Compositions Containing Amarouciaxanthin A Esters and Their Use

Abstract

The present invention relates to a composition comprising a compound of formula (I) or a stereoisomer thereof, in particular amarouciaxanthin A acetate, and to their medical and cosmetic uses. [Chemical 1] JPEG2025523091000020.jpg45149

Description

Technical Field

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

Background Art

[0002] Amarouciaxanthin A (ACX) is a natural xanthophyll first isolated from Amaroucium pliciferum (J Nat Prod, 1985, 48, 606-613). It is one of the main metabolites of fucoxanthin in mice after oral administration, and the hypothesized metabolism is the deacetylation of fucoxanthin (FCX) to fucoxanthinol, followed by rearrangement to ACX in the liver (Drug. Metab. Dispos., 2004, 32, 205-211).

[0003] A wide range of uses of fucoxanthin (FCX), such as antioxidants, anti-obesity agents, anti-diabetic agents, and anti-cancer agents, are well-known in the literature (Int J Mol Sci, 2013, 14, 13763-13781, Biochim Biophys Acta Mol Cell Biol Lipids, 2020, 1865, 158618). On the other hand, very recently, ACX has 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 algae, diatoms, and dinoflagellates and is commercially available from natural extracts. Unfortunately, ACX or its derivatives are present only in small amounts in nature, so there is no direct source for obtaining it. This has previously been obtained from natural extracts after a cumbersome purification process or by very long chemical syntheses that involve a low overall yield and the risk of not fully controlling its chiral centers (Org Lett, 2013, 15, 5310-5313).

[0005] Thus, there is a need for an ACX prodrug that can be synthesized in good yield without epimerization of the chiral center and that converts directly to ACX after administration without the intermediate metabolites that occur when FCX is administered. Also needed is an appropriate vehicle for effective solubilization and administration of the ACX prodrug to ensure their absorption and bioavailability. SUMMARY OF THE INVENTION

[0006] Thus, in a first aspect, the present invention relates to a composition comprising a compound of formula (I). CHEMICAL (wherein R is selected from the group consisting of straight or branched C1-C4 alkyl or a stereoisomer thereof and a vehicle, and the vehicle is selected from an oil or an emulsion).

[0007] In a second aspect, the present invention relates to a food product, dietary supplement, pharmaceutical cosmetic, cosmetic composition or functional food comprising the composition of the present invention.

[0008] In a third aspect, the present invention relates to a non-therapeutic method for improving skin health, comprising administering to a patient in need of improving skin health the composition of the first aspect of the present invention or the food product, dietary supplement, pharmaceutical cosmetic, cosmetic composition or functional food of the second aspect of the present invention.

[0009] A fourth aspect relates to the composition of the present invention for use in medicaments or a pharmaceutical composition comprising the composition of the present invention.

[0010] The fifth aspect relates to the composition of the present invention for use in the treatment and / or prevention of diseases selected from the group consisting of cancer, cardiovascular diseases, imbalance of gut microbiota, inflammatory diseases, autoimmune diseases, fibrosis, bacterial infections, neurological diseases, 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.

[0011] The sixth aspect relates to the composition of the present invention for use in the treatment and / or prevention of diseases mediated by glucocorticoid receptor activity, aging-related diseases or disorders, or as an adjuvant in the treatment of cancer by chemotherapy, preferably taxane-containing chemotherapy.

[0012] In the last aspect, the present invention relates to a cosmetic method for preventing and / or reducing cutaneous aging and / or improving the cosmetic adverse effects of aging, comprising administering to a subject in need thereof the composition of the first aspect or the food product, dietary supplement, pharmaceutical cosmetic, cosmetic composition or functional food of the second aspect of the present invention.

Brief Description of the Drawings

[0013]

Figure 1

Modes for Carrying Out the Invention

[0014] The composition of the present invention The inventors have observed that the formulation of amarouciaxanthin A acetate in oil or emulsion unexpectedly results in improved absorption and plasma levels of amarouciaxanthin compared to those obtained when an equivalent formulation of fucoxanthin is administered. Furthermore, the inventors have also observed that amarouciaxanthin A acetate exhibits improved solubility in certain lipophilic solvents compared to fucoxanthin.

[0015] Accordingly, in a first aspect, the present invention relates to a composition comprising a compound of formula (I).

Chemical formula

[0016] The term "alkyl" consists of carbon and hydrogen atoms, contains no unsaturation, has 1 to 4 carbon atoms, and is a linear or branched hydrocarbon chain radical bonded to the rest of the molecule by a single bond, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, iso-butyl and sec-butyl. Preferably, the alkyl is methyl.

[0017] The term "stereoisomer" refers to a compound having the same atoms connected by the same series of bonds but having different three-dimensional structures that are not interchangeable.

[0018] In a preferred embodiment, the compound of formula (I) is, more specifically, a compound of formula (Ia).

Chemical formula

[0019] In a preferred embodiment, in the compound of formula (I), R is methyl.

[0020] In a more preferred embodiment, in the compound of formula (Ia), R is methyl, i.e., amarouciaxanthin A acetate.

[0021] The method for synthesizing the compound of formula (I) or formula (Ia) is disclosed in the examples of the present application and is also described below.

[0022] A process for preparing a compound of formula (I) is a) a compound of formula (II) or (IIa):

Chem.

Chem.

Chem.

[0023] When step a) is carried out using a compound of formula (II), a compound of formula (III) is obtained in this step, a compound of formula (I) where R is methyl is obtained in step b), a compound of formula (IV) is obtained in step c1), and a compound of formula (I) where R is C2-C4 alkyl is obtained in step c2).

[0024] When step a) is carried out using a compound of formula (IIa), a compound of formula (IIIa) is obtained in this step, a compound of formula (Ia) where R is methyl is obtained in step b), a compound of formula (IVa) is obtained in step c1), and a compound of formula (Ia) where R is C2-C4 alkyl is obtained in step c2).

[0025] The oxidizing agent in step a) can be any suitable oxidizing agent capable of providing a compound of formula (III) or (IIIa). Examples of oxidizing agents are tetra-n-propylammonium perruthenate (TPAP) and 2-iodoxybenzoic acid (IBX), preferably TPAP.

[0026] A co-oxidizing agent may be used in step a). An example and a suitable co-oxidizing agent is N-methylmorpholine N-oxide (NMO).

[0027] Preferably, step a) is carried out using TPAP as the oxidizing agent and NMO as the co-oxidizing agent.

[0028] The reaction in 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.

[0029] The reaction of step a) is preferably carried out at a temperature within the range of 15°C to 35°C.

[0030] The amount of the oxidizing agent used in step a) is preferably 0.01 to 0.5 mol, more preferably 0.05 to 0.2 mol, per mole of the compound of formula (II) or (IIa).

[0031] When present, the amount of the co-oxidizing agent used in step a) is preferably 1.5 to 5 mol, more preferably 1.5 to 2.5 mol, per mole of the compound of formula (II) or (IIa).

[0032] Step a) is preferably carried out with water removal. For example, 4 Å molecular sieves can be used in step a).

[0033] Step a) can also be carried out without water removal.

[0034] Preferably, step a) is carried out for 0.5 to 5 hours.

[0035] Step a) provides a compound of formula (III) or (IIIa). When step a) is carried out using a compound of formula (II), a compound of formula (III) is obtained in this step. When step a) is carried out using a compound of formula (IIa), a compound of formula (IIIa) is obtained in this step.

[0036] The next step of the process is step b) of treating the compound of formula (III) or (IIIa) with SiO2 in the presence of a base, preferably a base selected from the group consisting of N-methylmorpholine and triethylamine, to obtain a compound of formula (I) or (Ia) wherein R is methyl.

[0037] The compound of formula (III) or (IIIa) is obtained in step a).

[0038] The amount of SiO2 used in step b) is preferably 10 to 50 moles per mole of the compound of formula (II) or (IIa).

[0039] Step b) is carried out in the presence of a base. Examples of suitable bases are N-methylmorpholine, trimethylamine, N,N-diisopropylethylamine and mixtures thereof, preferably N-methylmorpholine.

[0040] The amount of base used in step b) is preferably 0.1 to 5 moles per mole of the compound of formula (II) or (IIa).

[0041] Step a) may be carried out in the presence of NMO as a co-oxidant that provides N-methylmorpholine as a by-product, which is then used as a base in step b).

[0042] Steps a) and b) may be carried out in one pot.

[0043] 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 mixtures thereof, preferably dichloromethane.

[0044] The reaction of step b) is preferably carried out at a temperature in the range of 15 °C to 35 °C.

[0045] Preferably, step b) is carried out for 0.5 to 24 hours.

[0046] Step b) provides a compound of formula (I) or (Ia) where R is methyl. When step b) is carried out using a compound of formula (III), a compound of formula (I) where R is methyl is obtained in this step. When step b) is carried out using a compound of formula (IIIa), a compound of formula (Ia) is obtained in this step.

[0047] When the target compound of the process of the present invention is a compound of formula (I) or (Ia) wherein R is methyl, step c) is not carried out.

[0048] When the target compound of the process of the present invention is a compound of formula (I) or (Ia) wherein R is a linear or branched C2-C4 alkyl, step c) is carried out. Step c) comprises steps c1) and c2).

[0049] Step c1) is a compound of formula (I) or (Ia) wherein R is methyl, by treatment with an esterase, preferably a lipase, to give a compound of formula (IV) or (IVa):

Chemical formula

[0050] The compound of formula (IV) or (IVa) is obtained in step b).

[0051] Any esterase capable of providing compound (IV) or (IVa) from the compound of formula (I) or (Ia) respectively can be used. Examples of esterases are lipase and cholesterol esterase, preferably lipase.

[0052] Step c1) is preferably carried out in the presence of an emulsifier such as sodium taurocholate, sodium dodecyl sulfate or its hydrate.

[0053] Preferably, step c1) is carried out in an aqueous solvent, preferably at a pH of 6.5 to 7.5, and more preferably, step c1) is carried out in phosphate buffered saline (PBS).

[0054] The reaction of step c1) is preferably carried out at a temperature in the range of 30°C to 45°C.

[0055] Preferably, step c1) is carried out for 2 to 24 hours.

[0056] Step c1) provides a compound of formula (IV) or (IVa). When step c1) is carried out using a compound of formula (I), the compound of formula (IV) is obtained in this step. When step c1) is carried out using a compound of formula (Ia), the compound of formula (IVa) is obtained in this step.

[0057] The next step of the process of the present invention is to react a compound of formula (IV) or (IVa) with a carboxylic acid of formula (V): R-COOH (V) [wherein, R is a linear or branched C2-C4 alkyl.] in the presence of a coupling agent, preferably a carbodiimide, more preferably a carbodiimide selected from the group consisting of 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 carry out esterification to obtain a compound of formula (I) or (Ia):

Chemical formula

[0058] The compound of formula (IV) or (IVa) is obtained in step c1).

[0059] The coupling agent used in step c2) can be any suitable coupling agent known in the art for the esterification of carboxylic acids and alcohols. Examples of suitable coupling agents are carbodiimides, preferably dicyclohexylcarbodiimide (DDC), diisopropylcarbodiimide (DIC) and ethyl-(N’,N’-dimethylamino)propylcarbodiimide (EDC) or salts thereof. The esterification reaction of step c2) is carried out in the presence of DMAP.

[0060] Preferably, 1 to 2 moles of coupling agent are used in step c2) per mole of carboxylic acid (V).

[0061] Preferably, 0.01 to 0.5 moles of DMAP are used in step c2) per mole of carboxylic acid of formula (V).

[0062] Preferably, 1 to 2 moles of the compound of formula (IV) or (IVa) are used in step c2) per mole of carboxylic acid of formula (V).

[0063] Preferably, step c2) is carried out in an organic solvent such as dichloromethane, N,N-dimethylformamide or a mixture thereof.

[0064] The reaction of step c2) is preferably carried out at a temperature in the range of 0 °C to 30 °C.

[0065] Preferably, step c2) is carried out for 1 to 15 hours.

[0066] Step c2) provides a compound of formula (I) or (Ia) in which R is selected from the group consisting of linear or branched C2-C4 alkyl. When step c2) is carried out using a compound of formula (IV), a compound of formula (I) in which R is selected from the group consisting of linear or branched C2-C4 alkyl is obtained in this step. When step c2) is carried out using a compound of formula (IVa), a compound of formula (Ia) in which R is selected from the group consisting of linear or branched C2-C4 alkyl is obtained in this step.

[0067] In the process of the present invention - The oxidizing agent in step a) may be TPAP, - Step a) may be carried out in the presence of a co-oxidizing agent, - The co-oxidizing agent in step a) may be NMO, and / or - The base in step b) may be N-methylmorpholine.

[0068] Furthermore, steps a) and / or b) of the process of the present invention can be carried out in the presence of water, in particular using more than 0.05 moles of water per mole of the compound of formula (II) or (IIa). Thereby, a mixture of the compound of formula (I) or (Ia) and the compound of formula (VI) or (VIa) is obtained.

