Tocotrienol derivatives, their methods and uses

Abstract

This disclosure relates to an embodiment of the use of tocotrienols in pharmaceutical, veterinary, or cosmetic applications, particularly in cosmetic formulations, whereby stabilizing tocotrienols does not impair their function in the skin. Specifically, this disclosure relates to the modification, molecular stabilization, and penetration properties of tocotrienols in human skin using nicotinic acid. The compounds and compositions of this subject matter are useful in the medical, veterinary, or cosmetic industries as a preventative, therapeutic, or treatment of dermatological diseases or skin disorders, as a treatment or treatment of acne or seborrheic dermatitis, or as anti-aging agents.

Description

Technical Field

[0001] This disclosure relates to the use of stable tocotrienols in the medical, veterinary, or cosmetic industries, particularly the use of stable tocotrienols in the prevention, treatment, or management of skin diseases or disorders such as acne, seborrheic dermatitis, rosacea, or as an anti-aging agent. Background Technology

[0002] Vitamin E refers to tocochromanols, a group of eight molecules with similar chemical structures: four tocopherols, each consisting of a saturated (phytyl) side chain attached to a chromoalkyl alcohol ring (α, β, γ, σ) with different methylation levels; and four tocotrienols, each consisting of an unsaturated (phytyl) side chain attached to a chromoalkyl alcohol ring (α, β, γ, σ) with different methylation levels. Vitamin E is naturally found in all plant species and some cyanobacteria [1], and the concentration levels of each isomer depend on the organism, plant species, and plant part (leaves, roots, seeds, etc.). Important sources of tocochromanols are palm oil, rice bran, and annatto oil.

[0003] Tocopherols are potent antioxidants. They are known as antioxidants that break strong chains, scavenge superoxide radicals, and quench singlet oxygen. When tested for antioxidant capacity in solution or liposome membranes, tocopherols and tocotrienols exhibit the same antioxidant capacity in their respective isomers, but the antioxidant capacity decreases among the isomers in the order α>β=γ>δ[1]. This suggests that tocotrienols may exhibit higher antioxidant capacity due to their unsaturated fatty acid chains, which are more mobile within and between membranes and less restricted in their interaction with lipid radicals. Furthermore, unlike tocopherols, tocotrienols do not increase membrane rigidity[2].

[0004] In addition to its antioxidant effects, vitamin E also exhibits anti-inflammatory[3], antitumor and anti-angiogenic effects. The anti-inflammatory effect comes from the ability of these molecules to block the secretion of TNF-α and IL-1β and to produce cytosolic cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). All of these biological factors greatly influence the cellular signaling cascade of the inflammatory response. Studies have also found that 6-tocotrienol is the most effective of all isoforms for this purpose, and it also has the ability to block lipopolysaccharide (LPS)-induced expression of TNF-α, IL-1β, IL-6 and iNOS genes[4].

[0005] In the skin, vitamin E acts as an antioxidant and anti-inflammatory agent, protecting it from oxidative stress damage by scavenging reactive oxygen species (ROS), such as peroxide radicals and singlet oxygen, and by regenerating endogenous glutathione (GSH) to its reduced form. Compared to α-tocopherol, tocotrienols exhibit stronger antioxidant and anti-inflammatory capabilities because they activate additional anti-inflammatory pathways. However, the natural delivery of tocotrienols has significant drawbacks due to their low stability and poor bioavailability in their pure state.

[0006] Tocopherols, most commonly α-tocopherol, are found in the human body, for example in cell membranes and plasma (an average low-density lipoprotein (LDL) aggregate contains 5-12 α-tocopherol molecules and less than one tocotrienol or other antioxidant molecule). Humans cannot synthesize tocopherol molecules themselves and must obtain them from food sources; therefore, these are classified as essential nutrients[5].

[0007] The absorption of tocopherol is facilitated by α-tocopherol transfer protein (α-TTP); however, α-TTP exhibits a higher affinity for the α-isomer of tocopherol, which partly explains the low oral bioavailability of other isomers and forms of vitamin E [6].

[0008] The bioavailability and localization of vitamin E in the body largely depend on the route of administration. Oral administration is effective in delivering vitamin E to the body's internal systems, but less effective for delivering it to the outer layer of the skin, where it is most needed for treating surface ailments. This is due to the lipophilicity and size of the molecule. Therefore, local delivery is generally preferred for rapidly replenishing vitamin E levels in the skin.

[0009] Except for α-tocopherol, all other vitamin E isomers have significantly lower oral bioavailability. Small amounts of tocotrienol isomers bypass α-TTP by diffusion, but still exist in tissues at very low concentrations. It has been shown that supplementation with α-tocopherol greatly reduces the bioavailability and endogenous concentrations of other vitamin E isomers (especially tocotrienols) and diminishes their associated superior effects [7].

[0010] When applied topically, vitamin E has a high affinity for the stratum corneum due to its lipophilic nature, making it difficult to penetrate deeper into the skin. Therefore, topically delivered vitamin E remains on the outer layer of the skin for a longer period, where it is exposed to oxidative factors and rapidly degrades, losing its function. This is a significant limiting factor for topical application and further reduces delivery efficiency.

[0011] The high degradation rate of tocopherols is due to the antioxidant properties of these molecules, which cause them to react rapidly with singlet oxygen or other ROS present in the atmosphere. Furthermore, the chroman (benzodihydropyran) ring present in all vitamin E isomers is readily degraded by ultraviolet light.

[0012] Many strategies have been developed to reduce the degradation of vitamin E in cosmeceutical formulations. These include, for example, the inclusion of sacrificial co-antioxidants (such as vitamin C), colloidal encapsulation systems, or chemical modifications to the molecules.

