additive.

[0220] In one embodiment, the co-surfactant is selected from the group consisting of short chain alcohols, alkane diols and triols, PEG, glycol ethers, pyrrolidine derivatives, bile salts, organic acids and salts.

[0221] Suitably, when there are 2 kinds of surfactants, each surfactant is present in an amount of about 0.5 % by weight to about 5 % by weight based on the total weight of the composition. In another embodiment, there are 3 kinds of surfactants in the preparation. Suitably, when there are 3 kinds of surfactants, each surfactant is present in an amount of about 0.5 % by weight to about 5 % by weight based on the total weight of the composition. Similarly, if there are 4 or more kinds of surfactants, they are each present in an amount of about 0.5 % by weight to about 5 % by weight based on the total weight of the composition.

[0222] The composition according to the present invention may preferably be in a form suitable for administration by the oral route, in particular a liquid form, such as an oral solution, an oral suspension, drops, etc., or an encapsulated form, such as a capsule encapsulating the liquid preparation, in particular a gelatin-based hard capsule or soft capsule.

[0223] Those of ordinary skill in the art will be familiar with a range of techniques that can be used to disperse drugs in oils. For example, the compound of formula (I) can be dispersed in a solution containing lipids, dissolved with lipids, emulsified with lipids, mixed with lipids, combined with lipids, covalently bonded to lipids, contained in lipids as a suspensoid, contained in micelles or liposomes or complexed with micelles or liposomes, or otherwise associated with lipids or lipid structures by any means known to those of ordinary skill in the art. Dispersion may or may not result in the formation of liposomes.

[0224] In the compositions of the present invention, the compound of formula (I) is combined with one or more lipids and an aqueous solvent. The present invention contemplates any concentration or amount of the compound dispersed in the lipid. For example, in certain embodiments, the ratio of the compound of formula (I): lipid (weight: weight) can be 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, 1:50 or any ratio that can be derived therefrom.

[0225] In certain embodiments, the one or more lipids of the present composition may comprise about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87% %, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49 %, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76% %, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100% or any scope that can be derived therefrom. Therefore, it is contemplated that one or more lipids of the present composition may include any lipid, lipid type or other components in any combination or percentage range. In the composition of the present invention, formula (i) compound is combined with one or more lipids and an aqueous solvent.

[0226] The present invention contemplates any concentration or amount of a compound of formula (I) dispersed in a carrier. For example, in certain embodiments, the ratio of compound: lipid (weight: weight) can be 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, 1:50, or any ratio derivable therein.

[0227] In a preferred embodiment, the ratio of compound of formula (I) (expressed in milligrams) to lipid carrier (expressed in milliliters) is 0.01:1 to 200:1, 0.01:1 to 150:1, 0.01:1 to 50, preferably 0.1:1 to 50:1 or 0.1:1 to 5:1.

[0228] More preferably, the ratio of compound of formula (i) (expressed in mg) to lipid carrier (expressed in mg) is from 0.01:1 to 200:1, from 0.01:1 to 150:1, from 0.01:1 to 100:1, more preferably from 0.1:1 to 5:1.

[0229] In another embodiment, the concentration of the compound of formula (I) is 0.01 to 200 mg / mL, preferably 0.01 to 150 mg / mL, preferably 0.01 to 50 mg / mL, preferably 0.1 to 50 mg / mL, more preferably 0.1 to 5 mg / mL; and / or wherein the concentration of the compound according to formula (I) in the composition is 0.01 to 200 mg / mL, preferably 0.01 to 150 mg / mL, preferably 0.01 to 50 mg / mL, preferably 0.1 to 50 mg / mL, more preferably 0.1 to 5 mg / mL.

[0230] In another embodiment, the composition of the invention comprises at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more of a compound of formula (I) relative to the total weight of carotenoids in the composition (all values ​​are expressed as wt %).

[0231] The term "carotenoid" as used herein refers to an organic pigment that is structurally composed of a polyolefin chain and may terminate in a ring. Carotenoids are divided into two categories, xanthophylls (which contain oxygen atoms) and carotenes (which do not contain oxygen atoms).

[0232] In another embodiment, the composition is in liquid form. It should be understood that the composition can be liquid or solid, depending on the temperature. Therefore, in one embodiment, the composition is liquid at room temperature. Room temperature as used herein is understood to be a temperature between 20°C to 22°C, about 20°C, or 15°C to 25°C.

[0233] Food, nutritional supplement, cosmeceutical, cosmetic composition or nutritional product

[0234] Another aspect relates to a food, a nutritional supplement, a cosmeceutical, a cosmetic composition or a nutraceutical comprising the composition according to the invention.

[0235] The term "food" as used herein refers to any substance or product, solid or liquid, natural or processed, of any nature which, by reason of its properties, application, composition, preparation and state of storage, may be used, usually or desirably, for some of the following purposes: a) as normal nutrition for humans or animals or as a pleasurable food; or b) as a dietary product in the special case of human or animal food (feed). The term "food" includes all natural materials and manufactured products of any origin, either separately from one another or conveniently mixed together, suitable for use as animal food.

[0236] Ready-to-eat food is a food that does not need to be diluted, for example, by an aqueous solution suitable for consumption. In principle, as those skilled in the art would consider, the ingredients present in the ready-to-eat food are balanced, and it is not necessary to add other ingredients to the food to make it ready-to-eat. Concentrated food is a food in which one or more ingredients exist in a higher concentration than in the ready-to-eat food, so when used, it must be diluted, for example, by an aqueous solution suitable for consumption. The non-limiting illustrative examples of food provided by the invention include dairy products and derivatives such as fermented milk, yogurt, kefir (kephir), curd, cheese, butter, ice cream, milk-based desserts, etc., and non-dairy products such as baked products, cakes and cakes, cereals, chocolate, jam, fruit juice, other fruit derivatives, oils and margarine, dishes made, etc.

[0237] The term "cosmeceutical product" as used herein refers to a product suitable for use in the body or animal body, which contains one or more cosmeceutical products (functional cosmetics, dermaceuticals or active cosmetics), i.e., a topical hybrid product with cosmetic-pharmaceutical properties, which contains active ingredients that have an effect on the user's skin, hair and / or nails at a higher and more effective concentration, and is therefore at an intermediate level between cosmetics and drugs. Illustrative examples of cosmeceutical products include essential oils, ceramides, enzymes, minerals, peptides, vitamins, etc.