Chemical formula

[0069] Alternatively, the compound of formula (VI) or (VIa) can be obtained by heating the compound of formula (I) or (Ia) in the presence of water at 60-90 °C. Step a) can be carried out in the presence or absence of water. To avoid the presence of water in step a), a water scavenger such as 4 Å molecular sieves may be used. Step b) can be carried out in the presence or absence of water. To avoid the presence of water in step a), a water scavenger such as 4 Å molecular sieves may be used. Alternatively, both steps a) and b) are carried out in the presence or absence of water. To avoid the presence of water in steps a) and b), a water scavenger such as 4 Å molecular sieves may be used.

[0070] The term "presence of water" refers to an amount of water of 0.1 volume % to 100 volume %, preferably 100%. This amount of water is determined with respect to the solvent present in the reaction medium without considering the water removed by the water scavenger.

[0071] Thus, in one embodiment, the composition of the present invention comprises the compound of formula (I) or (Ia), preferably the compound of formula (Ia) (preferably R is methyl), and the above-mentioned compound of formula (VI) or (VIa), preferably the compound of formula (VIa) (preferably R is methyl).

[0072] In certain embodiments, 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, based on the total weight of the composition.

[0073] In certain embodiments, the amount of the compound of formula (VI) or (VIa) in the composition is 1 to 60% by weight, based on the total weight of the composition.

[0074] As used herein, the terms “oil,” “lipid,” or “fat,” when used ambiguously, are defined to include any of a broad range of substances that are characteristically insoluble in water and extractable with organic solvents. This broad class of compounds is well known to those skilled in the art, and when the term “lipid” is used herein, it is not limited to any particular structure. It includes organic compounds having lipophilic or amphipathic properties, including but not limited to fats, fatty oils, essential oils, waxes, steroids, sterols, phospholipids, glycolipids, sulfolipids, aminolipids, pigment lipids (lipochromes), and fatty acids. In the context of the present invention, an oil can be solid or liquid.

[0075] “Lipophilic” refers to organic compounds that dissolve in nonpolar solvents such as fats, oils, lipids, and organic solvents. Lipophilic compounds are sparingly soluble or insoluble in water. Thus, lipophilic compounds are hydrophobic. Amphipathic lipids, also referred to herein as “amphiphilic lipids,” refer to lipid molecules having both hydrophilic and hydrophobic characteristics. The hydrophobic group of an amphipathic lipid can be a long-chain hydrocarbon group, as described in more detail below herein. The hydrophilic group of an amphipathic lipid can include a charged group, such as an anionic or cationic group, or a polar uncharged group. Amphipathic lipids can have multiple hydrophobic groups, multiple hydrophilic groups, and combinations thereof. Due to the presence of both hydrophobic and hydrophilic groups, amphipathic lipids can be soluble in water and to some extent soluble in nonpolar organic solvents.

[0076] As used herein, "hydrophilic" is a physical property of molecules that can form hydrogen bonds with water (H2O) molecules and are soluble in water and other polar solvents. The terms "hydrophilic" and "polar" can be used interchangeably. Hydrophilic characteristics are due to the presence of polar or charged groups such as carbohydrate, phosphate, carboxylic acid, sulfate, amino, sulfhydryl, nitro, hydroxy groups and other similar groups.

[0077] Conversely, the term "hydrophobic" is a physical property of molecules that are repelled from a mass of water and can be called "non-polar" or "apolar", all of which are terms that can be used interchangeably with "hydrophobic". Hydrophobicity can be conferred by including apolar 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.

[0078] As used herein, "vehicle" refers to a compound or composition that can deliver a bioactive compound to a physiological site or cell.

[0079] The term oil refers to either a single oil or a blend of oils.

[0080] The term "blend 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, different types of oils 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 oil, vegetable oil or a mixture of both to obtain the desired composition.

[0081] Examples of oils include compounds containing long-chain aliphatic hydrocarbons and their derivatives. Lipids may be naturally occurring or synthetic (i.e., designed or produced by humans). However, lipids are typically biological substances. Biological lipids are well known in the art and include, for example, neutral fats, phospholipids, phosphoglycerides, steroids, terpenes, lysolipids, sphingoglycolipids, glycolipids, sulfatides, lipids having ether-linked and ester-linked fatty acids, and polymeric lipids, as well as combinations thereof. Of course, compounds other than those specifically described herein that are understood by those skilled in the art as lipids are also included in the compositions and methods of the present invention.

[0082] In certain embodiments, the oil includes neutral fats. Neutral fats refer to low molecular weight alcohols and fatty acids, also known as fatty acid esters (FAE) or fatty acid alkyl esters (FAAE). Fatty acid esters can be mono-esters, di-esters, or triesters depending on the number of fatty acids. When the alcohol is glycerol, the FAE is called a glyceride, and similarly, depending on the number of fatty acids esterified with the glycerol molecule, the glyceride can be a monoglyceride, diglyceride, or triglyceride, respectively.

[0083] In certain embodiments, the lipid includes a fatty acid ester or a fatty acid alkyl ester. In preferred embodiments, the lipid includes mono-, di-, and / or triesters. In another specific embodiment, the oil includes a blend of fatty acid esters. In another embodiment, the oil includes a blend of glycerides. In another embodiment, the oil includes a blend of mono-, di-, or triglycerides.

[0084] Fatty acids are generally molecules that contain a carbon chain with an acidic moiety (e.g., carboxylic acid) at the end of the chain. The carbon chain of a fatty acid can be of any length as long as the lipid molecule has a transition temperature of less than or equal to about 15 °C. For example, fatty acids 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 derivable therefrom.

[0085] The transition temperature is the point at which the phospholipid membrane becomes more fluid and changes from a rigidly ordered "gel" or "solid" phase to a liquid crystal phase with a higher degree of freedom of movement of individual molecules (see the discussion in New, 1990). This parameter can be measured for a single lipid or for a composition containing two or more lipids.

[0086] The fatty acids of FAE, more specifically 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. Saturated fatty acids do not contain carbon-carbon double bonds in the aliphatic chain. Examples of saturated fatty acids include, for example, palmitic acid and stearic acid. Monounsaturated fatty acids contain a single carbon-carbon double bond (C=C) in the aliphatic chain. Examples of monounsaturated fatty acids include, for example, oleic acid and palmitoleic acid. Polyunsaturated fatty acids (also known as PUFAs) contain at least two carbon-carbon double bonds in the aliphatic chain.

[0087] Examples of polyunsaturated fatty acids include, for example, linoleic acid (2 C=C) and linolenic acid (3 C=C). Furthermore, polyunsaturated fatty acids include omega-3 fatty acids and omega-6 fatty acids depending on the position of the final C=C bond in the aliphatic chain. For example, linoleic acid is an omega-6 fatty acid and linolenic acid is an omega-3 fatty acid.

[0088] Omega-3 fatty acids, also known as omega-3 oils 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 and are important components of animal lipid metabolism, playing important roles in human diet and human physiology. The three types of 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. Seaweeds 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, and sources of EPA and DHA include fish and fish oils, as well as algal oils. The term "omega-3 fatty acids" includes natural and synthetic omega-3 fatty acids, as well as their 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 incorporated herein by reference), precursors, salts, and mixtures. Examples of omega-3 fatty acid oils include omega-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 omega-3 fatty acids and glycerol such as mono-, di-, and triglycerides; and esters of omega-3 fatty acids and primary, secondary, and / or tertiary alcohols, such as fatty acid methyl esters and fatty acid ethyl esters, but are not limited thereto.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 components of oils, such as marine oils (e.g., fish oil and refined fish oil concentrates), algal oils, bacterial oils and plant-based oils.

[0089] In some embodiments of the present disclosure, at least one of the omega-3 fatty acids of the fatty acid oil mixture has a cis configuration. Examples include, but are not limited to, (all-Z)-9,12,15-octadecatrienoic acid (ALA), (all-Z)-6,9,12,15-octadecatetraenoic acid (STA), (all-Z)-11,14,17-eicosatrienoic acid (ETE), (all-Z)-5,8,11,14,17-eicosapentaenoic acid (EPA), (all-Z)-4,7,10,13,16,19-docosahexaenoic acid (DHA), (all-Z)-8,11,14,17-eicosatetraenoic acid (ETA), (all-Z)-7,10,13,16,19-docosapentaenoic acid (DPA), (all-Z)-6,9,12,15,19-henicosapentaenoic acid (HPA); (all-Z)-5,8,11,14-eicosatetraenoic acid, (all-Z)-4,7,10,13,16-docosapentaenoic acid (osbond acid), (all-Z)-9,12-octadecadienoic acid (linoleic acid), (all-Z)-5,8,11,14-eicosatetraenoic acid (AA), (all-Z)-6,9,12-octadecatrienoic acid (GLA); (all)-9-octadecenoic acid (oleic acid), 13(Z)-docosenic acid (erucic acid), (R-(Z))-12-hydroxy-9-octadecenoic acid (ricinoleic acid).

[0090] Omega-6 fatty acids (also called ω-6 fatty acids or n-6 fatty acids) are a family of polyunsaturated fatty acids that commonly have a final carbon-carbon double bond at the n-6 position, i.e., the sixth bond counting from the methyl end. Examples of omega-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, tetracosapentaenoic acid; esters of omega-6 fatty acids and glycerol such as mono-, di- and triglycerides; and esters of omega-6 fatty acids and 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 can be used in their pure form and / or as a component of an oil.

[0091] In certain embodiments, the oil is a vegetable oil, a microbial oil, a krill or a fish oil.

[0092] In another embodiment, the oil is a blend oil comprising any of a vegetable oil, a microbial oil and / or a fish oil.

[0093] In another embodiment, the oil is a blend of fatty acids, and the relative amounts of each can affect the overall characteristics of the oil, particularly its ability to resist oxidation and stabilize compounds suspended therein.

[0094] In certain embodiments, the oil is enriched in polyunsaturated or monounsaturated fatty acids. Within the context of the present invention, the term "enriched" is used to define an oil containing more than 20% w / w, more than 25% w / w, 30% w / w, more than 35% w / w, more than 40% w / w, more than 45% w / w, more than 50% w / w, more than 55% w / w, more than 60% w / w or more than 70% w / w of polyunsaturated and / or monounsaturated fatty acids based on the total weight of the oil.

[0095] In other embodiments, the oil can be a vegetable oil or an oil blend.

[0096] In another embodiment, the oil can be a blended vegetable oil containing more than 25% w / w, 30% w / w, more than 35% w / w, more than 40% w / w, more than 45% w / w, more than 50% w / w, more than 55% w / w, more than 60% w / w or more than 70% w / w polyunsaturated fatty acids, and the polyunsaturated fatty acids include omega-6 fatty acids and omega-3 fatty acids.

[0097] "Vegetable oil" refers to any edible oil obtained from plants. Typically, vegetable oils are extracted from the seeds or grains of plants. Vegetable oils are derived from several seeds, nuts, grains and fruits. Vegetable oils are composed of a complex mixture of triacylglycerols (TAG; usually >95%) and a small amount of diacylglycerols (usually <5%). Other minor constituents are tocopherols / tocotrienols (up to 900 mg kg-1) and phytosterol esters / phytosterols (up to 1%). Vegetable oils can be reliably characterized by expert chromatographic analysis by determining their TAG composition along with their fatty acid composition and minor constituents.

[0098] The term "triacylglycerol" ("TAG") refers to a neutral lipid composed of three fatty acyl residues esterified to a glycerol molecule. TAG can contain long-chain PUFAs and saturated fatty acids, as well as short-chain saturated and unsaturated fatty acids.

[0099] "Microbial oil" ("MO") or "bacterial oil", also called single cell oil (SCO), consists of triacylglycerols which are intracellular storage lipids. It is similar to vegetable oils which are another biologically produced oil. They are produced by oleaginous microorganisms, which are terms for bacteria, fungi, algae and yeasts that can accumulate 20% - 80% of their biomass as lipids. Lipid accumulation occurs until the end of the logarithmic phase and continues during the stationary phase until the carbon source begins to decline due to nutrient limitation. Oleaginous microorganisms are also potential sources of such fatty acids.

[0100] The most important sources are several species of yeast that can convert food into triglycerides and accumulate the lipids produced when given carbohydrates.

[0101] PUFAs produced by MO through fermentation are a good and renewable source of PUFAs. M. elongate , M. isabellina and M. alpina (Lounds et al., 2007) including Mortierella Several fungal species such as the genus are considered good sources of PUFAs. Some Phythium genus and Phytophtora genus can also produce ω-3 PUFAs (O’Brien et al., 1993). The red alga Porphyridium cruentum produces significant amounts of EPA and arachidonic acid (AA). However, Flexibacter genus and Shewanella Only a few Gram-negative marine bacteria such as the genus can produce PUFAs (Akimoto et al., 1990).

[0102] In certain embodiments, the lipid vehicle is fish oil or microbial oil enriched with DHA or EPA.

[0103] Fish oil is the oil derived from the tissues of oily fish. Fish oil contains omega-3 fatty acid eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are precursors of certain eicosanoids known to reduce inflammation in the body and improve hypertriglyceridemia.