[0013] Chemical modification is the most widely used strategy because it is simple and easy to obtain modified vitamin E molecules that can avoid skin penetration and molecular stability problems. These modifications are usually targeted at the hydroxyl group of the chromocyclic ring, which is the easiest and biologically most sensitive modification site. A large number of O-modified tocopherols for topical skin applications have been developed. Examples include tocopherol phosphate, tocopherol phosphate salt, tocopherol ascorbate phosphate, tocopherol succinate, tocopherol acetate, tocopherol chloroacetate, tocopherol propionate, tocopherol amino acid salt and tocopherol salicylate [8]. Currently, the most commonly used formulations for treating skin conditions are α-tocopherol acetate and α-tocopherol succinate.

[0014] The ester bond between α-tocopherol and the modified compound to which it is attached is particularly important. When the hydroxyl group is modified, vitamin E loses its antioxidant properties[1] and gains resistance to chemical degradation. The antioxidant capacity of vitamin E is achieved by transferring free radicals from ROS to hydroxyl groups, forming tocopherol and / or tocotrienyl free radicals that are more easily cleared by endogenous metabolic processes.

[0015] Ester bonds at the hydroxyl groups are of particular interest because nonspecific esterases exist in the skin that hydrolyze esterified tocopherols or tocotrienols, producing the original pure tocopherol or tocotrienol and the original pure modified compound. The hydrolysate retains its normal chemical and biological activity. The activity of these nonspecific esterases is not uniform throughout the skin, with higher activity reported in several areas, such as between the stratum corneum and stratum granulosum, the outer sheath of active hair follicles, young sebaceous cells, and old sebum deposits [9,10]. The latter is of particular interest due to sebum buildup in acne cases. Ester modifications are very stable in neutral formulations, but degradation can occur at excessively acidic or alkaline pH levels due to the inherent nature of esters. Chemical modifications of tocopherol molecules can enhance their permeability by altering the molecular polarity, making them easier to penetrate into the stratum corneum.

[0016] When tocopherol and tocotrienol molecules modified via ester bonds are destroyed by esterases, the modified compounds are also released into the skin, a significant factor to consider due to their potential side effects, antagonistic effects, synergistic effects, or cytotoxicity. The most common modifications on the market release compounds intended for normal metabolism, such as acetates and succinates, to minimize side effects. However, using modified molecules lacking therapeutic efficacy wastes an opportunity to further enhance the effectiveness of the formulation for topical treatment through a multi-pronged or synergistic approach.

[0017] Vitamin B3 in its amide (nicotinamide) or carboxylic acid (niacin) forms is a precursor to an essential coenzyme for many metabolic processes, such as the regulation of cellular energy metabolism, DNA synthesis, and transcription. Low levels of this vitamin can cause pellagra, a condition characterized by photosensitive dermatitis, diarrhea, and dementia [11,12]. However, it is now a rare condition in people with normal diets, as fish, meat, and wheat are rich sources of this vitamin.

[0018] Vitamin B3 also has neuroprotective and antioxidant effects, and can reduce sebum production, wrinkles, UV-induced immunosuppression, and skin pigmentation

[12] .

[0019] Cosmeceuticals containing niacinamide or related compounds can be effective in treating skin conditions. However, niacinamide and its related compounds can cause side effects such as redness at the application site and systemic inflammation because of their high permeability and ability to enter the bloodstream.

[13]

[0020] These facts are disclosed to illustrate the technical problem addressed by this disclosure. Summary of the Invention

[0021] This disclosure relates to the use of stable tocotrienols in the medical, veterinary, or cosmetic industries, particularly the use of stable tocotrienols in the prevention, treatment, or management of skin diseases or disorders such as acne, seborrheic dermatitis, rosacea, or as an anti-aging agent.

[0022] This disclosure describes the modification of tocotrienols with nicotinic acid, the modification of tocotrienols with linkers and nicotinic acid or nicotinol, the increased stability of modified tocotrienols in cosmetic formulations, the penetration of modified tocotrienols into human skin, and the conversion of modified tocotrienols into original tocotrienols and nicotinic acid, thereby allowing for efficient and simultaneous local delivery of tocotrienols and nicotinic acid.

[0023] Tocotrienols and tocopherols are part of the molecular group collectively known as vitamin E, also called "mother tocopherols". Niacin refers to vitamin B3, is a precursor to nicotinamide, and participates in the synthesis of other important metabolic molecules.

[0024] In one embodiment, the binding of α-tocopherol to nicotinic acid is achieved via an ester bond formed by a reaction between the hydroxyl group of α-tocopherol and the carboxyl group of nicotinic acid. The resulting molecule is referred to below as α-tocopherol nicotinic acid ester.

[0025] In one embodiment, the binding of different tocotrienols to nicotinic acid is achieved via an ester bond formed by a reaction between the hydroxyl group of the tocotrienol and the carboxyl group of the nicotinic acid. Molecules obtained from combinations of nicotinic acid with α-tocotrienol, γ-tocotrienol, and δ-tocotrienol are hereinafter referred to as α-tocotrienic acid ester, γ-tocotrienic acid ester, and δ-tocotrienic acid ester, respectively. They are collectively referred to as modified tocotrienols.