[0238] The term "nutraceutical" as used herein refers to a product suitable for humans or animals containing one or more therapeutic natural products that provide health benefits or are associated with disease prevention or alleviation, and includes dietary supplements that are present in non-food matrices (e.g., capsules, powders, etc.) of concentrated natural bioactive products that are normally present (or absent) in foods, and that, when taken in higher doses than those present in those foods, exert a beneficial effect on health with a greater effect than normal foods can have. Thus, the term "nutraceutical" includes isolated or purified foods and additives or food supplements that are usually present in dosage forms that are usually used orally (e.g., capsules, tablets, sachets, drinkable vials, etc.); such products provide physiological benefits or protection against disease, usually against chronic diseases. If desired, the nutritional products provided by the present invention may also contain one or more nutritional products (products or substances related to disease prevention or alleviation) in addition to luteins, such as flavonoids, ω-3 fatty acids, etc., and / or one or more prebiotics (indigestible food ingredients that stimulate the activity and / or growth of probiotics), such as oligofructose, pectin, inulin, galacto-oligosaccharides, lactulose, human milk oligosaccharides, dietary fiber, etc.

[0239] The term "nutritional composition" of the present invention as used herein relates to a food that beneficially affects one or more functions of the body to provide a better health condition. Thus, such a nutritional composition can be used to prevent and / or treat a disease or a factor causing a disease. Thus, the term "nutritional composition" of the present invention can be used as a synonym for a functional food or a food or medical food for a specific nutritional purpose. A nutritional composition is similar to a conventional food and is consumed as part of a normal diet.

[0240] The term "cosmetic composition" or "personal care composition" as used herein refers to a composition suitable for personal hygiene of humans or animals or for enhancing natural beauty or changing the appearance of the body without affecting the structure or function of the human or animal body, which comprises one or more products that provide such an effect. If desired, the cosmetic composition provided by the present invention may also contain one or more cosmetics or beauty products in addition to the combination of the present invention, i.e., such substances or mixtures, which are intended to contact the external parts of the human or animal body (e.g., epidermis, hair system, finger / toe nails, lips, etc.) or with teeth and buccal mucosa, with the sole or main purpose of cleaning it, scenting it, changing its appearance, protecting it, keeping it in good condition or correcting body odor. Illustrative examples of cosmetically acceptable carriers include products included in the INCI (International Nomenclature of Cosmetic Ingredients) list. Cosmetic or personal care compositions include products such as balms, pads, pomades, creams, etc., oils, surfactants, moisturizers, botanical extracts, vitamins, antioxidants, sunscreens, fragrances, preservatives, etc. Illustrative examples are moisturizers, botanical extracts, vitamins, antioxidants, and sunscreens.

[0241] The ingredients as described above are preferably provided in cosmetic compositions that can be formulated into creams, gels, lotions, oils, ointments, powders, sticks, cakes or other forms that can be applied topically. The resulting cosmetic composition can be in the form of a liquid, solid, semisolid, dispersion, suspension, solution or emulsion, and it can be water-based or anhydrous. The cosmetic composition of the present invention can also be in the form of a color cosmetic composition, such as foundation makeup, mascara, lip gloss, blush, eye shadow, etc. Certain other derivatives are lipophilic in nature and will be more likely to be present in the oil phase of the emulsion. The combination of the present invention is preferably present in the aqueous phase of the emulsion or encapsulated in the aqueous phase in the liposome.

[0242] The term "cosmetically effective amount" as used herein relates to a sufficient amount of a compound (i.e., a combination of the present invention) to provide the desired effect, and is generally determined, among other reasons, by the properties of the compound itself and the cosmetic effect to be achieved. The dosage for obtaining a cosmetically effective amount also depends on a range of factors, such as the age, weight, sex or tolerance of the animal (preferably a mammal, and more preferably a human).

[0243] In a particular embodiment of the present invention, the cosmetic composition according to the invention is applied by topical route.

[0244] If desired, the cosmetic composition of the present invention is incorporated into a fabric, nonwoven fabric, or medical device. Illustrative examples of the fabric, nonwoven fabric, or medical device include, but are not limited to, bandages, gauze, T-shirts, pantyhose, socks, underwear, belts, gloves, diapers, sanitary napkins, dressings, bed covers, wipes, adhesive patches, non-adhesive patches, occlusive patches, microelectric patches, and face masks.

[0245] All terms and embodiments described previously apply equally to this aspect of the invention.

[0246] Non-therapeutic methods

[0247] In a third aspect, the present invention relates to a non-therapeutic method for improving skin health, comprising the step of administering a composition according to the first aspect of the invention or a food, nutritional supplement, cosmeceutical, cosmetic composition or nutritional product according to the second aspect of the invention to a patient in need of improved skin health.

[0248] In the context of the present invention, "skin" is understood to include its layers, from the uppermost layer or stratum corneum to the lowermost layer or subcutaneous tissue, both inclusive. These layers are composed of different types of cells (e.g. keratinocytes, fibroblasts, melanocytes and / or adipocytes, etc.). In the context of the present invention, the term "skin" includes the scalp. The term "skin" includes human skin.

[0249] As used herein, "improved skin health" means achieving a measurable improvement in skin quality. The term "skin quality" refers to skin properties, such as skin hydration (e.g., improvement in dryness) or skin texture (e.g., skin thickness, roughness, scaling). For example, with respect to skin texture, the present invention includes methods of reducing skin roughness, improving scaling, and / or improving skin thickness in a subject in need thereof. One skilled in the art will select known methods of measuring improvements in skin quality.

[0250] In one embodiment, the method for improving skin health comprises at least one treatment selected from the group consisting of protecting skin tissue from aging, preventing or treating sensitive, dry or reactive skin, for improving skin density or firmness, and for increasing skin photoprotection.

[0251] In the context of the present invention, the term "aging" refers to the changes that the skin undergoes with age (chronoaging) or through exposure to the sun (photoaging) or to environmental agents such as tobacco smoke, extreme weather conditions of cold, heat or wind, chemical contaminants or pollutants, and includes all changes that are externally visible and / or perceptible by touch, such as, but not limited to, the occurrence of discontinuities in the skin (e.g. wrinkles, fine lines, wrinkles, unevenness or roughness), increase in pore size, loss of elasticity, loss of firmness, loss of smoothness, loss of ability to recover from deformation, sagging of the skin (e.g. sagging cheeks, the appearance of bags under the eyes or the appearance of a double chin, etc.), changes in skin color (e.g. the appearance of streaks, redness, bags under the eyes, or areas of hyperpigmentation (e.g. age spots or freckles, etc.), abnormal differentiation, hyperkeratosis, elastosis, keratosis, hair loss, orange peel skin, loss of collagen structure, and changes in the stratum corneum, dermis, epidermis, vascular system (e.g. spider veins, etc.), skin pigmentation (e.g. hyperpigmentation, hyperkeratosis, hyperplasia, keratosis, hair loss, orange peel skin, loss of collagen structure, and changes in the stratum corneum, dermis, epidermis, vascular system (e.g. spider veins, etc.), skin pigmentation (e.g. hyperpigmentation, ... Veins) or telangiectasia) or other histological changes in those tissues close to the skin, etc. The term "photoaging" classifies a group of processes that cause premature aging of the skin due to prolonged exposure of the skin to ultraviolet radiation and presents the same physical characteristics as aging, such as and not limited to loosening, sagging, color changes or irregular pigmentation, abnormalities and / or excessive keratinization. Skin changes due to aging (e.g., chronological aging, photoaging and / or environmental aging) are also referred to herein as symptoms or signs of skin aging.