[0104] “Fish oil” refers to the oil derived from the tissues of oily fish. Examples of oily fish include, but are not limited to, menhaden, anchovy, sardine, capelin, pollock, etc. Fish oil is a typical component of the feed used in aquaculture.

[0105] "Menhaden" refers to forage fish of the genera Brevoortia and Ethmidium, two genera of marine fish in the herring family. Recent taxonomic studies using DNA comparisons have organized North American menhaden into large (Gulf and Atlantic menhaden) and small (Finescale and Yellowfin menhaden) designations (Anderson, J.D., Fishery Bulletin, 105(3):368-378).

[0106] "Anchovy" from which anchovy fish meal and anchovy fish oil are produced is a family of small common marine forage fish (Engraulidae). There are about 140 species in 16 genera and are found in the Atlantic, Indian, and Pacific Oceans.

[0107] The term "krill" Euphausiacea refers to small crustaceans of the order and are found in oceans around the world. As used herein, "krill oil" refers herein to any mixture of extracted lipids derived from any part of the krill organism and may include oil obtained directly from krill, oil derived from a krill source and further modified / processed, and combinations thereof. Krill oil is a unique marine oil containing omega-3 or n-3 fatty acids (FA), and the bioactive eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are present mainly in phospholipids or PL (i.e., containing a FA profile of up to 35% w / w) (up to 95% w / w), containing up to 60% PL and up to 45% triglycerides in the oil.

[0108] Krill oil contains phospholipids bound with omega-3 fatty acids. For example, krill oil may contain phospholipids containing omega-3 fatty acids in an amount of about 20% to about 60%, such as about 30% to about 50%, based on the weight of the krill oil. In an exemplary embodiment, krill oil may contain triglycerides containing omega-3 fatty acids in an amount of less than about 30%, such as less than about 5%, based on the weight of the krill oil.

[0109] In an exemplary embodiment, a predetermined amount of omega-3 fatty acid-containing phospholipid contains omega-3 fatty acids bonded to the 1st and 2nd positions of the phospholipid rather than the 3rd position of the phospholipid. That is, a predetermined amount of omega-3 fatty acid-containing phospholipid can contain omega-3 fatty acids at the 2nd position (i.e., the middle position) of the phospholipid. For example, an omega-3 fatty acid-containing phospholipid containing omega-3 fatty acids bonded to the 1st and 2nd positions of the phospholipid rather than the 3rd position of the phospholipid may be present in an amount of about 70% to about 80%, for example about 80% to about 95%, based on the total weight of the omega-3 fatty acid-containing phospholipid.

[0110] In an exemplary embodiment, marine crustaceans or krill oil may be distinguishable from fish oil based at least on (1) the phospholipid content, (2) the content of omega-3 fatty acid-containing phospholipids, (3) the content of omega-3 fatty acid-containing triglycerides, and / or (4) the content of omega-3 fatty acid-containing phospholipids containing omega-3 fatty acids bonded to the 1st and 2nd positions of the phospholipid rather than the 3rd position of the phospholipid. For example, marine crustaceans or krill oil can contain a higher concentration of omega-3 fatty acid-containing phospholipids, a lower concentration of omega-3 fatty acid-containing triglycerides, and / or a higher content of omega-3 fatty acid-containing phospholipids containing omega-3 fatty acids bonded to the 1st and 2nd positions of the phospholipid rather than the 3rd position of the phospholipid.

[0111] 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 physiological literature, it is given the name 22:6(n-3). It can be synthesized from alpha-linolenic acid or obtained directly from maternal milk (breast milk), fatty fish, fish oil, or algal oil. The structure of DHA is a carboxylic acid having a 22-carbon chain (docosa- is derived 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 omega end. [3] Its common name is cerebric acid (derived from the Latin word cerebrum meaning "brain"), its systematic name is all-cis-docosa-4,7,10,13,16,19-hexa-enoic acid, and its abbreviation in fatty acid nomenclature is 22:6(n-3).

[0112] Eicosapentaenoic acid (EPA) is an omega-3 fatty acid. In physiological literature, it is given the name 20:5(n-3). It also has the common name timnodonic acid. In chemical structure, EPA is a carboxylic acid having a 20-carbon chain and five cis double bonds; the first double bond is located at the third carbon from the omega end. EPA is a polyunsaturated fatty acid (PUFA) that acts as a precursor to prostaglandin-3 (which inhibits platelet aggregation), thromboxane-3, and leukotriene-5 eicosanoids. EPA is both a precursor and a hydrolytic degradation product of eicosapentaenoyl ethanolamide (EPEA: C22H35NO2; 20:5, n-3).

[0113] Most of the docosahexaenoic acid in fish and multicellular organisms with access to cold-water marine food sources is derived from photosynthetic and heterotrophic microalgae, and it becomes increasingly concentrated in organisms the higher they are on the food chain. DHA is also commercially available from another species of the genus: Crypthecodinium cohnii and Schizochytrium Microalgae-produced DHA is plant-based.

[0114] In some embodiments of the present disclosure, the weight ratio of EPA:DHA in the fatty acid oil ranges from 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 weight ratio of EPA:DHA in the fatty acid oil mixture ranges from about 1:2 to about 2:1. In at least one embodiment, the weight ratio of EPA:DHA in the fatty acid oil mixture ranges from about 1:1 to about 2:1. In at least one embodiment, the weight ratio of EPA:DHA in the fatty acid oil mixture ranges from about 1:2 to about 1:3.

[0115] The term "enriched with DHA or EPA" is used to refer to the weight percentage of DHA or EPA relative to the total weight of the fatty acids of the oil, and is in the range of 30 to 100%, preferably 40 to 90%, 50 to 80%, and more preferably the weight percentage of DHA or EPA is 60 to 70%.

[0116] In certain embodiments, the vehicle 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, babassu 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, croton megalocarpus seed oil, borage seed oil, evening primrose oil, flaxseed oil, amaranth oil, apricot oil, apple seed oil, argan oil, avocado oil, babassu oil, ben nut oil, borneo tallow nut oil, cape chestnut oil, velvet bean oil, onamo oil, cohune oil, coriander seed oil, coconut seed oil, dika oil, grape seed oil, kapok seed oil, kenaf seed oil, larrea divaricata oil, mafura oil, marula oil, mustard oil, niger seed oil, okra seed oil, papaya seed oil, perilla seed oil, kaki seed oil, pequi oil, pirin nut oil, pomegranate seed oil, poppy seed oil, plukenetia oil, prune seed oil, quinoa oil, ramtil oil, rice bran oil, royle oil, sacha inchi oil, sapote oil, sedjo oil, taramina oil, tea seed oil, thistle oil, tiger nut oil, tomato seed oil, wheat germ oil, peanut oil, sesame oil, soybean oil, corn oil and mixtures thereof, preferably sunflower oil.

[0117] In certain embodiments, the oil is sunflower oil.

[0118] Sunflower oil is sunflower ( Helianthus annuus) is a non-volatile oil pressed from the seeds of sunflowers. Sunflower oil is generally used in food as frying oil and in cosmetic formulations as a skin softener. Sunflower oil is mainly composed of linoleic acid, polyunsaturated fats, and oleic acid, and the 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 omega-9) 30%, linoleic acid (polyunsaturated omega-6) 59%. Four types of sunflower oil with different fatty acid concentrations: high linoleic acid, high oleic acid, medium oleic acid, and a combination of high stearic acid and high oleic acid are produced by plant breeding and industrial processing. 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. Within the context of the present invention, any of the four types of sunflower oil or combinations thereof are contemplated as the oil vehicle for the compositions of the present invention.

[0119] In certain embodiments, the vehicle is a vegetable oil or vegetable-based oil blend comprising saturated fatty acids (SAFA), monounsaturated fatty acids (MUFA), and polyunsaturated fatty acids (PUFA).

[0120] In another embodiment, the vegetable oil or vegetable-based oil blend comprises from about 5% w / w to 95% w / w, from about 10% w / w to 80% w / w, from about 10% w / w to 70% w / w, from about 10% w / w to 60% w / w, from about 10% w / w to 50% w / w, from about 10% w / w to 40% w / w, from about 10% w / w to 30% w / w, from about 10% w / w to 20% w / w MUFA in the total weight of the oil.

[0121] In another specific embodiment, the omega-6 / omega-3 fat ratio in the vegetable oil or vegetable oil blend is 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.

[0122] In another embodiment, the vegetable oil or vegetable oil blend contains omega-6 fatty acids in an amount of 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 of the total weight of the oil.

[0123] In another embodiment, the vegetable oil or vegetable oil blend contains omega-3 fatty acids in an amount of 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.

[0124] Fatty acids may be specified using a mathematical formula that simplifies their representation by combining numbers and alphabetic characters for the number of carbon atoms, the number of double bonds, and the position of the double bonds. For example, a saturated fatty acid having 20 carbon atoms may be named C20:0, a monounsaturated fatty acid having 18 carbon atoms may be named C18:1, eicosapentaenoic acid may be named C20:5 n-3, etc. The symbol n- represents the position of the double bond counted from the terminal methyl group of the fatty acid. For example, n-3 indicates that the bond between the third and fourth carbon atoms counted from the terminal methyl group of the fatty acid is a double bond. This method of designation is well-known to those skilled in the art, and fatty acids specified according to this method can be easily identified by those skilled in the art.

[0125] In another specific embodiment, the oil contains highly unsaturated fatty acids or alkyl esters thereof. As used herein, the term "highly unsaturated fatty acid" means a fatty acid having 18 or more carbon atoms and 3 or more double bonds. The highly unsaturated fatty acid can be, for example, a fatty acid having 20 or more carbon atoms and 3 or more or even 4 or more double bonds, or a fatty acid having 20 or more carbon atoms and 5 or more double bonds. Exemplary highly unsaturated fatty acids include linolenic acid (18:3 n-3), linolenic acid (18:3 n-6), dihomo-linolenic acid (20:3 n-6), arachidonic acid (20:4 n-6), eicosapentaenoic acid (C20:5 n-3), docosapentaenoic acid (22:5 n-6), and docosahexaenoic acid (22:6 n-3).

[0126] As used herein, the composition containing highly unsaturated fatty acids or alkyl esters thereof means either a fatty acid composition containing highly unsaturated fatty acids or a fatty acid alkyl ester composition containing alkyl esters of highly unsaturated fatty acids. Here, the fatty acid composition is a composition containing fatty acids as the main component, and the fatty acid alkyl ester composition is a composition containing alkyl esters of fatty acids as the main component.

[0127] In the present invention, the highly unsaturated fatty acid is not particularly limited as long as its alkyl ester is obtained as the main distillate by distillation concentration. The highly unsaturated fatty acid can be eicosapentaenoic acid, docosahexaenoic acid, dihomo-linolenic acid, arachidonic acid, or a combination thereof. In a preferred embodiment, the highly unsaturated fatty acid can be eicosapentaenoic acid, docosahexaenoic acid, or a combination thereof. In a more preferred embodiment, the highly unsaturated fatty acid can be eicosapentaenoic acid.

[0128] In certain embodiments, the oil is enriched with polyunsaturated or monounsaturated fatty acids and / or alkyl esters. Within the context of the present invention, the term "enriched" is used to define an oil that contains more than 20% w / w, more than 25% w / w, 30% w / w, more than 35% w / w, more than 40% w / w, more than 45% w / w, more than 50% w / w, more than 55% w / w, more than 60% w / w of polyunsaturated and / or monounsaturated fatty acids and / or alkyl esters based on the total weight of the oil.

[0129] In certain embodiments, the oil is enriched with polyunsaturated fatty acids and / or omega-3 fatty acids, as defined by the term "enriched" as described above.

[0130] Another class of lipids includes phospholipids. Thus, in another embodiment, the oil contains phospholipids. Phospholipids generally contain either a glycerol or sphingosine moiety, an ionic phosphate group for producing an amphiphilic compound, and one or more fatty acids. Examples of types of phospholipids include, for example, phosphoglycerides in which a phosphate group is bonded to the first carbon of the glycerol of diglyceride, and sphingolipids (e.g., sphingomyelin) in which a phosphate group is esterified to a sphingosine amino alcohol. For example, in some embodiments, the lipid molecule is dilauroyl phosphatidylcholine, a phospholipid that contains two fully saturated fatty acid moieties.

[0131] Phospholipids may of course contain additional chemical groups, such as, for example, an alcohol bonded to the phosphate group. Those skilled in the art will be familiar with a wide class of agents known as phospholipids and the chemical groups that can be bonded to phospholipids.

[0132] Those skilled in the art will be familiar with many other classes of lipids that are known to exist.

[0133] Lipids can be obtained from natural sources, commercial sources, or chemically synthesized, as is known to those skilled in the art. For example, phospholipids can be derived from natural sources such as eggs or soy phosphatidylcholine, brain phosphatidic acid, brain or plant phosphatidylinositol, heart cardiolipin, and plant or bacterial phosphatidylethanolamine. In another example, lipids suitable for use according to the present invention can be obtained from commercial sources.