[0026] In one embodiment, the combination of α-tocotrienol with nicotinic acid or nicotinol and another molecule between them (hereinafter referred to as a "linker" or "connector") is achieved through ester or amide bonds between the hydroxyl, amino, and carboxyl groups of the various molecules involved in the reaction. The linkers used in this work are glycolic acid, ferulic acid, glycine, and succinic acid. The linkers described above are examples for illustrative purposes; other linkers may be used in the reaction. The molecules obtained by combining nicotinic acid with glycolic acid, ferulic acid, and glycine linkers and then with α-tocotrienol are hereinafter referred to as α-tocotrienol glycolyl nicotinate, α-tocotrienol ferulic acid nicotinate, and α-tocotrienol glycinyl nicotinate, respectively. The molecules obtained by combining nicotinyl and succinic acid linkers with α-tocotrienol are hereinafter referred to as α-tocotrienyl nicotinyl succinate. They are collectively referred to as modified α-tocotrienols with linkers.

[0027] In one embodiment, other tocotrienol isomers (γ, δ) modified with linkers and nicotinic acid or nicotinol can be obtained by selecting any isomer via the same synthetic route, thereby obtaining the corresponding modified tocotrienol with linkers.

[0028] In one embodiment, the esterification of tocotrienol and nicotinic acid is achieved via a coupling reaction of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) / 4-dimethylaminopyridine (DMAP). The chosen reaction type and conditions are described herein as examples of obtaining modified tocotrienol molecules. Modified tocotrienol molecules were successfully synthesized, and their structure and purity were determined using various analytical methods.

[0029] In one embodiment, the esterification of tocotrienols and nicotinic acid is achieved via an acyl halide coupling reaction, specifically using nicotinyl chloride. The chosen reaction type and conditions are described herein as examples of obtaining modified tocotrienol molecules. Modified tocotrienol molecules were successfully synthesized, and their structure and purity were determined using various analytical methods.

[0030] In one embodiment, the esterification / amidation of α-tocotrienols, linkers, and nicotinic acid / nicotinol is achieved through different synthetic routes specific to each compound.

[0031] In one embodiment, the synthesis of α-tocotrienol glycoloyl nicotinate and α-tocotrienol feruloyl nicotinate comprises esterifying glycolic acid or ferulic acid with nicotinic acid via an acyl halide coupling reaction, specifically using nicotinyl chloride, and then esterifying the resulting intermediate molecule with α-tocotrienol via an EDC / DMAP coupling reaction.

[0032] In one embodiment, the synthesis of α-tocotrienol glycine nicotinic acid ester includes esterifying α-tocotrienol and BOC-glycine-OH via an EDC / DMAP coupling reaction, followed by deprotection of the obtained intermediate molecule by selectively hydrolyzing the BOC group with trifluoroacetic acid, and then amidating the obtained intermediate and nicotinic acid via an EDC / DMAP coupling reaction.

[0033] In one embodiment, the synthesis of α-tocotrienol nicotinol succinate comprises an acid-catalyzed anhydride coupling reaction, specifically using sulfuric acid and succinic anhydride, to esterify nicotinic acid and succinic anhydride, followed by an EDC / DMAP coupling reaction to esterify the resulting intermediate molecule with α-tocotrienol.

[0034] In one implementation, the selected reaction type and reaction conditions can serve as an example of obtaining modified α-tocotrienols with linkers.

[0035] In one implementation, the structure and purity of the obtained modified tocotrienols and modified α-tocotrienols with linkers are confirmed by conventional analytical methods.

[0036] In one implementation, permeation experiments were conducted using a Franz diffusion cell to evaluate the permeation and transformation of modified tocotrienols and linker-conjugated modified α-tocotrienols in human skin. Their transformation characteristics were assessed and quantified by measuring nicotinic acid or nicotinol in the permeation solution.

[0037] In one embodiment, the skin penetration and permeability of modified tocotrienols and modified α-tocotrienols with linkers are compared with α-tocopherol nicotinic acid ester.

[0038] In one embodiment, the penetrability of modified tocotrienols and α-tocopherol nicotinate is assessed by quantifying the amount of unmodified molecules present in the skin after a specified time period.

[0039] Experimental results confirmed that modified tocotrienol molecules, modified α-tocotrienol with linkers, and α-tocopherol nicotinate penetrate the skin and are converted back to the original tocotrienol (or tocopherol), nicotinic acid, and nicotinol molecules. It was also found that the release rate of nicotinic acid differed for different modified tocotrienol molecules. α-Tocotrienol nicotinate released nicotinic acid three times faster than γ-tocotrienol nicotinate or δ-tocotrienol nicotinate. Nicotinic acid was also released faster from α-tocotrienol nicotinate than from α-tocopherol nicotinate.

[0040] In one embodiment, the chemical stability of α-tocopherol nicotinate, modified tocotrienol, some modified α-tocotrienol with linkers, unmodified tocotrienol and α-tocopherol in cosmetic formulations was evaluated in an accelerated aging test (45°C).

[0041] In one embodiment, the chemical stability of modified tocotrienols, linker-conjugated modified α-tocotrienols, α-tocopherol nicotinate molecules, and α-tocopherol, α-tocotrienol, γ-tocotrienol, and δ-tocotrienol molecules was evaluated and compared. Modified and unmodified molecules were mixed in cosmetic formulations and subjected to accelerated aging. Results showed that after 3 months under these conditions, the amounts of unmodified α-tocopherol, α-tocotrienol, γ-tocotrienol, and δ-tocotrienol decreased by 50% or more, while the modified molecules retained >95% of their initial mass. For linker-conjugated modified α-tocotrienols, the results showed that α-tocotrienol feruloyl nicotinate was unstable and degraded even at refrigerated temperatures, while α-tocotrienol glycoloyl nicotinate, α-tocotrienol glycyl nicotinate, and α-tocotrienol nicotinol succinate retained >95% of their initial mass. Therefore, except for α-tocotrienol feruloyl nicotinate, the modified molecules were very stable in the tested cosmetic formulations, and importantly, they were more stable than unmodified tocopherol.