[0252] In another embodiment, the composition is administered topically.

[0253] All terms and embodiments described previously apply equally to this aspect of the invention.

[0254] Medical Uses

[0255] The following uses of ACX have been described in the prior art: for the treatment and / or prevention of various medical conditions, such as cancer (Satomi Y, Anticancer Res. 2017; 37(4): 1557-62; Méresse S et al., Int J Mol Sci. 2020 Dec 4; 21(23); Peng J et al., Mar Drugs. 2011 Oct 10; 9(10): 1806-28), cardiovascular disease, hypertension, portal hypertension, pulmonary hypertension, hyperglycemia, diabetes (type 2), insulin resistance, as a hepatoprotective agent and for lipid management related diseases (Peng J et al., Mar Drugs. 2011 Oct 10; 9(10): 1806-28), metabolic syndrome and diabetes prevention (Maeda HJ ​​Oleo Sci. 2015 Jan 20;64(2):125-32), coronary atherosclerosis, rheumatoid arthritis and as an antiangiogenic agent (Méresse S et al., Int J Mol Sci. 2020 Dec 4;21(23)), intestinal flora imbalance, glaucoma, diabetic retinopathy, angiogenesis-related diseases, hemorrhagic telangiectasia and psoriasis (Xiao H et al., Mar Drugs. 2020 Dec 11;18(12)), as an anti-inflammatory agent, anaphylactic shock, sepsis, cytokine storm (Su et al., Front Pharmacol., 2019, DOI:10.3389 / fphar.2019.00906), lupus, sarcoidosis, chronic obstructive pulmonary disease (chronic obstructive pulmonary disease disease, COPD), asthma, primary biliary cholangitis, sclerosing cholangitis, autoimmune hepatitis, inflammatory bowel disease, Crohn's disease, multiple sclerosis, ulcerative colitis (Li X et al., Aging (Albany NY). 2021; 13: 2655-2667; Yang YP et al., Nat Prod Res. 2020 Jun; 34(12): 1791-1795; Zheng J et al., Mar Drugs. 2019; 17(10): 552; Yang X et al., J Environ Pathol Toxicol Oncol. 2019; 38(3): 229-238; Takatani N et al., Biochem Biophys Res Commun. 2020 Jul 23; 528(2): 305-310; Su et al., Front Pharmacol., 2019, DOI: 10.3389 / fphar.2019.00906), fibrosis (Xiao H et al., Mar Drugs. 2020 Dec 11; 18(12); Ma SY et al. Eur J Pharmacol. 2017 Sep 15; 811: 199-207), as an antibacterial agent (Karpiński TM, Adamczak A. Fucoxanthin-An Antibacterial Carotenoid. Antioxidants (Basel). 2019 Jul 24; 8(8)), as a neuroprotectant (Hu L et al. Biomed Pharmacother. 2018 Oct; 106: 1484-9), gout and kidney stones (Wang et al., Journal of KingSaud University-Science. 2020 April; 32(3):1896-1901), aging-related disorders (Guvatova Z et al., Mech Ageing Dev. 2020 July; 189:111260; Chen, S.-J. et al., Mar. Drugs 2021, 19, 114), glucocorticoid-induced muscle atrophy (Zhiyin L et al. Biomed Pharmacother. 2021 April 14; 139:111590), bone health (Walsh PJ et al. Mar Drugs. 2019 February 28; 17(3)), age-related macular degeneration (Chen SJ et al. Mar Drugs. 2021 February 18; 19(2)), eczema, atopic dermatitis and itch (Natsume C et al. Int J Mol. Sci. 2020 Mar 22;21(6)) and thyroid-related disorders (Yang Het al., Biol Trace Elem Res. 2021 May;199(5):1877-1884). .

[0256] Furthermore, the ACX esters of formula (I) or (Ia) are prodrugs of ACX, which spontaneously convert into ACX and its cis isomer in vivo. Therefore, the esters of the present invention are suitable for the treatment and prevention of the same diseases as reported for ACX.

[0257] Therefore, in a fourth aspect, the present invention relates to a composition of the present invention for use in medicine or to a pharmaceutical composition comprising a composition of the present invention and optionally a pharmaceutically acceptable excipient. It should be understood that some of the oils and emulsions defined above in the context of the composition of the present invention may also be pharmaceutically acceptable excipients, and therefore they may serve as carriers and pharmaceutically acceptable excipients for the composition.

[0258] In a fifth aspect, the present invention relates to a composition according to the present invention for treating and / or preventing a disease selected from the group consisting of cancer, cardiovascular disease, intestinal flora imbalance, inflammatory disease, autoimmune disease, fibrosis, bacterial infection, neurological disease, hyperuricemia-related disease, aging-related disorder, lipid-related disease, glucocorticoid-induced muscle atrophy, bone-related disease, eye disease, angiogenesis-related disease, psoriasis, eczema, atopic dermatitis and thyroid-related disorder.

[0259] In a specific embodiment,

[0260] - The cancer is gastric cancer, duodenal cancer, liver cancer, blood cancer, breast cancer, glioma, bladder cancer, pancreatic cancer, prostate cancer, colorectal cancer, cervical cancer, nasopharyngeal cancer, lung cancer, kidney cancer, metastatic cancer, melanoma, sarcoma, nerve cancer or skin cancer;

[0261] - Cardiovascular disease is hypertension, portal hypertension, pulmonary hypertension, hyperglycemia, type 2 diabetes, insulin resistance, metabolic syndrome or coronary atherosclerosis;

[0262] - Inflammatory disease is anaphylactic shock, sepsis or cytokine storm;

[0263] - Autoimmune diseases include lupus, sarcoidosis, chronic obstructive pulmonary disease, asthma, primary biliary cholangitis, sclerosing cholangitis, autoimmune hepatitis, inflammatory bowel disease, Crohn's disease, multiple sclerosis and ulcerative colitis;

[0264] - Fibrosis is hepatic fibrosis, renal fibrosis, pulmonary fibrosis, myocardial fibrosis, interstitial fibrosis, IgG4-related fibrosis, scleroderma, or retroperitoneal fibrosis;

[0265] - Neurological disease is Parkinson's disease, Alzheimer's disease, dementia, depression or cerebral ischemia;

[0266] - Hyperuricemia-related diseases include rheumatoid arthritis, gout or kidney stones;

[0267] - Lipid-related diseases are obesity, cholesterol, triglyceridemia, non-alcoholic steatohepatitis or non-alcoholic fatty liver disease;

[0268] - Bone-related diseases include bone loss;

[0269] - Eye disease is glaucoma, diabetic retinopathy or age-related macular degeneration; and / or

[0270] - Angiogenesis-related disease is hemorrhagic telangiectasia.