[0134] Examples of further fatty acid or fatty acid alkyl ester compositions or mixtures thereof (fatty acid oil mixtures) included in the present disclosure include, but are not limited to, the fatty acids defined in European Pharmacopoeia omega-3 ethyl ester 90 and refined marine oils such as European Pharmacopoeia omega-3 acid triglyceride, European Pharmacopoeia omega-3 acid ethyl ester 60, European Pharmacopoeia fish oil monograph rich in omega-3 acids, and / or, for example, USP fish oil monograph.

[0135] Examples of commercially available fatty acid oil mixtures containing different fatty acids suitable for the present disclosure include, but are not limited to: Incromega™ omega-3 marine oil concentrates such as Incromega™ TG7010 SR, Incromega™ E7010 SR, Incromega™ TG6015, Incromega™ EPA500TG SR, Incromega™ E400200 SR, Incromega™ E4010, Incromega™ DHA700TG SR, Incromega™ DHA700E SR, Incromega™ DHA500TG SR, Incromega™ TG3322 SR, Incromega™ E3322 SR, Incromega™ TG3322, Incromega™ E3322, Incromega™ Trio TG / EE (Croda International PLC, Yorkshire, UK); EPAX2050TG, EPAX5500EE, EPAX5500TG, EPAX5000EE, EPAX5000TG, EPAX6000EE, EPAX6000TG, EPAX6000FA, EPAX6500EE, EPAX6500TG, EPAX4510TG, EPAX1050TG, EPAX6015TG / EE, EPAX4020TG, and EPAX4020EE (EPAX is a wholly-owned subsidiary of the Norwegian company Austevoll Seafood ASA); Omacor® / Lovaza™ / Zodin® / Seacor® finished pharmaceuticals, K85EE, and AGP 103 (Pronova BioPharma Norge AS); MEG-3® EPA / DHA fish oil concentrate (Ocean Nutrition Canada); DHA FNO "functional nutritional oil" and DHA CL "clear liquid" (Lonza); Superba™ krill oil (Aker); omega-3 products containing DHA produced by Martek; Neptune krill oil (Neptune); cod liver oil products and reflux-preventing fish oil concentrates (TG) produced by Moller; Lysi omega-3 fish oil;Seven Seas Triomega (registered trademark) cod liver oil blend (Seven Seas); Fri Flyt omega-3 (Vesteralens); and Epadel (Mochida). These commercially available embodiments provide various omega-3 fatty acids, combinations, and other components as a result of a transesterification process or preparation method for obtaining omega-3 fatty acids from various sources such as marine sources, algal sources, bacterial sources, and plant-based sources.

[0136] Examples of synthetic oils include, but are not limited to, Maisine, Labrafac lipophile 1349, Labrafac MC60, and Plurol Oleique.

[0137] The lipid can be a crude oil or a refined oil. As used herein, the term "crude oil" means an oil that is a mixture of lipids extracted from an organism. Here, the term "refined oil" means an oil obtained from a crude oil by performing at least one fat / oil refining step selected from the group consisting of a degumming step, a deacidification step, a bleaching step, and a deodorization step to remove off-target substances such as phospholipids and sterols. One of ordinary skill in the art can distinguish between crude oil and refined oil by routine analysis.

[0138] The composition containing the compound of the present invention may be solubilized or dispersed in an oil, thus providing a solution or dispersion. One of ordinary skill in the art will be familiar with the range of techniques that can be used to disperse or solubilize a drug in an oil. For example, the compound of the present invention may be dispersed in a lipid-containing solution, dissolved in a lipid, emulsified with a lipid, mixed with a lipid, combined with a lipid, covalently bonded to a lipid, contained as a suspension in a lipid, contained or complexed with micelles or liposomes, or otherwise associated with a lipid or lipid structure by any means known to one of ordinary skill in the art.

[0139] Thus, according to the above, the composition can be a solution or a dispersion. Similarly, the oil can also include micelles, microemulsions, macroemulsions, and liposomes.

[0140] In some embodiments, the vehicle of the delivery system encapsulates the compounds of the present invention. The terms "encapsulate" and "enclose" are used interchangeably herein and refer to the incorporation or association of a substance or molecule (e.g., a bioactive compound) in or with an oil. For example, in embodiments where the oil is a liposome, the substance or molecule can associate with the lipid bilayer. The compound can also be encapsulated within micelles, microemulsions, or macroemulsions.

[0141] The term "micelle" refers to a colloidal aggregate of amphiphilic molecules formed at a well-defined concentration known as the critical micelle concentration. Micelles are oriented such that the nonpolar portions of the lipid molecules are inside the micelle and the polar portions are on the outside, exposed to water. The typical number of aggregated molecules in a micelle (aggregation number) ranges from about 50 to about 100.

[0142] Liposomes are self-assembling, substantially spherical vesicles that contain an aqueous interior or core surrounded by a lipid bilayer, which includes amphiphilic lipids having hydrophilic head groups and hydrophobic tails. The hydrophilic head groups of the amphiphilic lipid molecules are directed towards the aqueous solution, and the hydrophobic tails are directed towards the interior of the bilayer. As a result, the lipid bilayer structure includes two opposing monolayers called the "inner leaflet" and the "outer leaflet", and the hydrophobic tails are shielded from contact with the surrounding medium. The "inner leaflet" is the monolayer in which the hydrophilic head groups are directed towards the aqueous core of the liposome. The "outer leaflet" is the monolayer that contains the amphiphilic lipids, and the hydrophilic head groups are directed towards the outer surface of the liposome. Liposomes typically have a diameter in the range of about 25 nm to about 1 μm. The term "liposome" encompasses both multilamellar liposomes consisting of two to several hundred concentric lipid bilayers alternating with aqueous layers and unilamellar vesicles consisting of a single lipid bilayer.

[0143] Liposomes contain one or more lipids. The lipids can be neutral, anionic or cationic lipids at physiological pH.

[0144] As used herein, the term "emulsion" refers to a mixture of two immiscible liquids in which one liquid forms the continuous phase and droplets of the other liquid are dispersed as the discontinuous phase therein.

[0145] As described above, an "emulsion" is a heterogeneous system consisting of at least two immiscible liquids or phases in the presence of an active surface material such as a surfactant or an emulgent (emulsifier).

[0146] In the context of the present invention, the term "emulsion" encompasses microemulsions and macroemulsions.

[0147] As described herein, microemulsions are essentially swollen micelles, but not all micellar solutions can swell to form microemulsions. Microemulsions are thermodynamically stable, formed spontaneously and contain extremely small particles. The droplet diameter in a microemulsion is typically in the range of about 10 to about 100 nm. In contrast, the term "macroemulsion" refers to droplets having a diameter greater than about 100 nm.

[0148] Macroemulsions (commonly also referred to as emulsions) are thermodynamically unstable systems, having particle sizes in the range of 1 - 100 μm (order of magnitude), and in most cases do not form spontaneously. An emulsion consists of droplets of a dispersed phase in a continuous phase. Macroemulsions scatter light effectively and appear milky white because the 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. An important aspect in preparing emulsions from both fundamental and technical viewpoints is to obtain the desired droplet size and a narrow size distribution. Surfactants (as main emulsifiers) are used to reduce the interfacial tension between the two phases and induce emulsion stability for a useful amount of time. Emulsions can otherwise be stabilized with other emulsifiers such as polymers, solid particles or proteins.

[0149] In a preferred embodiment, the emulsion is an oil-in-water emulsion (O / W). In an O / W emulsion, droplets of oil are dispersed in the aqueous phase. In the context of the present invention, the main oil constituent of the emulsion is the compound of the present invention. According to a particular embodiment, the oil emulsion of the present invention is an oil-in-water emulsion having an average droplet size of less than 1.0 micron. According to certain typical embodiments, the emulsion has an average droplet size of about 30 nm to 500 nm.

[0150] An oil-in-water emulsion (O / W) is a dispersion of oil droplets or colloidal particles in an aqueous medium, where the colloidal particles have an oily core surrounded by an interfacial film of an emulsifier and a surface active agent or surfactant. According to the teachings of the present invention, the main component of the oil constituent of the emulsion is the compound of the present invention.

[0151] In another embodiment, the emulsion is a multiple emulsion. In another embodiment, the emulsion is an O / W / O emulsion.

[0152] According to the present invention, an O / W / O emulsion is a multiple emulsion in which an aqueous phase (hydrophilic) separates an internal and an external oil phase. The internal and external phases may or may not be the same. A multiple emulsion is a complex polydisperse system in which both oil-in-water and water-in-oil emulsions coexist simultaneously and are stabilized by lipophilic and hydrophilic surfactants, respectively. The ratio of these surfactants is important in achieving a stable multiple emulsion. A multiple emulsion is also called an emulsion of emulsions or a double or triple emulsion since the internal phase itself contains dispersed globules that are miscible with the continuous phase. These are also called liquid membrane systems since two immiscible phases (liquid membranes) act as thin semipermeable films through which solutes must diffuse in order to move from one phase to another.

[0153] Any emulsifier and / or surfactant that does not interfere with the activity of the compounds of the present invention and the biocompatibility characteristics of the emulsion can be used in accordance with the teachings of the present invention. Further, surfactants that can solubilize oil within micelles are also suitable for the delivery system.

[0154] "Surfactant" refers to amphiphilic compounds that are generally recognized in the art as having surface-active qualities. Surfactants generally include anionic, cationic, nonionic, and zwitterionic compounds. As further used herein, an emulsifier is equivalent to a surfactant.

[0155] A surfactant can, for example, lower the surface tension of a liquid or the surface tension between two liquids. For example, a surfactant according to the present disclosure can lower the surface tension between a fatty acid oil mixture and an aqueous solution. Chemically speaking, a surfactant is a molecule that has at least one hydrophilic part and at least one hydrophobic (i.e., lipophilic) part. The properties of a surfactant can be reflected in the hydrophilic-lipophilic balance (HLB) value of the surfactant, which is a measure of the degree of hydrophilicity versus lipophilicity of the surfactant. The HLB value usually ranges from 0 to 20, with an HLB value of 0 representing high hydrophilicity and an HLB value of 20 representing high lipophilicity. Surfactants are often used in combination with other surfactants whose HLB values are additive. The HLB value of a surfactant mixture can be calculated as follows.

[0156] HLBA (proportion of surfactant A) + HLBB (proportion of surfactant B) = HLBA+B mixture

[0157] Surfactants are generally classified as ionic surfactants, such as anionic or cationic surfactants, and non-ionic surfactants. When a surfactant contains two oppositely charged groups, the surfactant is named an amphoteric surfactant. Other types of surfactants include, for example, phospholipids.

[0158] In at least one embodiment of the present disclosure, the composition comprises at least one surfactant selected from non-ionic, anionic, cationic and amphoteric surfactants.

[0159] In a preferred embodiment, the surfactant is selected from the group consisting of polysorbate, sorbitan ester, PEO-PPO block copolymer, POE alkyl ether, POE castor oil, POE hydrogenated castor oil, POE stearate, POE vitamin E, sucrose ester, alkyl polyglucoside, polyglycolated glyceride, polyether alcohol, phospholipid, alkyl sulfate.

[0160] Other non-limiting examples of surfactants suitable for the present disclosure are described below.

[0161] According to the present disclosure, other exemplary nonionic surfactants include diacetyl monoglyceride, diethylene glycol monopalmitostearate, ethylene glycol monopalmitostearate, glyceryl behenate, glyceryl distearate, glyceryl monolinoerate, glyceryl monooleate, glyceryl monostearate, macrogol cetostearyl ether such as cetomacrogol 1000 and polyoxy 20 cetostearyl ether, macrogol 15 hydroxystearate, macrogol lauryl ether such as laureth 4 and lauro macrogol 400, macrogol monomethyl ether, macrogol oleyl ether such as polyoxyl 10 oleyl ether, macrogol stearate such as polyoxyl 40 stearate, menthol glycol, mono- and diglycerides, nonoxynol such as nonoxynol-9, nonoxynol-10 and nonoxynol-11, octoxynol such as octoxynol 9 and octoxynol 10, poloxamer such as poloxamer, poloxamer 188, poloxamer 407, polyoxyl castor oil such as polyoxyl 35 castor oil, polyoxyl hydrogenated castor oil such as polyoxyl 40 hydrogenated castor oil, propylene glycol diacetate, propylene glycol dilaurate and propylene glycol monolaurate such as propylene glycol laurate, but are not limited thereto. Further examples include propylene glycol monopalmitostearate, quillaia, sorbitan esters and sucrose esters.

[0162] Exemplary anionic surfactants suitable for the present disclosure include, for example, salts of perfluorocarboxylic acids and perfluorosulfonic acids, alkyl sulfates such as sodium dodecyl sulfate and ammonium lauryl sulfate, sulfate ethers such as sodium lauryl ether sulfate, and alkylbenzene sulfonates.