[0042] In one embodiment, the modified molecule is shown to be able to penetrate human skin and be converted into the parent molecule. α-Tocotrienol nicotinate, preferably α-tocotrienol glycoloyl nicotinate, has a higher conversion rate than other modified tocotrienols.

[0043] Another aspect of this disclosure relates to pharmaceutical or cosmetic compositions comprising at least one compound of formula (I), (II) or (III) of this disclosure and at least one pharmaceutically or cosmetically acceptable excipient.

[0044] One aspect of this disclosure relates to compounds having the following general formula (I).

[0045]

[0046] in

[0047] The choices of R1, R2, R3, and R4 are independent of each other;

[0048] R1 is H or CH3;

[0049] R2 is H or CH3;

[0050] R3 is H or CH3;

[0051] R4 can be selected from the following list:

[0052]

[0053] R5 is a diester residue or an amide ester residue.

[0054] * indicates a binding site.

[0055] Preferably, the compounds disclosed herein can be used in medicine; more preferably, the compounds disclosed herein can be used to prevent, treat or manage skin diseases or skin disorders, or as anti-aging agents.

[0056] In one embodiment, R5 is a linker, preferably a molecular residue of a suitable linker that forms a diester or ester and amide when covalently linked to nicotinic acid (or nicotinol) or tocotrienol.

[0057] In one embodiment, the diester residue or amide ester residue (R5) is derived from any suitable at least bifunctional molecule via a suitable esterification reaction, wherein at least one reactive group is a carboxylic acid. The remaining functional groups must contain at least one reactive group selected from the group consisting of carboxylic acid (-COOH), hydroxyl (-OH), or amino (-NH2).

[0058] In one embodiment, a compound having the following general formula (II):

[0059]

[0060] in

[0061] The choices of R1, R2, and R3 are independent of each other;

[0062] R1 is H or CH3.

[0063] R2 is H or CH3.

[0064] R3 is H or CH3.

[0065] In one embodiment, the compound is of formula (III).

[0066]

[0067] in

[0068] R1, R2, R3, and R5 can be chosen independently of each other;

[0069] R1 is H or CH3;

[0070] R2 is H or CH3;

[0071] R3 is H or CH3;

[0072] R5 is a diester residue or an amide residue.

[0073] In one embodiment, R5 is a glycolate diester residue, a succinate diester residue, a ferulic acid diester residue, or a glycine amide ester residue.

[0074] In one embodiment, the compound may be selected from the following molecules:

[0075]

[0076] α-Tocotrienol nicotinate;

[0077]

[0078] γ-Tocotrienol nicotinate;

[0079]

[0080] δ-Tocotrienol nicotinate;

[0081]

[0082] α-Tocotrienol glycine nicotinate;

[0083]

[0084] α-Tocotrienol glycoloyl nicotinate;

[0085]

[0086] α-Tocotrienol feruloyl nicotinate;

[0087]

[0088] α-Tocotrienol nicotinic acid succinate.

[0089] In one embodiment, the compounds disclosed herein can be used in medicine, veterinary medicine, or as cosmetics. That is, for the prevention, treatment, or management of skin diseases, skin disorders, or anti-aging. Preferably, they are used for the prevention, treatment, or management of inflammatory skin diseases. More preferably, they are used for the prevention, treatment, or management of acne or seborrheic dermatitis.

[0090] In one embodiment, the pharmaceutical or cosmetic composition disclosed herein may comprise at least one compound of formula (I) by weight, comprising up to 20% of the total mass of the composition.

[0091] In one embodiment, the composition may comprise 0.01% to 10% by weight of at least one compound of formula (I) of the total composition, more preferably 0.1% to 5% by weight of at least one compound of formula (I) of the total composition, and even more preferably 0.1% to 2% by weight of at least one compound of formula (I) of the total composition.

[0092] Another aspect of this disclosure relates to methods for preventing, treating, or managing acne, rosacea, or seborrheic dermatitis, including applying compounds, cosmetic / pharmaceutical compositions, and / or patches of the subject matter to the skin.

[0093] In one embodiment, the composition may be a topical composition. Preferably, the topical composition is a gel, cream, lotion, ointment, serum, paste, foam, etc.

[0094] A cosmetic treatment method for acne or seborrheic dermatitis is also disclosed, which involves applying a cosmetic / pharmaceutical composition to the skin. Attached Figure Description

[0095] The following figures provide preferred embodiments for illustration and description and should not be considered as limiting the scope of the invention.

[0096] Figure 1 : A schematic diagram of modified tocotrienols, which are incorporated into cosmetic formulations, penetrate human skin, and are transformed into parent molecules.

[0097] Figure 2 Chromatograms of α-tocotrienol nicotinate, γ-tocotrienol nicotinate, and δ-tocotrienol nicotinate after synthesis and purification.

[0098] Figure 3 Image of the Franz diffusion cell used in the osmosis experiment. 1-Donor chamber; 2-Skin sample; 3-Recipient chamber; 4-Sampling channel; 5-Constant temperature water bath.