[0271] In another aspect, the present invention relates to a method for treating and / or preventing a disease selected from the following: cancer, cardiovascular disease, intestinal flora imbalance, inflammatory disease, autoimmune disease, fibrosis, bacterial infection, neurological disease, hyperuricemia-related disease, aging-related disorder, lipid-related disease, glucocorticoid-induced muscle atrophy, bone-related disease, eye disease, angiogenesis-related disease, psoriasis, eczema, atopic dermatitis and thyroid-related disorder, which comprises administering the composition of the present invention to a subject in need thereof.

[0272] The term "prevention" and variations thereof as used herein relate to the administration of a combination according to the invention or a medicament comprising the combination to a subject who has not yet been diagnosed as being likely to suffer from a disease but who is generally expected to develop the disease or to be at an increased risk of developing the disease. Prevention is intended to avoid the occurrence of the disease. Prevention may be complete (e.g., the complete absence of the disease). Prevention may also be partial, such that, for example, the occurrence of the disease in the subject is lower than the occurrence of the disease without the administration of the composition of the invention. Prevention also refers to reducing susceptibility to clinical conditions.

[0273] The term "treatment" as used herein refers to any type of treatment intended to terminate, prevent, improve the clinical conditions described herein or reduce susceptibility to it. In a preferred embodiment, the term treatment relates to the preventive treatment of a disease or condition as defined herein (i.e., treatment that reduces susceptibility to a clinical condition). Therefore, "treatment" and its equivalents refer to obtaining a desired pharmacological or physiological effect, covering any treatment of a pathological condition or disease in a mammal (including a human). The effect can be preventive in terms of preventing a disease or its symptoms completely or in part, and / or can be therapeutic in terms of partially or completely curing a disease and / or the adverse effects attributable to the disease. That is, "treatment" includes (1) preventing the disease from occurring or recurring in a subject, (2) inhibiting the disease, such as preventing its development, (3) stopping or terminating the disease or at least the symptoms associated therewith, so that the host no longer suffers from the disease or its symptoms, for example, such as causing the regression of the disease or its symptoms by restoring or repairing the function of loss, deletion or defect or stimulating an ineffective process, or (4) alleviating, alleviating or improving the disease or the symptoms associated therewith, wherein improvement is broadly used to refer to at least reducing the size of a parameter.

[0274] The term "cancer" as used herein refers to a disease characterized by uncontrolled cell division (or increased resistance to survival or apoptosis), and the ability of the cells to invade other adjacent tissues (invasion) and spread through lymphatics and blood vessels to other areas of the body where the cells are not normally located (metastasis), circulate through the bloodstream, and then invade normal tissues in other parts of the body. Tumors are classified as benign or malignant depending on whether they can spread by invasion and metastasis: benign tumors are tumors that cannot spread by invasion or metastasis, i.e., they grow only locally; while malignant tumors are tumors that can spread by invasion and metastasis. As used herein, the term cancer includes, but is not limited to, the following types of cancer: breast cancer; biliary tract cancer; bladder cancer; brain cancer, including glioblastomas, particularly glioblastoma multiforme and medulloblastomas; cervical cancer; head and neck cancer; choriocarcinoma; colon cancer, colorectal cancer; endometrial cancer; esophageal cancer; gastric cancer; blood neoplasms, including acute lymphoblastic and myeloid leukemias; T-cell acute lymphoblastic leukemia / lymphoma; hairy cell leukemia; chronic myeloid leukemia, multiple myeloma; AIDS-related leukemia and adult T-cell leukemia / lymphoma; intraepithelial neoplasms, including Bowen's disease and Paget's disease; liver cancer, hepatoma; lung cancer, pleural mesothelioma; lymphomas, including Hodgkin's disease Disease) and lymphocytic lymphoma; neuroblastoma; oral cancer, including squamous cell carcinoma; parotid cancer; ovarian cancer, including those arising from epithelial cells, stromal cells, germ cells and mesenchymal cells; pancreatic cancer; prostate cancer; kidney cancer, adrenal cancer; rectal cancer; sarcoma, including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma and osteosarcoma; skin cancer, including melanoma, Merkel cell carcinoma, Kaposi's sarcoma, basal cell carcinoma and squamous cell carcinoma; cervical cancer, endometrial cancer; testicular cancer, including reproductive tumors, such as seminoma, non-seminoma (teratoma, choriocarcinoma), stromal tumor and germ cell tumor; thyroid cancer, including thyroid adenocarcinoma and medullary carcinoma; and renal cancer, including adenocarcinoma and Wilms tumor. Other cancers will be known to the ordinary technician. In a specific embodiment, the cancer is gastric cancer, duodenal cancer, liver cancer, blood cancer, breast cancer, glioma, bladder cancer, pancreatic cancer, prostate cancer, colorectal cancer, cervical cancer, nasopharyngeal cancer, lung cancer, kidney cancer, metastatic cancer, melanoma, sarcoma, neural cancer or skin cancer.

[0275] In a specific embodiment, the cardiovascular disease is hypertension, portal hypertension, pulmonary hypertension, hyperglycemia, type 2 diabetes, insulin resistance, metabolic syndrome or coronary atherosclerosis.

[0276] In a specific embodiment, the inflammatory disease is anaphylactic shock, sepsis, or cytokine storm.

[0277] In a specific embodiment, the autoimmune disease is lupus, sarcoidosis, chronic obstructive pulmonary disease, asthma, primary biliary cholangitis, sclerosing cholangitis, autoimmune hepatitis, inflammatory bowel disease, Crohn's disease, multiple sclerosis, and ulcerative colitis.

[0278] As used herein, "fibrosis" refers to the formation of excess fibrous connective tissue in an organ or tissue during a repair or reaction process. Although fibrosis can be a benign state, the present invention preferably relates to pathological fibrosis. In a specific embodiment, fibrosis is liver fibrosis, kidney fibrosis, lung fibrosis, myocardial fibrosis, interstitial fibrosis, IgG4-related fibrosis, scleroderma, or retroperitoneal fibrosis.

[0279] In a specific embodiment, the neurological disease is Parkinson's disease, Alzheimer's disease, dementia, depression or cerebral ischemia.

[0280] In a specific embodiment, the hyperuricemia-related disease is rheumatoid arthritis, gout or kidney stones.

[0281] In a specific embodiment, the lipid-related disease is obesity, cholesterol, triglyceridemia, non-alcoholic steatohepatitis or non-alcoholic fatty liver disease.

[0282] In one embodiment, the bone-related disease is bone loss.

[0283] In a specific embodiment, the eye disease is glaucoma, diabetic retinopathy or age-related macular degeneration.

[0284] In a specific embodiment, the angiogenesis-related disease is hemorrhagic telangiectasia.

[0285] In another aspect, the present invention relates to a composition of the present invention for use in the treatment and / or prevention of a disease mediated by glucocorticoid receptor activity, a aging-related disease or a aging-related disorder; or as an adjuvant for the treatment of cancer with chemotherapy, preferably chemotherapy comprising a taxane.