[0163] Examples of cationic surfactants suitable for the present disclosure include quaternary ammonium compounds such as benzalkonium chloride, cetylpyridinium chloride, benzethonium chloride, and cetyltrimethylammonium bromide or other trimethylalkylammonium salts.

[0164] Examples of zwitterionic surfactants include, but are not limited to, dodecyl betaine, coco ampho glycinate, and cocamidopropyl betaine.

[0165] In some embodiments of the present disclosure, the surfactant may include phospholipids, their derivatives, or analogs thereof. Such surfactants can be selected, for example, from natural, synthetic, and semi-synthetic phospholipids, their derivatives, and their analogs. Exemplary phospholipid surfactants include phosphatidylcholine having saturated, unsaturated, and / or polyunsaturated lipids, such as dioleoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, dilauroyl phosphatidylcholine, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, docosahexaenoyl (DHA) choline, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, and phosphatidylinositol. Other exemplary phospholipid surfactants include soy lecithin, egg lecithin, dioleoyl phosphatidylcholine, distearoyl phosphatidylglycerol, PEGylated phospholipids, and dimyristoyl phosphatidylcholine.

[0166] According to certain embodiments, the emulsifier is one or more selected from the group consisting of polyoxyethylene polyoxypropylene copolymer (trade name: Poloxamer (trademark)), transesterification reaction products of natural vegetable oil triglycerides and polyalkylene polyols (trade names: Labrafil M 2125 (trademark), Labrafil M 1944CS (trademark), Labrasol (trademark)), glycerol fatty acid ester (trade name: Plurol (trademark) oleique), polyoxyl 40 hydrogenated castor oil (trade name: polyethylene glycol alkyl ether (trade name: Brij (trademark))), polyoxyethylene sorbitan triglyceride ester (trade name: Tween (trademark)), sorbitan fatty acid ester (trade name: Span Cremophor RH 40), vitamin E polyethylene glycol succinate, lecithin, sodium lauryl sulfate, and bile acids and their derivatives.

[0167] While not 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 present invention may be due to the improved bioavailability of the emulsified oil. The improved bioavailability can be the result of increased solubility of the active ingredient, improved stability during passage through the gastrointestinal tract, improved absorbability from the gastrointestinal tract, improved uptake by cells, or combinations thereof.

[0168] According to certain exemplary embodiments, the compositions of the present invention are formulated for oral or parenteral administration as either an oil dilution, dispersion or emulsion. However, other dosage forms including transdermal administration are also within the scope of the present invention.

[0169] In the case of oral administration, an effective amount of the composition can be administered in a form selected, but not limited, from solid, semi-solid or liquid states. Specific examples include tablets, capsules, powders, granules, solutions, suspensions and syrups.

[0170] Administering the composition of the present invention as a solid dosage form, either as a salt or an ester thereof, is highly desirable from the perspective of the convenience and compliance of the subject. Capsules for delivery to the gastrointestinal tract are known in the art and include capsules for oral or rectal administration. Typically, the capsule is designed to dissolve in the aqueous environment of the gastrointestinal tract.

[0171] In certain embodiments, the emulsion is a microemulsion.

[0172] In another particular embodiment, the emulsion is a self-emulsifying system.

[0173] A self-emulsifying system is defined as an isotropic mixture of oil, surfactant, and co-solvent. Self-emulsifying formulations are readily distributed in the gastrointestinal tract. The aqueous contents of the stomach and the digestive motility of the intestine provide the environment and sufficient agitation necessary for the spontaneous formation of the emulsion. Thus, formulating the composition as a self-emulsifying system makes it possible to avoid the use of an aqueous phase and its formulation as a capsule dosage form for oral delivery.

[0174] Ease of manufacture and scale-up is a further important advantage of self-emulsifying systems compared to other drug delivery systems such as solid dispersions, liposomes, and nanoparticles. Self-emulsifying systems require very simple and economical manufacturing equipment such as a simple mixer equipped with a stirrer and a volumetric liquid filling device for large-scale production.

[0175] According to a typical embodiment, the self-emulsifying system comprises a compound of the present invention and at least one emulsifier, surfactant, or a combination thereof.

[0176] Within the context of the present invention, the term "self-emulsifying system" includes "self-microemulsifying drug delivery systems" (SMEDDS) or "self-emulsifying drug delivery systems" (SEDDS). SMEDDS and SEDDS are compositions that contain an active agent intimately mixed with pharmaceutically acceptable excipients such that the system can produce a colloidal structure by spontaneously forming a microemulsion when the active agent is dissolved at a desired concentration and diluted with an aqueous medium, such as water, or gastric juice. The colloidal structure can be solid or liquid particles, including droplets and nanoparticles. In SEDDS or SMEDDS systems, the type of microemulsion produced is either transparent or turbid depending on the drug load and the type of surfactant used.

[0177] SEDDS is an isotropic mixture of oil, a hydrophobic surfactant, and may contain a co-solvent that rapidly produces a fine o / w emulsion during gentle agitation or digestive movements encountered in the gastrointestinal tract. SMEDDS is an isotropic mixture of oil, a hydrophilic surfactant, and a co-solvent that rapidly forms an O / W microemulsion upon dilution in an aqueous medium after gentle agitation experienced in the gastrointestinal tract. The fundamental difference between SEDDS and SMEDDS is that SEDDS typically produces an opaque emulsion with droplet sizes greater than 300 nm, while SMEDDS forms a transparent microemulsion with droplet sizes less than 250 nm. Additionally, the oil concentration in SMEDDS is less than 20%, compared to 40 - 80% in SEDDS.

[0178] In one embodiment, SEDDS is prepared using a surfactant with an HLB of 5 - 12. In another embodiment, SMEDDS is prepared using a surfactant with an HLB of 4 - 12.

[0179] Formulation methods for oral administration are known to those skilled in the art. For example, to formulate the composition into tablets, capsules, powders, granules, solutions or suspensions, the compounds of the present invention are preferably combined with an oil or emulsion or the self-emulsifying composition described above containing it and mixed with a binder, a disintegrant and / or a lubricant. If necessary, the resulting composition may be mixed with a diluent, a buffer, a permeation enhancer, a preservative, a penetration enhancer and / or a fragrance using known methods. Examples of binders include crystalline cellulose, cellulose derivatives, corn starch, and gelatin. Examples of disintegrants include corn starch, potato starch, and sodium carboxymethyl cellulose. Examples of lubricants include talc and magnesium stearate. Furthermore, additives such as lactose and mannitol may be used.

[0180] The composition according to the present invention may also contain at least one conventional excipient or additive in the case of an oily composition, such as a co-solvent, such as an alcohol, or an antioxidant.

[0181] The co-solvent, such as an alcohol, may be present in the composition in a ratio of, for example, 0 to 5%, particularly 1 to 5% (v / v) of the total volume of the composition.

[0182] In certain embodiments, the composition additionally contains an antioxidant.

[0183] "Antioxidants" are simply described as compounds (such as enzymes, organic molecules) that can slow down the rate of oxidation reactions or counteract the damaging effects of oxygen. Technically, this term applies to molecules that react with oxygen, but it often applies to molecules that protect against any free radicals (i.e., molecules with unpaired electrons, such as hydroxyl radicals, lipidoxyl or peroxyl radicals, singlet oxygen, and peroxynitrite formed from nitrogen oxides (NO)). Free radicals are either natural by-products of cellular processes in living organisms or are generated by exposure to environmental factors. In cellular organisms, free radicals can cause damage to cells and tissues and ultimately lead to disease. Since radicalized antioxidant molecules are more stable as free radicals than the original free radicals, antioxidants neutralize free radicals by donating one of their own electrons to the free radicals.

[0184] Antioxidants can be selected from compounds that are common in this field, such as citric acid and its derivatives, especially hydroxide substances such as sodium citrate, calcium citrate or potassium citrate; ascorbic acid and its derivatives, especially isoascorbic acid, sodium ascorbate or calcium ascorbate; thiol derivatives such as cysteine, acetylcysteine, dithiothreitol; and ethylenically unsaturated substances such as sorbic acid.

[0185] In certain embodiments, the antioxidant is selected from the group consisting of α-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 combinations thereof.

[0186] The antioxidant can be present in the composition, for example, in 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).

[0187] Preferred antioxidants are selected from ascorbic acid and its derivatives.

[0188] In another embodiment, when the vehicle is an emulsion, it further contains a co-surfactant.

[0189] Thus, as described above, when the vehicle is an emulsion, it already contains a surfactant. Therefore, according to this embodiment, the emulsion contains a first surfactant and a second surfactant or a co-surfactant, and the first and second surfactants are different from each other. As described above, surfactants are often used in combination with other surfactants whose HLB values are additive.

[0190] In one embodiment, the co-surfactant is selected from the group consisting of short-chain alcohols, alkanediols and triols, PEG, glycol ethers, pyrrolidine derivatives, bile salts, organic acids and salts.

[0191] Suitably, when two surfactants are present, each surfactant is present in an amount of about 0.5% to about 5% by weight, based on the total weight of the composition. In another embodiment, three surfactants are present in the formulation. Suitably, when three surfactants are present, each surfactant is present in an amount of about 0.5% to about 5% by weight, based on the total weight of the composition. Similarly, when four or more surfactants are present, each of them is present in an amount of about 0.5% to about 5% by weight, based on the total weight of the composition.

[0192] The composition according to the invention is preferably in a form suitable for administration by the oral route, in particular in a liquid form, such as an oral solution, an oral suspension, drops, etc., or in a capsule form, such as a capsule encapsulating said liquid preparation, in particular a hard or soft capsule based on gelatin.

[0193] Those skilled in the art will be familiar with the range of techniques that can be used to disperse a drug in oil. For example, the compound of formula (I) may be dispersed in a lipid-containing solution, dissolved in a lipid, emulsified with a lipid, mixed with a lipid, combined with a lipid, covalently bound to a lipid, contained as a suspension in a lipid, contained or complexed with micelles or liposomes, or otherwise associated with a lipid or lipid structure by any means known to those skilled in the art. The dispersion may or may not result in the formation of liposomes.

[0194] In the composition of the invention, the compound of formula (I) is combined with one or more lipids and an aqueous solvent. Any concentration or amount of the compound for dispersion in the lipid is contemplated by the invention. For example, in certain embodiments, the ratio (wt:wt) of the compound of formula (I):lipid 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 therefrom.

[0195] In certain embodiments, the lipid or lipids of the composition can comprise from 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 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 range derivable therein, by weight or volume of the composition. Thus, it is contemplated that the lipid or lipids of the composition can include any combination or percentage range of lipids, lipid types, or other components. In the compositions of the present invention, the compounds of formula (I) are combined with one or more lipids and an aqueous solvent.

[0196] Any concentration or amount of the compound of formula (I) for dispersion in a vehicle is contemplated by the present invention. For example, in certain embodiments, the compound:lipid ratio (wt:wt) 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.

[0197] In a preferred embodiment, the ratio of the compound of formula (I) (expressed in milligrams) to the lipid vehicle (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.

[0198] More preferably, the ratio of the compound of formula (I) (expressed in milligrams) to the lipid vehicle (expressed in milligrams) is 0.01:1 to 200:1, 0.01:1 to 150:1, 0.01:1 to 100:1, more preferably 0.1:1 to 5:1.

[0199] 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 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.

[0200] In another embodiment, the composition of the present 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 the compound of formula (I) with respect to the total weight of the carotenoids in the composition (all values are expressed in wt%).

[0201] As used herein, the term "carotenoid" refers to an organic dye that is structurally composed of a polyene hydrocarbon chain and may be terminated by a ring. Carotenoids are divided into two classes: xanthophylls (containing oxygen atoms) and carotenes (not containing oxygen atoms).

[0202] In another embodiment, the composition is in liquid form. It will be understood that the composition can be liquid or solid depending on the temperature. Thus, in one embodiment, the composition is liquid at room temperature. As used herein, room temperature is understood to be a temperature of 20-22°C, around 20°C, or 15-25°C.

[0203] Food products, dietary supplements, pharmaceutical cosmetics, cosmetic compositions or functional foods Another aspect relates to a food product, a dietary supplement, a pharmaceutical cosmetic, a cosmetic composition or a functional food comprising the composition according to the invention.

[0204] As used herein, the term "food" is any substance or product of any nature, solid or liquid, natural or processed, which can be used, usually or preferably, for some of the following purposes, depending on its characteristics, uses, components, preparation and state of preservation: a) as normal nutrition for humans or animals, or as a luxury food; or b) as a diet product, in the special case of human or animal food (feed). The term "feed" includes all natural materials and end products of any origin that are suitable as animal food, either separately or conveniently mixed with each other.

[0205] A cooked food is, for example, a food that does not need to be diluted with an aqueous solution suitable for consumption. In principle, the components present in a cooked food are balanced and, as would be understood by a person skilled in the art, there is no need to add additional components to the food to make it cooked. A concentrated food is one in which one or more components are present at a higher concentration than in a cooked food and therefore, for use, it is necessary to dilute it, for example, with an aqueous solution suitable for consumption. Non-limiting exemplary examples of the foods provided by the present invention include dairy products and derivatives, such as fermented milk, yogurt, kefir, curd, cheese, butter, ice cream, milk-based desserts, etc., as well as non-dairy products, such as baked goods, cakes and pastries, cereals, chocolate, jam, juice, other fruit derivatives, oils and margarine, cooked dishes, etc.