[0099] Figure 4: A. The change of nicotinic acid concentration in the permeate solution with permeation time when the concentrations of A–α-tocopherol nicotinate, α-tocotrienol nicotinate, and γ-tocotrienol nicotinate are 5% m / m; B. The side-by-side comparison of nicotinic acid concentration in the final permeate solution after 48 hours when the concentrations of B–α-tocopherol nicotinate (α-TN), α-tocotrienol nicotinate (α-T3-N), γ-tocotrienol nicotinate (γ-T3-N), α-tocotrienol feruloyl nicotinate (N-Fer-T3), α-tocotrienol glycyl nicotinate (N-Gly-T3), α-tocotrienol ethanol nicotinate (N-Glc-T3), and α-tocotrienol nicotinol succinate (N-Suc-T3) are 10% m / m. Detailed Implementation

[0100] This disclosure is further described, with particular use of embodiments thereof. Therefore, this disclosure is not limited to the descriptions and illustrations provided. Their use is intended to make the disclosure sufficiently detailed and understandable. Furthermore, the accompanying drawings are intended for illustrative purposes and not for limiting purposes.

[0101] This disclosure relates to embodiments for the use of tocotrienols in medicine, veterinary medicine, or cosmetics, namely by stabilizing tocotrienols, particularly in cosmetic formulations, without impairing their function in the skin. In particular, this disclosure relates to the modification of tocotrienols with nicotinic acid, molecular stabilization, and penetration properties in human skin.

[0102] The compounds and compositions of this subject matter may be used in the medical, veterinary or cosmetic industries for the prevention, treatment or management of skin diseases, skin disorders, or as a treatment or management of acne, seborrheic dermatitis or as an anti-aging agent.

[0103] In one embodiment, α-tocopherol, α-tocotrienol, γ-tocotrienol, or δ-tocotrienol are reacted with nicotinic acid according to the procedure described in the general procedure. Figure 1 )

[0104] In one embodiment, the modification of tocotrienols and tocopherols was carried out via EDC / DMAP coupling. The reaction process was monitored using thin-layer chromatography (TLC), and the product was recovered after liquid-liquid extraction and column chromatography purification. The structure and purity of the new molecule were confirmed by proton nuclear magnetic resonance (H-NMR), mass spectrometry (MS), Fourier transform infrared spectroscopy (FTIR), and high-performance liquid chromatography (HPLC).

[0105] In one embodiment, the modification of tocotrienols and tocopherols with nicotinic acid is achieved through a reaction procedure based on the coupling agent EDC and catalyzed by DMAP.

[0106] In one embodiment, EDC (1 mol eq.) and DMAP (0.05 mol eq.) are added to dichloromethane (DCM) and stirred at room temperature until completely dissolved (typically about 20 minutes is sufficient). The solution is then cooled to ~0°C in an ice-water bath, and nicotinic acid (1 mol eq.) is added until complete dissolution is observed. Then, tocotrienols or tocopherols pre-dissolved in DCM for easy handling are added to the reaction mixture, followed immediately by N,N-diisopropylethylamine (DIEA) (1 mol eq.). The reaction mixture is then stirred continuously overnight. Successful formation of the desired product is monitored by TLC analysis.

[0107] In one embodiment, the obtained reaction product is purified. After a specified reaction time, the reaction mixture is extracted with water by liquid-liquid extraction to remove some unreacted reagents and unwanted water-soluble byproducts. The evolution of the extract is monitored by TLC.

[0108] In one embodiment, the organic fraction is then dried over anhydrous sodium sulfate to remove residual water, followed by evaporation to remove the solvent. The solid residue is recovered and further purified by normal-phase rapid column chromatography. The collected fractions are analyzed by TLC and combined accordingly. The solvent is then removed under vacuum in a rotary evaporator, followed by drying overnight in a high-vacuum chamber.

[0109] In one embodiment, α-tocotrienol nicotinate was synthesized using nicotinic acid, EDC, DIEA, and DMAP. The amounts of nicotinic acid, EDC, DIEA, and DMAP used were in excess relative to α-tocotrienol. In one procedure, 1745 mg of α-tocotrienol and 1251 mg of nicotinic acid were reacted in 30 mL of DCM using 4164 mg of EDC, 1745 μL of DIEA, and 85 mg of DMAP. α-Tocotrienol nicotinate was purified by column chromatography using silica gel 60 and eluted with DCM / methanol 40:1.

[0110] In one embodiment, γ-tocotrienol nicotinate was synthesized using nicotinic acid, EDC, DIEA, and DMAP. The amounts of nicotinic acid, EDC, DIEA, and DMAP used were in excess relative to γ-tocotrienol. In one procedure, 1326 mg of γ-tocotrienol and 985 mg of nicotinic acid were reacted in 30 mL of DCM using 2160 mg of EDC, 1380 μL of DIEA, and 85 mg of DMAP. Purification of γ-tocotrienol nicotinate was performed by column chromatography using silica gel 60 and elution with DCM / methanol 40:1.

[0111] In one embodiment, δ-tocotrienol nicotinate was synthesized using nicotinic acid, EDC, DIEA, and DMAP. The amounts of nicotinic acid, EDC, DIEA, and DMAP used were in excess relative to δ-tocotrienol. In one procedure, 584 mg of δ-tocotrienol and 566 mg of nicotinic acid were reacted in 30 mL of DCM using 1607 mg of EDC, 778 μL of DIEA, and 53.2 mg of DMAP. Purification of δ-tocotrienol nicotinate was performed by column chromatography using silica gel 60 and elution with DCM / methanol 30:1.

[0112] In one implementation, a number of different synthetic routes are used to synthesize modified α-tocotrienols with linkers, depending on the actual needs and considerations for each specific molecule.

[0113] In one implementation, the progress of the reaction is monitored by TLC.

[0114] In one implementation, the structure and purity of the new molecule were confirmed by H-NMR, MS, FTIR, and HPLC.