[0286] The term "glucocorticoid receptor", also referred to as GR, GCR or NR3C1 (nuclear receptor subfamily 3, group C, member 1), used herein refers to a receptor that binds to Cortisol and other glucocorticoids. Human genes are shown in the Ensembl database with accession number ENSG00000113580 (Ensembl version 106, April 2022).

[0287] The term "adrenocortical hormone" or "corticosteroid" as used herein refers to a class of steroid hormones produced in the adrenal cortex of vertebrates, as well as synthetic analogs of these hormones. Corticosteroids are involved in a wide range of physiological processes, including stress response, immune response, and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels and behavior. There are two types of adrenocortical hormones, glucocorticoids and mineralocorticoids.

[0288] Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor. The structure of glucocorticoids contains a steroid ring system.

[0289] As used herein, the term "Cortisol" or "hydrocortisone" refers to a glucocorticoid of the formula:

[0290]

[0291] In a specific embodiment, the disease mediated by glucocorticoid receptor activity is selected from Cortisol-induced immunosuppression, Cortisol-induced insulin resistance, altered skin barrier homeostasis, Cushing's syndrome, subclinical Cushing's syndrome, subclinical hypercortisolemia, metabolic syndrome, inflammatory bowel disease, muscle wasting and muscular dystrophy, insomnia associated with circadian rhythm disturbances, hypertension, osteoporosis, water retention, Cortisol-induced DNA damage, migraine, psychosis, decreased appetite, depression, stress disorders, and cognitive disorders such as Alzheimer's disease, catatonia, amyotrophic lateral sclerosis, delirium, post-traumatic stress disorder, impaired memory retrieval, and borderline personality disorder.

[0292] In another embodiment, the senescence-associated disorder is fibrosis, particularly wherein the fibrosis is characterized by a high number of senescent cells, more particularly the fibrosis is pulmonary fibrosis, chronic obstructive pulmonary disease, myocardial fibrosis or renal fibrosis; or wherein the senescence-associated disease is cancer, preferably a blood cancer or a skin cancer.

[0293] All terms and embodiments described previously apply equally to this aspect of the invention.

[0294] Beauty Methods

[0295] The utility of ACX compounds in preventing and / or reducing skin aging and / or for improving the cosmetic adverse effects of aging has been described in the prior art (Peng et al. Mar Drugs. 2011 Oct 10; 9(10): 1806-28; KangSY et al. J Cosmet Sci. 2020; 71(2): 53-64). As previously described, ACX esters of formula (I) or (Ia) are spontaneously converted to ACX and its cis isomer in vivo. Therefore, the esters of the present invention are suitable for use in the same cosmetic methods as reported for ACX.

[0296] Therefore, in a final aspect, the present invention relates to a cosmetic method for preventing and / or reducing skin aging and / or for improving the cosmetic adverse effects of aging, which comprises applying to a subject in need thereof a composition of the present invention, a food, a cosmeceutical, a nutraceutical or a cosmetic composition according to the second aspect. In a more specific embodiment, a cosmetic method for preventing and / or reducing skin aging and / or improving the cosmetic adverse effects of aging comprises applying to a subject in need thereof a composition of the present invention according to the first aspect (wherein the composition comprises a compound of formula (I) or (Ia), preferably a compound of formula (Ia), preferably wherein R is methyl) or a food, a cosmeceutical, a nutraceutical or a cosmetic composition according to the second aspect.

[0297] As used herein, the term "cosmetic method" relates to a method for enhancing the appearance of skin in a subject. Cosmetic compositions for use in the cosmetic method of the present invention include skin creams, lotions, powders, lipsticks, eye and facial foundations, wipes, gels, deodorants, hand soaps, baby products, bath oils, bubble baths, bath salts, butters, and many other types of products.

[0298] Skin aging is a multifactorial process that affects almost every aspect of its biology and function; it is driven by both intrinsic (e.g., time, genetic factors, hormones) and extrinsic (e.g., UV exposure, pollution, cigarette smoke) factors. Skin aging also results from aging.

[0299] Cellular senescence is a growth arrest that occurs as a result of different damaging stimuli, including DNA damage, telomere shortening and dysfunction or oncogenic stress. Senescent cells exert pleiotropic effects on development, tissue aging and regeneration, inflammation, wound healing and tumor suppression. Senescent cells are characterized by their inability to proliferate, resistance to apoptosis and secretion of factors that promote inflammation and tissue degradation.

[0300] Senescent keratinocytes and fibroblasts have been shown to accumulate in human skin with age. Furthermore, senescent cells express genes for degradative enzymes, growth factors, and inflammatory cytokines with long-term pleiotropic effects.

[0301] As used herein, "cosmetic adverse effects of aging" refers to the characteristics of aging that are inherent or occur over time, and include, by way of illustration and not limitation, visible signs such as thin and dry skin, fine wrinkles, decreased elasticity, abnormal pigmentation, graying of hair, and hair loss.

[0302] As used herein, "skin aging" relates to a state of aging and in particular damage of the epidermal cells of human skin caused by partial damage or complete destruction of the cells, conversion of imide bonds to amide bonds in collagen and / or elastin caused by toxic by-products of oxygen metabolism, free radical pathology or photodamage and general aging.

[0303] The cosmetic methods of the present invention are intended to reduce epidermal cells and thereby reduce skin aging in humans by reducing or inhibiting aging, including through one or more of the following effects: reversing photodamage or other regenerative effects, such as increasing underlying skin vascularity, increasing the rate of cell replication and desquamation to produce a more youthful appearance, increasing collagen synthesis and uniformity, delaying skin atrophy and thinning of the epidermis and dermis, etc.

[0304] The cosmetic method of the present invention is a non-therapeutic method.

[0305] The combinations of the present invention may be administered in a cosmetically effective amount.

[0306] The term "cosmetically effective amount" as used herein relates to a sufficient amount of a compound or composition of the invention that provides the desired effect, and is generally determined by, among other reasons, the properties of the compound itself and the cosmetic effect to be achieved. The dosage for obtaining a cosmetically effective amount also depends on a series of factors, such as the age, weight, sex or tolerance of the animal (preferably a mammal, and more preferably a human).

[0307] In a specific and preferred embodiment of the cosmetic method according to the invention, the cosmetic composition according to the invention is applied by topical route. Suitable formulations for topical application of the combination according to the invention have already been detailed in the context of the cosmetic composition according to the invention and are equally applicable to the cosmetic method according to the invention.

[0308] If desired, the cosmetic composition of the present invention is incorporated into a fabric, nonwoven fabric, or medical device. Illustrative examples of the fabric, nonwoven fabric, or medical device include, but are not limited to, bandages, gauze, T-shirts, pantyhose, socks, underwear, belts, gloves, diapers, sanitary napkins, dressings, bed covers, wipes, adhesive patches, non-adhesive patches, occlusive patches, microelectric patches, and face masks.