[0206] As used herein, the term "cosmeceutical product" refers to one or more cosmeceutical products (cosmeceuticals, dermo-cosmetics or active cosmetics), i.e., topical hybrid products having cosmeceutical - pharmaceutical characteristics containing active ingredients that have an effect on the skin, hair and / or nails of the user at higher and more effective concentrations, and thus they are located at an intermediate level between cosmetics and pharmaceuticals. Examples of cosmeceutical products include essential oils, ceramides, enzymes, minerals, peptides, vitamins and the like.

[0207] As used herein, the term "functional food product" refers to a product suitable for use in humans or animals, including one or more natural products that provide a health benefit or have a therapeutic effect related to the prevention or reduction of disease, including dietary supplements presented in a non - food matrix (e.g., capsules, powders, etc.) of concentrated natural bioactive products that are normally present (or absent) in food, and when ingested in a higher dose than the dose present in these foods, have a beneficial effect on health that is greater than the effect that normal foods may have. Thus, the term "functional food product" includes isolated or purified food products, as well as additives or food supplements commonly provided in dosage forms normally used orally, such as capsules, tablets, sachets, drinking medications, etc.; such products provide a physiological benefit or protection against diseases, generally chronic diseases. If desired, the functional food products provided by the present invention can contain, in addition to xanthophyll, one or more functional foods (products or substances related to the prevention or reduction of disease), such as flavonoids, omega - 3 fatty acids, etc., and / or one or more prebiotics (non - digestible food components that stimulate probiotic activity and / or growth), such as oligofructose, pectin, inulin, galactooligosaccharides, lactulose, human milk oligosaccharides, dietary fiber, etc.

[0208] As used herein, the term "nutritional composition" of the present invention relates to food products that beneficially affect one or more functions of the body to provide better health and wellness. Thus, such nutritional compositions can be intended for the prevention and / or treatment of diseases or disease causative factors. Accordingly, the term "nutritional composition" of the present invention can be used as a synonym for functional foods or foods for specific nutritional purposes, or medical foods. Nutritional compositions are similar to those of conventional foods and are ingested as part of a normal diet.

[0209] As used herein, the term "cosmetic composition" or "personal care composition" refers to a composition suitable for use in human or animal personal hygiene, or a composition for enhancing natural beauty or altering the appearance of the human or animal body without affecting the structure or function thereof, including one or more products that provide such effects. Optionally, the cosmetic compositions provided by the present invention, in addition to the combinations of the present invention, can contain one or more cosmetics or cosmetic products, i.e., substances or mixtures intended to be placed in contact with the external parts of the human or animal body (e.g., epidermis, hair system, nails, lips, etc.) or the mucous membranes of the teeth and cheeks, for the exclusive or primary purpose of cleansing, perfuming, altering appearance, protecting, maintaining good condition, or correcting body odor. Exemplary examples of cosmetically acceptable vehicles include products contained in the INCI (International Nomenclature of Cosmetic Ingredients) list. Cosmetic or personal care compositions include products such as balms, pads, pomades, creams, oils, surfactants, moisturizers, plant extracts, vitamins, antioxidants, sunscreens, perfumes, preservatives, etc. Exemplary examples of moisturizers, plant extracts, vitamins, antioxidants, and sunscreens.

[0210] The above components are preferably provided in a cosmetic composition that can be formulated into creams, gels, lotions, oils, ointments, powders, sticks, cakes, or other forms that can be topically applied. The resulting cosmetic composition can be in the form of a liquid, solid, semi-solid, dispersion, suspension, solution, or emulsion, and can be either aqueous or anhydrous. The cosmetic composition of the present invention can also be in the form of color cosmetic compositions such as foundations, mascaras, lip colors, blushes, and eye shadows. Certain other derivatives are essentially lipophilic and are more likely to be found in the oil phase of an emulsion. The combination of the present invention is preferably found in the aqueous phase of an emulsion or encapsulated in the aqueous phase within liposomes.

[0211] As used herein, the term "cosmetically effective amount" relates to an amount of a compound (i.e., the combination of the present invention) sufficient to provide the desired effect, and generally, among other factors, the characteristics of the compound itself and the cosmetic effect to be achieved are determined. The dosage for obtaining a cosmetically effective amount also depends on various factors such as, for example, the age, weight, gender, or tolerance of an animal, preferably a mammal, more preferably a human.

[0212] In certain embodiments of the present invention, the cosmetic composition of the present invention is administered by a topical route.

[0213] Optionally, the cosmetic composition of the present invention is incorporated into a cloth, non-woven fabric, or medical device. Exemplary examples of such cloth, non-woven fabric, or medical device include, but are not limited to, bandages, gauze, T-shirts, pantyhose, socks, underwear, girdles, gloves, diapers, sanitary napkins, dressings, bed covers, towels, adhesive patches, non-adhesive patches, occlusive patches, microcurrent patches, and face masks.

[0214] All of the foregoing terms and embodiments are equally applicable to this aspect of the present invention.

[0215] Non-therapeutic methods In a third aspect, the present invention relates to a non-therapeutic method for improving skin health, comprising the step of administering to a patient in need of improving skin health a composition according to the first aspect of the present invention or a food product, dietary supplement, pharmaceutical cosmetic, cosmetic composition or functional food according to the second aspect of the present invention.

[0216] In the context of the present invention, "skin" is understood to be the layer including both the uppermost or stratum corneum and the lowermost or subcutaneous tissue, inclusive. These layers are composed of different types of cells such as, inter alia, keratinocytes, fibroblasts, melanocytes and / or adipocytes. In the context of the present invention, the term "skin" includes the scalp. The term "skin" includes human skin.

[0217] As used herein, "improvement of skin health" means achieving a measurable improvement in the quality of the skin. The term "quality of the skin" refers to skin characteristics such as skin moisturization (e.g., improvement of dryness) or skin texture (e.g., skin thickness, roughness, scaliness). For example, with respect to skin texture, the present invention includes methods for reducing skin roughness, improving scaliness, and / or improving skin thickness in a subject in need thereof. One of ordinary skill in the art will select known methods for measuring improvement in the quality of the skin.

[0218] 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, improving skin density or firmness, and enhancing skin photoprotection.

[0219] In the context of the present invention, the term "aging" refers to the changes that the skin experiences with age (aging over time), or upon exposure to environmental factors such as sunlight (photoaging) or tobacco smoke, extreme climatic conditions of cold, heat or wind, chemical contaminants or pollutants, and includes, for example, but not limited to, the occurrence of discontinuities on the skin such as wrinkles, fine lines, creases, irregularities or roughness, the enlargement of pores, the loss of elasticity, the loss of firmness, the loss of smoothness, the loss of the ability to recover from deformation, in particular the sagging of the cheeks, the appearance of under-eye bags or double chins, the sagging of the skin, the appearance of spots, redness, under-eye bags, or the appearance of pigmentation areas such as age spots or freckles, especially due to aging, changes in the color of the skin, abnormal differentiation, hyperkeratosis, elastosis, keratosis, hair loss, orange peel skin, the loss of collagen structure, and other external and / or perceptible by touch all changes, including histological changes in the stratum corneum, dermis, epidermis, vascular system (e.g., the appearance of spider veins or telangiectasias), or tissues close to the skin. The term "photoaging" encompasses a series of processes due to long-term exposure of the skin to ultraviolet light that leads to premature aging of the skin and exhibits the same physical characteristics as aging, such as, but not limited to, laxity, sagging, color changes or irregular pigmentation, abnormal and / or excessive keratinization. The changes in the skin due to aging (e.g., aging over time, photoaging and / or environmental aging) are also referred to herein as symptoms or signs of skin aging.

[0220] In another embodiment, the composition is administered topically.

[0221] All of the foregoing terms and embodiments are equally applicable to this aspect of the present invention.

[0222] Medical uses The usefulness of ACX for treating and / or preventing various medical symptoms is described, for example, in the following prior art: cancer (Satomi Y, Anticancer Res. 2017;37(4):1557-62; Meresse 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 diseases, hypertension, portal hypertension, pulmonary arterial hypertension, hyperglycemia, diabetes (type 2), insulin resistance, liver protective and lipid management-related diseases (Peng J et al., Mar Drugs. 2011 Oct 10;9(10):1806-28), metabolic syndrome and diabetes prevention (Maeda H. J Oleo Sci. 2015 Jan 20;64(2):125-32), atherosclerosis, rheumatoid arthritis and anti-angiogenesis (Meresse S et al., Int J Mol Sci. 2020 Dec 4;21(23)), gut microbiota imbalance, glaucoma, diabetic retinopathy, angiogenesis-related diseases, hereditary hemorrhagic telangiectasia and psoriasis (Xiao H et al., Mar Drugs. 2020 Dec 11;18(12)), anti-inflammatory, anaphylactic shock, sepsis, cytokine storm (Su et al., Front Pharmacol., 2019, DOI: 10.3389 / fphar.2019.00906), lupus, sarcoidosis, chronic obstructive pulmonary 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.July 23, 2020; 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), antibacterial agent (Karpinski TM, Adamczak A. Fucoxanthin - An Antibacterial Carotenoid. Antioxidants (Basel). 2019 Jul 24;8(8)), neuroprotective agent (Hu L et al. Biomed Pharmacother. 2018 Oct;106:1484 - 9), gout and kidney stones (Wang et al., Journal of King Saud University - Science. 2020 Apr;32(3)1896 - 1901), age - related disorders (Guvatova Z et al., Mech Ageing Dev. 2020 Jul;189:111260; Chen, S.-J. et al., Mar. Drugs 2021, 19, 114), glucocorticoid - induced muscle atrophy (Zhiyin L et al. Biomed Pharmacother. 2021 Apr 14;139:111590), bone health (Walsh PJ et al. Mar Drugs. 2019 Feb 28;17(3)), age - related macular degeneration (Chen S - J et al. Mar Drugs. 2021 Feb 18;19(2)), eczema, atopic dermatitis, itch (Natsume C et al. Int J Mol Sci. 2020 Mar 22;21(6)), and thyroid - related diseases (Yang H et al., Biol Trace Elem Res. 2021 May;199(5):1877 - 1884).

[0223] Furthermore, the ACX esters of formula (I) or (Ia) are prodrugs of ACX that are spontaneously converted in vivo to ACX and its cis isomers. Thus, the esters of the present invention are suitable for the treatment and prevention of the same diseases as those reported for ACX.

[0224] Accordingly, in a fourth aspect, the present invention relates to a composition of the present invention for use in medicine, or a pharmaceutical composition comprising the composition of the present invention and optionally a pharmaceutically acceptable adjuvant. Some of the oils and emulsions defined above in the context of the composition of the present invention may be pharmaceutically acceptable adjuvants, and thus it will be understood that they can act as vehicles for the composition and pharmaceutically acceptable adjuvants.

[0225] A fifth aspect is that the present invention relates to a composition according to the present invention for use in the treatment and / or prevention of diseases selected from the group consisting of cancer, cardiovascular diseases, intestinal microbiota imbalance, inflammatory diseases, autoimmune diseases, fibrosis, bacterial infections, neurological diseases, 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.

[0226] In certain embodiments, - 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, neuroblastoma, or skin cancer, - the cardiovascular disease is hypertension, portal hypertension, pulmonary arterial hypertension, hyperglycemia, type 2 diabetes, insulin resistance, metabolic syndrome or 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, - Fibrosis is hepatic fibrosis, renal fibrosis, pulmonary fibrosis, myocardial fibrosis, interstitial fibrosis, IgG4-related fibrosis, scleroderma or retroperitoneal fibrosis, - A neurological disease is Parkinson's disease, Alzheimer's disease, dementia, depression or cerebral ischemia, - Hyperuricemia-related diseases are rheumatoid arthritis, gout or kidney stones, - Lipid-related diseases are obesity, cholesterol, triglyceridemia, non-alcoholic steatohepatitis or non-alcoholic fatty liver disease, - Bone-related diseases are osteopenia, - Eye diseases are glaucoma, diabetic retinopathy or age-related macular degeneration, and / or - Angiogenesis-related diseases are hereditary hemorrhagic telangiectasia.

[0227] In another aspect, the present invention relates to a method for treating and / or preventing a disease selected from the group consisting of cancer, cardiovascular disease, gut microbiota imbalance, inflammatory disease, autoimmune disease, fibrosis, bacterial infection, neurological disease, hyperuricemia-related disease, aging-related disorder, lipid-related disease, glucocorticoid-induced myopathy, bone-related disease, eye disease, angiogenesis-related disease, psoriasis, eczema, atopic dermatitis, and thyroid-related disorder, the method comprising administering a composition of the present invention to a subject in need thereof.