[0115] In one embodiment, the synthesis of α-tocotrienol glycolic acid nicotinic acid ester is carried out in two steps. The first step is the esterification reaction of glycolic acid and nicotinic acid, as follows: 500 mg of nicotinic acid chloride hydrochloride, 640 mg (3 eq.) glycolic acid, and 20 mL of acetonitrile are added to a round-bottom flask and stirred in an ethanol ice bath; the mixture is stirred until the temperature reaches -10°C, at which point 1 mL of DIEA is added and the mixture is allowed to react for 1 hour. After the specified reaction time, 2.5 mL of palmitoyl chloride is added to the reaction medium, followed immediately by 2 mL of DIEA. The mixture is allowed to react for another 30 minutes. 10 mL of deionized water is added to the reaction medium and stirred overnight; then the reaction medium is filtered, and the filtrate is recovered. The acetonitrile in the filtrate is removed under vacuum in a rotary evaporator at approximately 45°C, and the remaining water is removed by freeze-drying. In the second step, the crude product obtained in the first step can be used without further purification. 400 mg of crude product, 540 mg (6 eq.) EDC, 5 mg DMAP, and 20 mL of DCM are mixed in a round-bottom flask and stirred. 200 mg of α-tocotrienol dissolved in 0.5 mL LCM was added to the mixture, followed by 0.5 mL of DIEA. The reaction was stirred for 1 hour within a temperature range of 18 °C to 25 °C. The reaction medium was extracted sequentially with 30 mL of 5% citric acid and three 50 mL portions of deionized water. The organic fractions were recovered, combined, dried over sodium sulfate, and filtered. The solvent was removed under vacuum in a rotary evaporator at approximately 45 °C. The structure and purity of the new molecule were confirmed by ¹H NMR, MS, FTIR, and HPLC.

[0116] In one embodiment, the synthesis of α-tocotrienol feruloyl nicotinate was carried out in two steps. In the first step, 720 mg (1.5 eq) of ferulic acid was dissolved in 20 mL of acetonitrile in a round-bottom flask and cooled to -10 °C using an ethanol ice bath. 980 mg of nicotinyl chloride hydrochloride was added to the reaction vessel and the mixture was stirred for 5 min, followed by the dropwise addition of 2 mL of DIEA over 1 min with vigorous stirring. The reaction was stirred for another 2 h to ensure completion. The reaction medium was then extracted sequentially with three 50 mL aliquots of deionized water; the organic fractions were recovered, combined, and dried over sodium sulfate. The solvent was then removed under vacuum in a rotary evaporator at approximately 30 °C. The obtained crude product was redissolved in a minimal amount of 5% formic acid acetonitrile solution and purified by preparative HPLC (Waters Atlantis C18 preparative column, 19 x 250 mm 10 μm, 60:40 acetonitrile:water, 20 mL / min) in a reversed-phase system. In the second step, 50 mg of the intermediate obtained in the first step, along with 96 mg of EDC (3 eq.) and 5 mg of DMAP in 10 mL of DCM, were added to a round-bottom flask and stirred thoroughly for 10 minutes. 70 mg of α-tocotrienol dissolved in 5 mL of DCM for easy handling was added to the reaction vessel, followed immediately by 0.2 mL of DIEA under vigorous stirring. The reaction was stirred for 2 hours to ensure completion. The reaction medium was then extracted sequentially with 30 mL of 5% (w / v) citric acid solution and three 50 mL aliquots of deionized water. The organic fraction was recovered and dried over sodium sulfate. The solvent was removed under vacuum in a rotary evaporator at approximately 30 °C. The obtained crude product was redissolved in a minimal amount of 5% formic acid acetonitrile solution and purified by preparative HPLC (Waters Atlantis C18 preparative column, 19 x 250 mm, 10 μm, 100% acetonitrile, 20 mL / min) in a reversed-phase system.

[0117] In one embodiment, the synthesis of α-tocotrienol glycine nicotinate is carried out in three steps. In the first step, 120 mg BOC-glycine-OH (1.5 eq.), 410 mg EDC (4.5 eq.), 20 mg DMAP, and 15 mL DCM are added to a round-bottom flask under vigorous stirring. For ease of handling, 120 mg α-tocotrienol is dissolved in 5 mL DCM and then added to the reaction vessel under vigorous stirring, followed immediately by 3 mL DIEA. The reaction is stirred for another 2 hours to ensure completion. The reaction medium is extracted sequentially with 30 mL of 5% citric acid aqueous solution and two 50 mL aliquots of deionized water. The organic fractions are recovered, combined, and dried over sodium sulfate. The solvent is removed under vacuum in a rotary evaporator at approximately 40 °C. The crude product is used in the following steps without further purification. In the second step, a solution containing 3 mL DCM + 3 mL trifluoroacetic acid (TFA) is added to the crude product under stirring and allowed to react for 1 hour to ensure removal of the BOC protecting group. The reaction medium was azeotropically evaporated with methanol under vacuum in a rotary evaporator at approximately 40°C. The crude product was redissolved in DCM and extracted with three 50 mL aliquots of deionized water. The organic fractions were recovered, combined, dried under sodium sulfate, and filtered. In the third step, the organic fraction filtered in the second step was transferred to a round-bottom flask with vigorous stirring, and a pre-prepared fresh solution was added: 5 mL of DCM containing 120 mg nicotinic acid (2 eq.), 1.2 g EDC (6 eq.), and 5 mg DMAP. The mixture was stirred for another 10 minutes. 1 mL of DIEA was added to the reaction medium, and the reaction was stirred at room temperature for another hour to ensure completion. The reaction was extracted sequentially with 30 mL of 5% citric acid and three 50 mL aliquots of deionized water. The organic fractions were recovered, combined, and dried under sodium sulfate. The solvent was removed under vacuum in a rotary evaporator at approximately 40°C. The obtained crude product was redissolved in a minimal amount of DCM and purified by normal-phase rapid chromatography. The column was packed with 50 g of silica gel 60 dispersed in a 10:1 DCM:methanol solution, loaded with the entire amount of crude product obtained in step 3, and eluted with a 10:1 DCM:methanol solution.