[0309] All terms and embodiments described previously apply equally to this aspect of the invention.

[0310] The following examples illustrate specific embodiments of the present invention. They are not intended to limit the scope of the invention defined in this specification in any way.

[0311] Example

[0312] Analytical methods

[0313] Nuclear Magnetic Resonance (NMR)

[0314] NMR spectra were obtained on a Varian 400 MHz or 500 MHz instrument. 1 H chemical shifts are given relative to deuterated solvent.

[0315] Example 1. Synthesis of amarouciaxanthin A acetate

[0316] Fucoxanthin (1 eq.), NMO monohydrate (2 eq.) and freshly dried Molecular sieves. TPAP (0.12 eq.) was added at room temperature. When the reaction reached complete conversion (>97%), SiO2 (30 eq.) was added to the reaction. The reaction was stirred at room temperature until complete conversion. The reaction was filtered to remove SiO2. The filtrate was washed with aqueous 5% Na2S2O3. The organic layer was washed twice with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was dried using high vacuum to obtain the desired compound as a red solid.

[0317] 1 H-NMR (400MHz, CDCl3) δ7.10(d,J=10.9Hz,1H),6.83-6.50(m,5H),6.45(d,J=11.6Hz,1H),6.35(d,J=15.0H z,1H),6.27(d,J=11.7Hz,1H),6.13(d,J=11.5Hz,1H),6.05(s,1H),5.84(s,2H),5.44-5.33(m,1H),3.05(d ,J=15.0Hz,1H),2.92(d,J=15.0Hz,1H),2.47(d,J=18.1Hz,1H),2.38-2.24(m,2H),2.04(s,3H),1.99(m,7H ), 1.95 (s, 3H), 1.90 (d, J = 1.0Hz, 3H), 1.81 (s, 3H), 1.51 (t, J = 12.2Hz, 1H), 1.40 (m, 8H), 1.14-1.02 (m, 9H).

[0318] Example 2. Synthesis of paracentrone acetate

[0319] Amarouchiaxanthin A acetate was mixed with water and heated to 70° C. After the reaction ceased, it was cooled and extracted with dichloromethane. The organic layer was dried, filtered and evaporated to dryness. The resulting residue was purified by SiO2 column chromatography to obtain the desired compound as a brown solid.

[0320] Paracentrone Acetate: 1 H-NMR (500MHz, CDCl3) δ7.14 (dd, J = 10.7, 1.2Hz, 1H), 6.77-6.53 (m, 5H), 6.42-6.30 (m, 2H) ,6.26(d,J=11.5Hz,1H),6.12(dd,J=11.4,1.0Hz,1H),6.06(d,J=7.2Hz,1H),5.38(m,1H),2 .36(s,3H),2.31-2.25(m,1H),2.03(s,3H),2.02-1.96(m,6H),1.93(d,J=0.9Hz,3H),1.81( t,J=3.6Hz,3H),1.50(m,1H),1.44-1.39(m,1H),1.36(d,J=15.3Hz,6H),1.09-1.03(m,3H).

[0321] Example 3. Synthesis of amarouciaxanthin A acetate using different oxidants

[0322] The same procedure as in Example 1 was followed, but TPAP and NMO were replaced by IBX, Dess-Martin periodinane and Swern oxidation. The results are summarized in the following table:

[0323]

[0324]

[0325] Example 4. Synthesis of amarouciaxanthin A

[0326] Amarouchiaxanthin A acetate (1 eq.) and sodium taurocholate (30 eq.) were dissolved in MeOH. The solvent was evaporated to dryness. The residue was dissolved in phosphate buffered saline (PBS, pH 7) and lipase (1340 U / mg compound) was added. The reaction was shaken at 37°C until maximum conversion (approximately 80%). The reaction was quenched with MeOH and extracted with Et2O and brine. The aqueous layer was extracted with Et2O until no color was observed in the organic layer. The combined organic layers were dried, filtered and evaporated to dryness. The residue was purified by SiO2 column chromatography and amarouchiaxanthin A was obtained as a red solid, and unreacted amarouchiaxanthin A acetate was recovered.

[0327] 1 H-NMR (500 MHz, acetone) δ7.53 (dd, J = 10.8, 1.1 Hz, 1H), 6.93-6.81 (m, 2H), 6.80-6.67 (m, 3H), 6.52 (d, J = 11.6 Hz, 1H), 6.36 (dd, J = 17.7, 13.4 Hz, 2H), 6.16 (dd, J = 11.4, 1.0 Hz, 1H), 6.02 (s, 1H), 5.91 (s, 1 H),5.74-5.69(m,1H),4.28-4.17(m,1H),3.61(d,J=1.6Hz,1H),3.48(d,J=5.1Hz,1H),3.21(q,J= 15.5Hz,2H),2.80(d,J=1.6Hz,3H),2.78-2.75(m,1H),2.62(d,J=17.6Hz,1H),2.21-2.11(m,2H),

[0328] Peaks under acetone, 2.02 (s, 2H), 1.99 (s, 2H), 1.94 (t, J=3.3 Hz, 2H), 1.91 (m, 1H), 1.89-1.83 (m, 5H), 1.40-1.24 (m, 7H), 1.07-0.98 (m, 6H).

[0329] Example 5. Conversion of ACX-Ac to ACX after oral absorption and the conversion of ACX-Ac, FX and ACX after oral administration Bioavailability

[0330] It is well described that orally administered fucoxanthin (FCX) has minimal absorption. Instead, it is thought to be metabolized by intestinal or pancreatic cells to fucoxanthin and subsequently converted to amarouciaxanthin (ACX) in the liver.

[0331] Amarouciaxanthin A acetate (ACX-Ac) is a novel compound that acts as a prodrug of ACX. Unlike FX, there are no intermediate metabolites.

[0332] Immunocompetent mice from the strain Hsd:ICR (CD-1) (female, 6 to 7 weeks old, from ENVIGO) were housed under sterile conditions with a daily light / dark cycle (12 h) at a constant temperature of 20° C. to 22° C. and relative humidity (45% to 65%). Sterile water and food were available ad libitum.

[0333] ACX-Ac was dissolved in sunflower oil at 1 mg / mL and sterilized by filtration. FCX was dissolved in sunflower oil at 2 mg / mL and sterilized by filtration. Animals were weighed prior to assay to determine the appropriate dispensing volume at 5 mL / kg (FCX) or 10 mL / kg (ACX-Ac). The formulations were administered intragastrically once at 10 mg / kg. Blood was collected at various time points as described in Table 1. The blood was extracted on recipients containing 5 μL of 0.5 M EDTA, either via the facial vein or by intracardiac puncture (end point).

[0334] Blood samples were analyzed by HPLC-MS / MS according to a proprietary analytical method, and the concentration of ACX in each sample was determined. The software version 2.0 (Simulations Plus, Lancaster, CA 93534, USA) performed non-compartmental pharmacokinetic analysis using individual plasma concentrations versus sampling time.