[0228] As used herein, the terms "prevention", "preventing" or "prevent" relate to the administration of a combination according to the present invention or a medicament comprising said combination to a subject who has not been diagnosed as having a disease but who is normally expected to develop the disease or to be at high risk of developing the disease. Prevention is intended to avoid the appearance of the disease. Prevention may be complete (e.g., complete absence of the disease). Prevention may be partial, e.g., the occurrence of the disease in the subject is less than would have occurred without administration of the composition of the present invention. Prevention also refers to a reduction in susceptibility to clinical symptoms.

[0229] As used herein, the term "treatment" refers to any type of therapy aimed at terminating, preventing, ameliorating or reducing susceptibility to the clinical symptoms described herein. In preferred embodiments, the term "treatment" relates to prophylactic treatment of a disorder or condition as defined herein (i.e., therapy to reduce susceptibility to clinical symptoms). Thus, "treatment", "treating" and their equivalent terms refer to obtaining the desired pharmacological or physiological effect, including any treatment of pathological symptoms or disorders in mammals, including humans. The effect can be prophylactic in that it completely or partially prevents the disorder or its symptoms, and / or can be therapeutic in that it partially or completely cures the disorder and / or the adverse effects resulting from the disorder. That is, "treatment" includes (1) preventing the disorder from occurring or recurring in a subject, (2) inhibiting the disorder (such as preventing its occurrence), (3) arresting or terminating the disorder or at least the symptoms associated therewith, such that the host no longer suffers from the disorder or its symptoms, e.g., causing regression of the disorder or its symptoms by restoring or repairing a lost, missing or defective function, or by stimulating an inefficient process, or (4) reducing, alleviating or ameliorating the disorder or the symptoms associated therewith (ameliorating is used broadly to mean at least a reduction in the magnitude of a parameter).

[0230] As used herein, the term "cancer" refers to a disease characterized by uncontrolled cell division (or increased survival or apoptosis resistance) and the ability of such cells to invade other adjacent tissues (invasion), spread through lymphatic 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 locations in the body. Depending on whether they can spread by invasion and metastasis, tumors are classified as either benign or malignant: 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 glioblastoma, particularly glioblastoma multiforme and medulloblastoma; cervical cancer; head and neck carcinomas; choriocarcinoma; colon cancer, colorectal cancer; endometrial cancer; esophageal cancer; gastric cancer; hematological neoplasms including acute lymphoblastic leukemia and myelogenous leukemia; T-cell acute lymphoblastic leukemia / lymphoma; hairy cell leukemia; chronic myelogenous leukemia, multiple myeloma; AIDS-related leukemia and adult T-cell leukemia / lymphoma; intraepithelial neoplasms including Bowen's disease and Paget's disease; liver cancer, hepatocarcinoma; lung cancer, pleural mesothelioma; lymphomas including Hodgkin's disease and lymphocytic lymphoma; neuroblastoma; oral cancer including squamous cell carcinomas; parotid gland 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; sarcomas 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 germ cell tumors such as seminoma, nonseminoma (teratoma, choriocarcinoma), stromal tumors, and embryonal cell tumors; thyroid cancer including thyroid adenocarcinoma and medullary carcinoma; and renal cancer including adenocarcinoma and Wilms' tumor. Other cancers are well known to those of skill in the art. In certain embodiments, the cancer is gastric cancer, duodenal cancer, liver cancer, blood cancer, breast cancer, glioblastoma, bladder cancer, pancreatic cancer, prostate cancer, colorectal cancer, cervical cancer, nasopharyngeal cancer, lung cancer, kidney cancer, metastatic cancer, melanoma, sarcoma, neurocancer, or skin cancer.

[0231] In certain embodiments, the cardiovascular disease is hypertension, portal hypertension, pulmonary arterial hypertension, hyperglycemia, type 2 diabetes, insulin resistance, metabolic syndrome or atherosclerosis.

[0232] In certain embodiments, the inflammatory disease is anaphylactic shock, sepsis or cytokine storm.

[0233] In certain embodiments, 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.

[0234] As used herein, "fibrosis" relates to the formation of excessive fibrous connective tissue in an organ or tissue in a repair or reactive process. Fibrosis may be a benign condition, but the present invention preferably relates to fibrosis in a pathological condition. In certain embodiments, the fibrosis is liver fibrosis, kidney fibrosis, pulmonary fibrosis, myocardial fibrosis, interstitial fibrosis, IGG4-related fibrosis, scleroderma or retroperitoneal fibrosis.

[0235] In certain embodiments, the neurological disease is Parkinson's disease, Alzheimer's disease, dementia, depression or cerebral ischemia.

[0236] In certain embodiments, the hyperuricemia-related disease is rheumatoid arthritis, gout or kidney stones.

[0237] In certain embodiments, the lipid-related disease is obesity, cholesterol, triglyceridemia, non-alcoholic steatohepatitis or non-alcoholic fatty liver disease.

[0238] In certain embodiments, the bone-related disease is osteopenia.

[0239] In certain embodiments, the eye disease is glaucoma, diabetic retinopathy or age-related macular degeneration.

[0240] In certain embodiments, the angiogenesis-related disease is hereditary hemorrhagic telangiectasia.

[0241] In a further aspect, the present invention relates to a composition for use as an adjuvant in the treatment and / or prevention of diseases mediated by glucocorticoid receptor activity, age-related diseases or disorders, or in the treatment of cancer by chemotherapy, preferably taxane-containing chemotherapy.

[0242] The term "glucocorticoid receptor", also known as GR, GCR or NR3C1 (nuclear receptor subfamily 3, group C, member 1), as used herein, refers to the receptor to which cortisol and other glucocorticoids bind. The human gene is shown in the Ensembl database with accession number ENSG00000113580 (Ensembl release 106, Apr 2022).

[0243] As used herein, the terms "corticoid" or "corticosteroid" refer 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 the stress response, immune response, and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior. There are two types of corticosteroids: glucocorticoids and mineralocorticoids.

[0244] Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor. The structure of glucocorticoids includes a steroid ring system.

[0245] As used herein, the term "cortisol" or "hydrocortisone" refers to the glucocorticoid of the following formula:

Chemical formula

[0246] In certain embodiments, diseases mediated by glucocorticoid receptor activity are 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 hypercortisolism, metabolic syndrome, inflammatory bowel disease, muscle atrophy and muscular dystrophy, insomnia associated with circadian rhythm disorders, hypertension, osteoporosis, water retention, cortisol-induced DNA damage, migraine, psychosis, anorexia, depression, stress disorders and cognitive disorders such as Alzheimer's disease, catatonia, amyotrophic lateral sclerosis, delirium, post-traumatic stress disorder, memory recall disorder, and borderline personality disorder.

[0247] In another embodiment, the aging-related disorder is fibrosis, and in particular, fibrosis is characterized by having a large number of senescent cells. More specifically, fibrosis is pulmonary fibrosis, chronic obstructive pulmonary disease, myocardial fibrosis or renal fibrosis, or the aging-related disease is cancer, preferably blood cancer or skin cancer.

[0248] All of the foregoing terms and embodiments are equally applicable to this aspect of the invention.

[0249] Cosmetic methods The usefulness of the compounds of ACX in the prevention and / or reduction of cutaneous aging and / or the improvement of the cosmetic detrimental effects of aging has been described in the prior art (Peng J et al. Mar Drugs. 2011 Oct 10;9(10):1806-28; Kang SY et al. J Cosmet Sci. 2020;71(2):53-64.). As described above, the ACX esters of formula (I) or (Ia) are spontaneously converted in vivo to ACX and its cis isomers. Thus, the esters of the present invention are suitable for their use in the same cosmetic methods as those reported for ACX.

[0250] Accordingly, in a last aspect, the present invention relates to a cosmetic method for preventing and / or reducing cutaneous aging and / or improving the cosmetic detrimental effects of aging, comprising administering to a subject in need thereof a composition of the invention, a food, a pharmaceutical cosmetic, a functional food or a cosmetic composition according to the second aspect. In a more particular embodiment, the cosmetic method for preventing and / or reducing cutaneous aging and / or improving the cosmetic detrimental effects of aging comprises a composition of the invention comprising a compound of formula (I) or (Ia) according to the first aspect, preferably formula (Ia), preferably wherein R is methyl, or a food, a pharmaceutical cosmetic, a functional food or a cosmetic composition according to the second aspect, administering to a subject in need thereof.

[0251] As used herein, the term "cosmetic method" relates to methods used to improve the appearance of the skin of a subject. Cosmetic compositions used in the cosmetic methods of the present invention include skin care creams, lotions, powders, lipsticks, eye makeup, facial makeup, tallets, gels, deodorants, hand disinfectants, baby products, bath oils, bubble baths, bath salts, butters and many other types of products.

[0252] Skin aging is a multifactorial process that affects almost all aspects of its biology and function. It is driven by both endogenous (e.g., time, genetic factors, hormones) and exogenous (e.g., UV exposure, pollution, tobacco smoke) factors. Skin aging also occurs due to aging.

[0253] Cellular senescence is a growth arrest that occurs as a result of different damage stimuli including DNA damage, telomere shortening and dysfunction or carcinogenic 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 deterioration.

[0254] Aged keratinocytes and fibroblasts appear to accumulate with age in human skin. Furthermore, senescent cells express gene-degrading enzymes, growth factors, and inflammatory cytokines that have broad and multifaceted effects.

[0255] As used herein, "cosmetically detrimental effects of aging" are associated with the characteristics of intrinsic or chronological aging and include, by way of example, non-limiting visible signs such as thin and dry skin, fine wrinkles, loss of elasticity, abnormal pigmentation, graying of hair, and hair loss.

[0256] "Skin aging", as used herein, refers to the state of aging and particularly damage to epidermal cells of human skin caused by partial damage or complete destruction of cells, toxic by-products of oxygen metabolism, free radical pathogenic mechanisms, or the conversion of imide bonds to amide bonds in collagen and / or elastin caused by photo-damage and general aging.

[0257] The cosmetic method of the present invention is intended to reduce human epidermal cells by reducing or inhibiting aging, thereby reducing skin aging, which includes one or more effects such as reversing photo-damage or other regenerative effects, for example, increasing the underlying cutaneous vascular system, increasing the rate of cell replication and exfoliation that results in a younger appearance, increasing collagen synthesis and homogeneity, and delaying skin atrophy and thinning of the epidermis and dermis.

[0258] The cosmetic method of the present invention is a non-therapeutic method.

[0259] The combination of the present invention can be administered in a cosmetically effective amount.

[0260] As used herein, the term "cosmetically effective amount" relates to an amount of a compound or composition of the present invention sufficient to provide the desired effect, and generally, among other factors, the characteristics of the compound itself and the cosmetic effect to be achieved are determined. The dosage for obtaining a cosmetically effective amount also depends on various factors such as, for example, the age, weight, gender or tolerance of the animal, preferably a mammal, more preferably a human.

[0261] In certain preferred embodiments of the cosmetic method of the present invention, the cosmetic composition of the present invention is administered by a topical route. Suitable formulations for topical administration of the combination of the present invention are detailed in connection with the cosmetic compositions of the present invention and are equally applicable to the cosmetic method of the present invention.

[0262] Optionally, the cosmetic composition of the present invention is incorporated into a cloth, non-woven fabric or medical device. Exemplary examples of such cloth, non-woven fabric or medical device include, but are not limited to, bandages, gauze, T-shirts, pantyhose, socks, underwear, girdles, gloves, diapers, sanitary napkins, dressings, bed covers, towels, adhesive patches, non-adhesive patches, occlusive patches, microcurrent patches and face masks.

[0263] All of the foregoing terms and embodiments are equally applicable to this aspect of the present invention.

[0264] The following examples represent specific embodiments of the present invention. They are not intended to limit the scope of the present invention as defined herein in any way.

Examples

[0265] Analytical methods Nuclear magnetic resonance (NMR) NMR spectra were obtained on a Varian 400 MHz or 500 MHz instrument. 1 1H chemical shifts are referenced to the deuterated solvent.

[0266] Example 1. Synthesis of amarouciaxanthin A acetate Dissolve fucoxanthin (1 equivalent), NMO monohydrate (2 equivalents), and freshly dried 4 Å molecular sieves in dichloromethane (DCM). Add TPAP (0.12 equivalent) at room temperature. Once the reaction reaches complete conversion (>97%), add SiO2 (30 equivalents) to the reaction. Stir the reaction at room temperature until complete conversion. Filter the reaction to remove SiO2. Wash the filtrate with a 5% aqueous Na2S2O3 solution. Wash the organic layer twice with brine, dry over Na2SO4, filter, and evaporate to dryness. Dry the residue under high vacuum to obtain the desired compound as a red solid.