[0118] In one embodiment, the synthesis of α-tocotrienol nicotinol succinate is carried out in two steps. First, 770 mg of succinic anhydride, 1.9 g of nicotinol (1.9 eq.), and 20 mL of acetonitrile are added to a round-bottom flask and stirred for 10 minutes. Then, 200 μL of 98% sulfuric acid is added to the mixture under vigorous stirring. Although the reaction proceeds rapidly, the reaction is stirred for another hour to ensure complete reaction, resulting in the formation of white and pale yellow precipitates. The reaction medium is filtered, the filtrate is recovered, and transferred to a round-bottom flask with stirring. 4 mL of palmitoyl chloride and 2.5 mL of DIEA are added to the reaction vessel, and the mixture is stirred for another hour. The reaction medium is filtered again, and the filtrate is recovered. The filtrate is then extracted with three 30 mL portions of hexane. The acetonitrile fraction is recovered, and the solvent is removed under vacuum in a rotary evaporator at approximately 40 °C. The obtained crude product is dissolved in 50 mL of deionized water and filtered through a sintered glass filter (size 4). The filtrate is recovered, lyophilized, and used for the next step without further purification. In the second step, 296 mg of crude product obtained in the previous step, 542 mg of EDC (6 eq.) in 15 mL of DCM, and 20 mg of DMAP were mixed in a round-bottom flask. Then, 200 mg of α-tocotrienol dissolved in 5 mL of DCM was added to the reaction medium, followed immediately by 4 mL of DIEA under vigorous stirring. The reaction was stirred for another 2 hours to ensure completion. The reaction was then extracted sequentially with 5% citric acid solution and three 50 mL aliquots of deionized water. The organic fractions were recovered, combined, and dried over sodium sulfate. The solvent was removed under vacuum in a rotary evaporator at approximately 40 °C. The obtained crude product was dissolved in a minimal amount of 5% formic acid-acetonitrile solution and purified by preparative HPLC (Waters Atlantis C18 preparative column, 19 x 250 mm 10 μm, 100% acetonitrile, 20 mL / min) in a reverse-phase system.

[0119] In one implementation, TLC analysis was performed on an aluminum-substrate silica 60 plate impregnated with the fluorescent probe F254 (Merck). The plate was 8 cm long, and the sample run length was 7.5 cm. The plate was visualized under UV light (254 nm and 365 nm) before any developing solution (staining) was applied. The stains used (TLC stain, Seebach's stain, Draggendorff stain) were used for both general identification and selective detection of compounds.

[0120] In one embodiment, the reaction products were further characterized by FTIR, HPLC, MS, and ¹H-NMR. FTIR measurements were performed using a compressed potassium bromide (KBr) particle window on a Shimadzu IRPrestige-21 spectrophotometer. Spectra were obtained in transmission mode, ranging from 4000 cm⁻¹. -1 Up to 400cm-1 The resolution is 4cm. -1 The value is the average of 32 individual measurements. HPLC analysis was performed on a Knauer chromatograph consisting of three modules: a Smartline Manager 5000, a Smartline Pump 1000, and a Smartline UV Detector 2600. The UV detector was equipped with a photodiode array (PDA) for continuous monitoring in the 190–450 nm range. The column system consisted of a pre-column (reversed-phase C18 Atlantis T3 5 μm, 4.6 x 20 mm) and a column (reversed-phase C18 Atlantis T3 5 μm, 4.6 x 250 mm), which was maintained at 30 °C using a dedicated oven. Elution was performed with acetonitrile (containing 0.1% v / v acetic acid) at a rate of 1 mL / min, with an injection volume of 50 μL. MS spectra were obtained on a Quattro Micro Mass Triple Quadrupole Mass Spectrometer (Waters) by direct injection of the sample-containing solution. The probe desolvation temperature and gas flow rate (N2) were set to 300 °C and 600 L / h, respectively, while the capillary was set to 120 °C and 20 L / h. The capillary voltage was 4.00 keV, and the cone voltage was 40 V. Argon (Ar) was used as the collision gas for recording spectra in sub-mode. After selecting and locking the corresponding molecular ion m / z and adjusting the collision energy, recording was performed in the m / z range of 50 to 600. The target molecule was dissolved in an acetonitrile:methanol 1:1 solution and infused at a rate of 20 μL / min.

[0121] In one embodiment, after complete solvent removal, the modified molecule was further characterized according to the described protocol. FTIR results were shown at approximately 1740 cm⁻¹. -1 A strong absorption band exists at 2750-3500 cm⁻¹, which is characteristic of ester bonds, while at 2750-3500 cm⁻¹... -1 The absence of absorption bands in the region is characteristic of hydroxyl and carboxyl groups. HPLC chromatograms of each purified reaction product ( Figure 2 Only one peak was observed, while the MS spectrum showed the expected molecular ion peak (according to Table I). The H-NMR spectrum peaks were consistent with the expected structure. Modified tocotrienols and modified α-tocotrienols with linker molecules were obtained with a purity of 97% m / m or higher.

[0122] Table I - MS analysis results of the reaction products - theoretical molecular weight and molecular ion peak of the synthesized molecules.