[0335] Table 1. Treatment groups in the FCX oral kinetics assay.

[0336] Group Number of animals Blood extraction 1 3 5 minutes, 8 hours 2 3 15 minutes, 24 hours 3 3 30 minutes, 48 ​​hours 4 3 1 hour 5 3 2 hours 6 3 4 hours

[0337] Table 2. Treatment groups in the ACX-Ac oral kinetics assay.

[0338] Group Number of animals Blood extraction 1 3 2 minutes, 8 hours 2 3 30 minutes, 24 hours 3 3 2 hours, 48 ​​hours 4 3 4 hours, 72 hours 5 3 15 minutes, 16 hours 6 3 1 hour, 36 hours

[0339] As described in the literature, oral absorption of fucoxanthin was negligible after administration of this lutein oil formulation. ACX-Ac was also not detected in plasma samples upon oral administration. The absorption of ACX was subsequently analyzed.

[0340] Compared to the plasma levels of ACX obtained after administration of FX, the plasma levels of ACX after administration of ACX-Ac were significantly higher, as shown in Figure 1 and as seen in Table 3.

[0341] Table 3. Estimated pharmacokinetic constants of ACX after oral delivery of different formulations. Plasma concentrations of ACX were used for non-compartmental pharmacokinetic analysis.

[0342] Determination 1 Determination 2 Compounds administered FX ACX-Ac Carrier Sunflower Oil Sunflower Oil dose 10mg / kg 10mg / kg Route of administration Oral Oral Pharmacokinetic parameters Cmax(μM) 2.867 9.346 AUCt (μM·hour) 51.19 80.59

[0343] Cmax, maximum observed plasma concentration; AUCt, area under the concentration-time curve from 0 to the time of the last quantifiable observation (calculated using the linear-log trapezoidal rule); StDev, statistical deviation.

[0344] Example 6. Evaluation of the solubility of ACX, ACX-Ac and FX in different lipid carrier formulations.

[0345] About 25 mg of compound was weighed into a glass vial, and 1 mL of lipophilic solvent was added to the vial containing the compound. The vial was vortexed for 1 minute and then sonicated for 30 minutes. The resulting solution was visually observed for any undissolved particles.

[0346] Sample preparation

[0347] The sonicated sample was filtered through a 0.22 μm PTFE filter, and 500 μL of the filtered sample was dissolved with 25 mL of EtOH: hexane (80:20) solution ("Dilution 1"). 1 mL of "Dilution 1" was dissolved with 10 mL of ACN to obtain "Dilution 2". 1 mL of "Dilution 2" was filtered through a 0.22 μm PTFE filter and used directly for determination by HPLC. Concentrations were calculated by extrapolation from the calibration curve.

[0348] Calibration curve

[0349] Accurately weigh (precision balance) 1.00 mg of standard compound and dilute it to 100 ppm in a volumetric flask. Several concentrations (50, 25, 12.5, 5, 2.5 ppm) were prepared from the initial 100 ppm solution to prepare a calibration curve (r>0.99).

[0350] Table 4. Comparison of lipid carrier formulations

[0351]

[0352] 1 Labrasol ALF: SEEDS: (Self-emulsifying drug delivery system, MCT (Medium Chain Triglycerides). Mono-, di- and tri-glycerides of caprylic (C8) and capric (C10) acids and primarily PEG-8 (MW 400) mono- and di-esters. No unsaturation.

[0353] 2Labrafil M2125: SEEDS, LCT (long chain triglycerides). Mono-, di- and tri-glycerides of linoleic acid (C18:2) and mono- and di-glycerides of PEG-6 (MW 300). Unsaturated.

[0354] 3 Maisine: LCT, synthetic oil. Mainly linoleic acid (C18:2) and oleic acid (C18:1) monoglycerides, diglycerides and triglycerides. Unsaturated.

[0355] 4 Labrafac Lipophile 1349: MCT, synthetic oil. Medium chain triglycerides of caprylic (C8) and capric (C10) acids. No unsaturation.

[0356] 5 Plurol Oleique: LCT, synthetic oil. Polyglyceryl-3 esters of oleic acid (C18:1). Unsaturated.

[0357] 6 Labrafil M1944CS: LCT, SEDDS. Mono-, di- and tri-glycerides of oleic acid (C18:1) and mono- and di-glycerides of PEG-6 (MW 300). Unsaturated.

[0358] 7 Sunflower oil: LCT, vegetable oil. Triglycerides of linoleic acid (C18:2) and oleic acid (C18:1). Unsaturated.

[0359] 8 CMC solution in water: Aqueous. Carboxymethyl cellulose.

[0360] 9 DHA (fish oil): LCT, oil rich in PUFA. Omega-3 fatty acids.

[0361] 10 Labrafac MC60: MCT, synthetic oil. Mono- and di-glycerides of caprylic (C8) and capric (C10) acids.

Claims

1. A composition comprising a compound of formula (I) or a stereoisomer thereof, and a carrier: Wherein R is selected from a linear or branched C1-C4 alkyl group, and wherein the carrier is selected from an oil or an emulsion.

2. The composition according to claim 1, wherein the compound has formula (Ia): wherein R is as defined in claim 1.

3. A composition according to claim 1 or 2, wherein R is methyl.

4. The composition according to any one of claims 1 to 3, wherein the carrier is an oil rich in polyunsaturated fatty acids or monounsaturated fatty acids.

5. The composition according to any one of claims 1 to 3, wherein the emulsion is an O / W emulsion, an O / W / O emulsion or a self-emulsifying system.

6. The composition according to any one of claims 1 to 5, wherein the oil is a vegetable oil, a microbial oil, a krill oil or a fish oil.

7. The composition according to claim 6, wherein the oil is rich in polyunsaturated fatty acids and / or omega-3 fatty acids.

8. The composition of claim 7, wherein the lipid carrier is a vegetable oil selected from the group consisting of sunflower seed oil, coconut oil, canola oil, cottonseed oil, olive oil, palm oil, rapeseed oil, safflower oil, almond oil, beech nut oil, brazil nut oil, cashew oil, hazelnut oil, macadamia oil, mongolia oil, pecan oil, pine nut oil, pistachio oil, walnut oil, pumpkin seed oil, grapefruit seed oil, lemon oil, orange oil, acai oil, black seed oil, black currant seed oil, borage seed oil, evening primrose oil, linseed oil, amaranth oil, apricot oil, apple seed oil, argan oil, avocado oil, babassu oil, ben oil, Borneo tallow seed oil, cape chestnut oil, carob oil, cocklebur oil, feather palm oil, coriander seed oil, date seed oil, dika oil, grape seed oil, kapok seed oil, kenaf seed oil, flat grass oil, mafura oil, marula oil, mustard oil, nige seed oil, okra seed oil, papaya seed oil, perilla seed oil, persimmon seed oil, pequi oil, pili nut oil, pomegranate seed oil, poppy seed oil, bacas oil, prune kernel oil, quinoa oil, calendula oil, rice bran oil, royle oil, sacha inchi oil, sapote oil, seje oil, taraminra oil, tea seed oil, thistle oil, cyperus oleifera oil, tomato seed oil, wheat germ oil, peanut oil, sesame oil, soybean oil, corn oil, and mixtures thereof, preferably sunflower seed oil.