[0267] 1 1H-NMR (400 MHz, CDCl3) δ 7.10 (d, J = 10.9 Hz, 1H), 6.83 - 6.50 (m, 5H), 6.45 (d, J = 11.6 Hz, 1H), 6.35 (d, J = 15.0 Hz, 1H), 6.27 (d, J = 11.7 Hz, 1H), 6.13 (d, J = 11.5 Hz, 1H), 6.05 (s, 1H), 5.84 (s, 2H), 5.44 - 5.33 (m, 1H), 3.05 (d, J = 15.0 Hz, 1H), 2.92 (d, J = 15.0 Hz, 1H), 2.47 (d, J = 18.1 Hz, 1H), 2.38 - 2.24 (m, 2H), 2.04 (s, 3H), 1.99 (m, 7H), 1.95 (s, 3H), 1.90 (d, J = 1.0 Hz, 3H), 1.81 (s, 3H), 1.51 (t, J = 12.2 Hz, 1H), 1.40 (m, 8H), 1.14 - 1.02 (m, 9H).

[0268] Example 2. Synthesis of paracentrone acetate Mix amarouciaxanthin A acetate with water and heat to 70 °C. If the reaction does not proceed, cool and extract with dichloromethane. Dry the organic layer, filter, and evaporate to dryness. Purify the resulting residue by SiO2 column chromatography to obtain the desired compound as a brown solid.

[0269] Paracentrone acetate: 1H-NMR (500 MHz, CDCl3) δ 7.14 (dd, J = 10.7, 1.2 Hz, 1H), 6.77 - 6.53 (m, 5H), 6.42 - 6.30 (m, 2H), 6.26 (d, J = 11.5 Hz, 1H), 6.12 (dd, J = 11.4, 1.0 Hz, 1H), 6.06 (d, J = 7.2 Hz, 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 = 0.9 Hz, 3H), 1.81 (t, J = 3.6 Hz, 3H), 1.50 (m, 1H), 1.44 - 1.39 (m, 1H), 1.36 (d, J = 15.3 Hz, 6H), 1.09 - 1.03 (m, 3H).

[0270] Example 3. Synthesis of amarouciaxanthin A acetate using different oxidants The same procedure as in Example 1 was carried out, but TPAP and NMO were replaced with IBX, Dess-Martin periodinane, and Swern oxidation. The results are summarized in the following table.

[0271] [Table 1]

[0272] Example 4. Synthesis of amarouciaxanthin A Amarouciaxanthin A acetate (1 equivalent) and sodium taurocholate (30 equivalents) are dissolved in MeOH. The solvent is evaporated to dryness. The residue is dissolved in phosphate buffered saline (PBS, pH 7), and lipase (1340 U / mg compound) is added. The reaction is shaken at 37 °C until maximum conversion (approximately 80%). The reaction is quenched with MeOH and extracted with Et2O and brine. The aqueous layer is extracted with Et2O until no color is observed in the organic layer. The combined organic layers are dried, filtered, and evaporated to dryness. The residue is purified by SiO2 column chromatography to obtain amarouciaxanthin A as a red solid, and unreacted amarouciaxanthin A acetate is recovered.

[0273] 11H-NMR (500 MHz, acetone) δ 7.53 (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, 1H), 5.74 - 5.69 (m, 1H), 4.28 - 4.17 (m, 1H), 3.61 (d, J = 1.6 Hz, 1H), 3.48 (d, J = 5.1 Hz, 1H), 3.21 (q, J = 15.5 Hz, 2H), 2.80 (d, J = 1.6 Hz, 3H), 2.78 - 2.75 (m, 1H), 2.62 (d, J = 17.6 Hz, 1H), 2.21 - 2.11 (m, 2H), peak 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).

[0274] Example 5. Conversion of ACX-Ac to ACX after oral absorption and bioavailability of ACX-Ac, FX and ACX after oral administration It has been well documented that orally administered fucoxanthin (FCX) has minimal absorption. Instead, it is thought to be metabolized to fucoxanthinol by intestinal or pancreatic cells and then converted to amarouciaxanthin (ACX) in the liver.

[0275] Amarouciaxanthin A acetate (ACX-Ac) is a novel compound that acts as a prodrug of ACX. Unlike FX, there are no intermediate metabolites.

[0276] Immunocompetent mice of the Hsd:ICR (CD-1) strain (female, 6 - 7 weeks old from ENVIGO) were housed under a daily light / dark cycle (12 hours) at a constant temperature of 20 - 22 °C and relative humidity of 45 - 65% under sterile conditions. Sterile water and food were freely available.

[0277] 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. The body weights of the animals were measured before the assay, and appropriate dispensing volumes were determined at 5 mL / kg (FCX) or 10 mL / kg (ACX-Ac). The formulations were administered orally as a single dose at 10 mg / kg. As described in Table 1, blood was collected at different time points. This was extracted via the facial vein or by intracardiac puncture (endpoint) in a recipient containing 5 μL of 0.5 M EDTA.

[0278] Blood samples were analyzed by HPLC-MS / MS according to an in-house analytical method to determine the concentration of ACX in each sample. Non-compartmental pharmacokinetic analysis was performed using PKPlus® software version 2.0 (Simulations Plus, Lancaster, CA 93534, USA) with the individual plasma concentration versus sampling time.

[0279] [Table 2]

[0280] [Table 3]

[0281] As described in the literature, the oral absorption of fucoxanthin after administration of this xanthophyll oil formulation was negligible. ACX-Ac was not detected in plasma samples even when administered orally. Subsequently, the absorption of ACX was analyzed.

[0282] The plasma levels of ACX were substantially higher after administration of ACX-Ac compared to those obtained after administration of FX, as seen in Figure 1 and Table 3.

[0283] [Table 4]

[0284] Example 6. Evaluation of the solubility of ACX, ACX-Ac and FX in different lipid vehicle formulations. Approximately 25 mg of the compound was weighed into a glass vial, and 1 mL of a lipophilic solvent was added to the vial containing the compound. The vial was vortexed for 1 minute and subsequently sonicated for 30 minutes. The resulting solution was visually observed for undissolved particles.

[0285] Sample Preparation The sonicated sample was filtered through a 0.22 μm PTFE filter, and 500 μL of this filtered sample was dissolved in 25 mL of an EtOH:hexane (80:20) solution ("Dilution 1"). 1 mL of "Dilution 1" was dissolved in 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 the assay by HPLC. The concentration was calculated by extrapolation from the calibration curve.

[0286] Calibration Curve 1.00 mg of the standard compound was accurately weighed (using an accurate scale) and diluted to 100 ppm in a volumetric flask. To prepare the calibration curve (r > 0.99), several concentrations (50, 25, 12.5, 5, 2.5 ppm) were prepared from the initial 100 ppm solution.

[0287] [Table 5]

Claims

1. A composition comprising the compound of formula (I). 【Chemistry 1】 (In the formula, R is a linear or branched C) １ -C ４ Selected from the group consisting of alkyl groups or their stereoisomers and vehicles, where the vehicle is selected from oils or emulsions.

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

3. The composition according to claim 1, wherein R is methyl.

4. The composition according to claim 1, wherein the vehicle is an oil concentrated with polyunsaturated or monounsaturated fatty acids.

5. The composition according to claim 1, wherein the emulsion is an O / W emulsion, an O / W / O emulsion, or a self-emulsifying system.

6. The composition according to claim 1, wherein the oil is a vegetable oil, a microbial oil, krill oil, or 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 aforementioned lipid vehicle is 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, blackcurrant seed oil, borage seed oil, evening primrose oil, flaxseed oil, amaranth oil, apricot oil, apple seed oil, argan oil, avocado oil, babassu oil, ben oil, borneo tallow nut oil, Cape chestnut oil, carob oil, cockle oil, burdock oil, saffron palm oil, The composition according to claim 7, wherein the oil is a vegetable oil selected from the group consisting of coriander seed oil, date palm seed oil, dika oil, grape seed oil, kapok seed oil, kenaf seed oil, larlemanthia oil, mahurua oil, marula oil, mustard oil, nige seed oil, okra seed oil, papaya seed oil, perilla seed oil, oyster seed oil, pequi oil, pili nut oil, pomegranate seed oil, poppy seed oil, pracaxi oil, prune seed oil, quinoa oil, ramuchil oil, rice bran oil, royle oil, sacha inchi oil, sapote oil, sedum oil, taraminna oil, tea seed oil, thistle oil, tiger nut oil, tomato seed oil, wheat germ oil, peanut oil, sesame oil, soybean oil, corn oil, and mixtures thereof, preferably sunflower oil.

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

10. The composition according to claim 6, wherein the lipid vehicle is fish oil or microbial oil concentrated with DHA or EPA.

11. The composition according to claim 1, further comprising an antioxidant.

12. The composition according to claim 1, further comprising a surfactant when the vehicle is an emulsion.

13. The composition according to claim 1, wherein the ratio of compound of formula (I) (represented in milligrams) to lipid vehicle (represented 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, and more preferably 0.1:1 to 5:

1.

14. The composition according to claim 1, wherein the composition is in liquid form.

15. The composition according to claim 1, 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 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 claim 1, 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 product, nutritional supplement, medicated cosmetic, cosmetic composition, or functional food product comprising the composition described in claim 1.

18. A non-therapeutic method for improving skin health, comprising the step of administering to a patient in need of improvement in skin health the composition according to claim 1, or a food product, nutritional supplement, medicated cosmetic, cosmetic composition, or functional food product 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 the skin tissue from aging, preventing or treating sensitive, dry, or reactive skin, improving skin density or hardness, and enhancing photoprotection of the skin.

20. The method according to claim 18, wherein the composition is administered topically.

21. A pharmaceutical composition comprising the composition described in any one of claims 1 to 16.

22. The pharmaceutical composition according to claim 21 for the treatment and / or prevention of a disease selected from the group consisting of cancer, cardiovascular disease, intestinal microbiota imbalance, inflammatory disease, autoimmune disease, fibrosis, bacterial infection, neurological disease, hyperuricemia-related disease, aging-related disorder, lipid-related disorder, glucocorticoid-induced muscular atrophy, bone-related disease, eye disease, angiogenesis-related disorder, psoriasis, eczema, atopic dermatitis, and thyroid-related disorder.

23. The aforementioned cancers are gastric cancer, duodenal cancer, liver cancer, hematological 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. The aforementioned cardiovascular disease is hypertension, portal hypertension, pulmonary arterial hypertension, hyperglycemia, type 2 diabetes, insulin resistance, metabolic syndrome, or coronary artery sclerosis. The inflammatory disease is anaphylactic shock, sepsis, or cytokine storm. The aforementioned autoimmune diseases are lupus, sarcoidosis, chronic obstructive pulmonary disease, asthma, primary cholangitis, sclerosing cholangitis, autoimmune hepatitis, inflammatory bowel disease, Crohn's disease, multiple sclerosis, and ulcerative colitis. The aforementioned fibrosis is hepatic fibrosis, renal fibrosis, pulmonary fibrosis, myocardial fibrosis, interstitial fibrosis, IGG4-related fibrosis, scleroderma, or retroperitoneal fibrosis. The aforementioned neurological disorder is Parkinson's disease, Alzheimer's disease, dementia, depression, or cerebral ischemia. The aforementioned hyperuricemia-related disease is rheumatoid arthritis, gout, or kidney stones. The aforementioned lipid-related disorders are obesity, high cholesterol, triglyceridemia, non-alcoholic fatty liver disease, or non-alcoholic fatty liver disease. The aforementioned bone-related disease is bone loss. The aforementioned eye disease is glaucoma, diabetic retinopathy, or age-related macular degeneration, and / or The aforementioned neovascularization-related disease is hemorrhagic telangiectasia. The pharmaceutical composition according to claim 22.

24. The pharmaceutical composition according to claim 21, for the treatment and / or prevention of diseases mediated by glucocorticoid receptor activity, or age-related diseases or disorders.

25. The pharmaceutical composition 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 atrophy and muscular dystrophy, insomnia associated with circadian rhythm disorders, hypertension, osteoporosis, fluid retention, cortisol-induced DNA damage, migraine, psychosis, loss of appetite, depression, stress disorders and cognitive impairments, such as Alzheimer's disease, catatonia, amyotrophic lateral sclerosis, delirium, post-traumatic stress disorder, memory recall disorder, and borderline personality disorder.

26. The pharmaceutical composition according to claim 24, wherein the aging-related disorder is fibrosis, and in particular the fibrosis is characterized by having a large number of senescent cells, more specifically the fibrosis is pulmonary fibrosis, chronic obstructive pulmonary disease, myocardial fibrosis or renal fibrosis, or the aging-related disorder is cancer, preferably hematological cancer or skin cancer.

27. A cosmetic method for preventing and / or reducing cutaneous aging, comprising administering to a subject in need thereof the composition described in claim 1, or a food product, nutritional supplement, medicated cosmetic, cosmetic composition, or functional food product described in claim 17 (excluding medical acts performed on humans).

28. A cosmetic method for improving the adverse cosmetic effects of aging, comprising administering the composition described in claim 1, or the food product, nutritional supplement, medicated cosmetic, cosmetic composition, or functional food product described in claim 17, to a subject in need of such treatment (excluding medical procedures performed on humans).

29. The composition according to any one of claims 1 to 16, for use as an adjuvant in the treatment of cancer by chemotherapy, preferably by taxane-containing chemotherapy.

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