9. The composition according to claim 8, wherein the vegetable oil is sunflower oil.

10. The composition of claim 6, wherein the lipid carrier is fish oil or microbial oil enriched with DHA or EPA.

11. The composition according to any one of claims 1 to 10, additionally comprising an antioxidant.

12. The composition according to any one of claims 1 to 11, wherein When the carrier is an emulsion, it additionally comprises a surfactant.

13. A composition according to any one of claims 1 to 12, wherein the ratio of the compound of formula (I) (expressed in milligrams) to the lipid carrier (expressed in milliliters) is 0.01:1 to 200:1, preferably 0.01:1 to 150:1, preferably 0.01:1 to 50:1, preferably 0.1:1 to 50:1, more preferably 0.1:1 to 5:

1.

14. The composition according to any one of claims 1 to 13, wherein the composition is in liquid form.

15. A composition according to any one of claims 1 to 14, wherein the concentration of the compound of formula (I) is 0.01 to 200 mg / mL, 0.01 to 150 mg / mL, preferably 0.01 to 50 mg / mL, preferably 0.1 mg / mL to 50 mg / mL, more preferably 0.1 to 5 mg / mL; and / or wherein the concentration of the compound of formula (I) in the composition is 0.01 to 200 mg / mL, preferably 0.01 to 150 mg / mL, preferably 0.01 to 50 mg / mL, preferably 0.1 mg / mL to 50 mg / mL, more preferably 0.1 to 5 mg / mL.

16. The composition according to any one of claims 1 to 15, comprising at least 55% by weight of the compound of formula (I) relative to the total weight of carotenoids in the composition.

17. A food, nutritional supplement, cosmeceutical, cosmetic composition or nutraceutical comprising the composition according to any one of claims 1 to 8.

18. A non-therapeutic method for improving skin health comprising the step of administering to a patient in need of improved skin health a composition according to any one of claims 1 to 16 or a food, nutritional supplement, cosmeceutical, cosmetic composition or nutraceutical according to claim 17.

19. The method according to claim 18, wherein the method for improving skin health comprises at least one treatment selected from the group consisting of: protecting skin tissue from aging, preventing or treating sensitive, dry or reactive skin, for improving skin density or firmness, and for increasing skin photoprotection.

20. The method of claim 18 or 19, wherein the composition is administered topically.

21. A composition according to any one of claims 1 to 16 for use in medicine, or a pharmaceutical composition comprising the composition of the invention.

22. A composition according to any one of claims 1 to 16, for treating and / or preventing a disease selected from the group consisting of cancer, cardiovascular disease, intestinal flora imbalance, inflammatory disease, autoimmune disease, fibrosis, bacterial infection, neurological disease, hyperuricemia-related disease, aging-related disorder, lipid-related disease, glucocorticoid-induced muscle atrophy, bone-related disease, eye disease, angiogenesis-related disease, psoriasis, eczema, atopic dermatitis and thyroid-related disorder.

23. A composition for use according to claim 22, wherein: - the cancer is gastric cancer, duodenal cancer, liver cancer, blood cancer, breast cancer, glioma, bladder cancer, pancreatic cancer, prostate cancer, colorectal cancer, cervical cancer, nasopharyngeal cancer, lung cancer, kidney cancer, metastatic cancer, melanoma, sarcoma, neurocarcinoma or skin cancer; - The cardiovascular disease is hypertension, portal hypertension, pulmonary hypertension, hyperglycemia, type 2 diabetes, insulin resistance, metabolic syndrome or coronary atherosclerosis; - The inflammatory disease is anaphylactic shock, sepsis or cytokine storm; - the autoimmune disease is lupus, sarcoidosis, chronic obstructive pulmonary disease, asthma, primary biliary cholangitis, sclerosing cholangitis, autoimmune hepatitis, inflammatory bowel disease, Crohn's disease, multiple sclerosis and ulcerative colitis; - the fibrosis is liver fibrosis, kidney fibrosis, lung fibrosis, myocardial fibrosis, interstitial fibrosis, IgG4-related fibrosis, scleroderma or retroperitoneal fibrosis; - The neurological disease is Parkinson's disease, Alzheimer's disease, dementia, depression or cerebral ischemia; - The hyperuricemia-related disease is rheumatoid arthritis, gout or kidney stones; - The lipid-related disease is obesity, cholesterol, triglyceridemia, non-alcoholic steatohepatitis or non-alcoholic fatty liver disease; - the bone-related disease is bone loss; - the eye disease is glaucoma, diabetic retinopathy or age-related macular degeneration; and / or - The angiogenesis-related disease is hemorrhagic telangiectasia.

24. A composition according to any one of claims 1 to 16 for use in the treatment and / or prevention of a disease mediated by glucocorticoid receptor activity, a senescence-related disease or senescence-related disorder; or as an adjuvant for the treatment of cancer with chemotherapy, preferably chemotherapy comprising a taxane.

25. A composition for use according to claim 24, wherein the disease mediated by glucocorticoid receptor activity is selected from the group consisting of Cortisol-induced immunosuppression, Cortisol-induced insulin resistance, altered skin barrier homeostasis, Cushing's syndrome, subclinical Cushing's syndrome, subclinical hypercortisolemia, metabolic syndrome, inflammatory bowel disease, muscle wasting and muscular dystrophy, insomnia associated with circadian rhythm disturbances, hypertension, osteoporosis, water retention, Cortisol-induced DNA damage, migraine, psychosis, decreased appetite, depression, stress disorders and cognitive disorders such as Alzheimer's disease, catatonia, amyotrophic lateral sclerosis, delirium, post-traumatic stress disorder, impaired memory retrieval and borderline personality disorder.

26. The composition for use according to claim 24, wherein the aging-related disorder is fibrosis, in particular wherein the fibrosis is characterized by a large number of senescent cells, more particularly wherein the fibrosis is pulmonary fibrosis, chronic obstructive pulmonary disease, myocardial fibrosis or renal fibrosis; or wherein the aging-related disease is cancer, preferably blood cancer or skin cancer.

27. A cosmetic method for preventing and / or reducing skin aging, comprising administering to a subject in need thereof the composition according to any one of claims 1 to 16 or the food, nutritional supplement, cosmeceutical, cosmetic composition or nutritional product according to claim 17.

28. A cosmetic method for ameliorating the cosmetic adverse effects of aging, comprising administering to a subject in need thereof the composition of any one of claims 1 to 16 or the food, nutritional supplement, cosmeceutical, cosmetic composition or nutritional product of claim 17.

Images