[0123] molecular Theoretical molecular weight Molecular peak, [M+H]+ α-Tocopherol 430.71 431.24 α-Tocotrienol 424.66 425.16 γ-Tocotrienol 410.63 411.41 δ-Tocotrienol 396.61 397.13 α-Tocopheryl Nicotinate 535.82 536.24 α-Tocotrienol Nicotinate 529.77 531.25 γ-Tocotrienol Nicotinate 515.74 516.40 δ-Tocotrienol Nicotinate 501.72 502.31 α-Tocotrienol glycoloyl nicotinate 587.80 588.11 α-Tocotrienol feruloyl nicotinate 705.94 706.24 α-Tocotrienol glycine nicotinate 586.82 587.11 α-Tocotrienol Nicotinyl Succinate 615.86 616.97

[0124] In one implementation, the skin penetration of the modified compound was evaluated. Penetration tests were performed using full-thickness human skin. These samples were obtained from healthy donors who underwent cosmetic surgery at a local hospital. The excised skin was stored in a PBS solution containing 10% antibiotics and maintained at 4°C until further processing in the laboratory. Upon receipt of the skin samples, the underlying adipose tissue was removed and discarded. The remaining skin (dermis and epidermis) was cut into fragments approximately 1.5 x 1.5 cm. When performing penetration tests with fresh skin, the samples were used immediately. Otherwise, pre-cut skin samples were frozen at -80°C and stored for further use. When thawing frozen skin samples, the samples were removed from storage and thawed to room temperature for 1 hour before further processing.

[0125] The osmosis experiments were conducted in Franz diffusion cells. These cells consist of a donor chamber and a acceptor chamber. The donor chamber contains the formulation containing the osmotic molecules, and the acceptor chamber contains the acceptor fluid for timely collection and accumulation of the osmotic molecules. Skin samples were placed between the donor and acceptor chambers and were also equipped with a sampling channel that allowed for sample (a certain volume of acceptor fluid) collection without disassembling the diffusion cell, thus enabling the continuation of the osmosis experiment. Figure 3 ).

[0126] At the start of the experiment, the recipient chamber is filled with recipient fluid. The skin sample is carefully placed in place to avoid air bubbles forming underneath. The donor and recipient are positioned and clamped. The assembly is then placed in a constant temperature (37°C) bath for 30 minutes to allow temperature equilibration. After equilibration, the recipient fluid level is adjusted as needed. The recipient chamber is equipped with a magnetic stirrer to ensure solution homogeneity during the osmosis experiment.

[0127] In one embodiment, nicotinic acid released from modified tocopherol and tocotrienol molecules is monitored in a permeate solution. The content of nicotinic acid is quantified by HPLC using an ion-pairing method. The nicotinic acid concentration is calculated based on a standard calibration curve of a known nicotinic acid concentration solution measured under identical conditions. HPLC analysis is performed on a Knauer chromatograph consisting of three modules: a Smartline Manager 5000, a Smartline Pump 1000, and a Smartline UV Detector 2600. The UV detector is equipped with a photodiode array (PDA) for continuous monitoring in the 190–450 nm range. Online chromatograms are monitored at 254 nm. The eluent contains ion-pairing eluent (50 mM tetrabutylammonium hydroxide (TBAOH), pH corrected to 7.4 with disodium hydrogen phosphate (Na₂H₂PO₄)), 10% acetonitrile, at a flow rate of 1 mL / min, using an Atlantis T3 4.6 x 250 mm column (with a guard column of the same type, 4.6 x 20 mm), at a temperature of 30 °C.

[0128] In one embodiment, the skin penetration assay was performed using formulations containing modified tocotrienols and tocopherol molecules at different concentrations. The modified molecules were dissolved at concentrations of 5% and 10% m / m in equal volumes of a mixture of 2-(2-ethoxyethoxy)ethanol and propylene glycol, and 150 μL of these solutions were applied to skin samples. In the experiment with a donor solution concentration of 5% m / m, the nicotinic acid concentration of the penetration solution was quantified at different time points (8, 24, 33, and 48 hours). In the experiment with a donor solution concentration of 10% m / m, the nicotinic acid concentration of the penetration solution was quantified 48 hours after penetration. The results obtained are shown in Table II and... Figure 4 The Chinese side indicated that...

[0129] Table II - Concentration of nicotinic acid in the osmotic solution (μL / mL).

[0130]

[0131]

[0132] α-TN: α-Tocopherol nicotinate; α-T3-N: α-Tocotrienol nicotinate; γ-T3-N: γ-Tocotrienol nicotinate; ND: Not detectable.

[0133] In one embodiment, the skin penetration assay was performed using formulations of modified α-tocotrienols with linker molecules at different concentrations. The modified molecules were dissolved at a concentration of 10% m / m in an equal volume of a mixture of 2-(2-ethoxyethoxy)ethanol and propylene glycol, and 150 μL of these solutions were applied to skin samples. The nicotinic acid concentration in the penetration solutions of α-tocotrienol feruloyl nicotinate, α-tocotrienol glycyl nicotinate, and α-tocotrienol glycolyl nicotinate assays was quantified by HPLC using the described ion-pairing method. The nicotinic acid concentration in the penetration solution of α-tocotrienol nicotinol succinate was measured by HPLC using the same system configuration but with water as the eluent. The concentrations of nicotinic acid and nicotinic acid succinate were determined after 24 and 48 hours of penetration. The results are listed in Table III.

[0134] Table III - Concentrations of nicotinic acid and nicotinol in the osmotic solution (μg / mL).

[0135]

[0136] N-Fer-T3: α-Tocotrienol feruloyl nicotinate; N-Gly-T3: α-Tocotrienol glycyl nicotinate; N-Suc-T3: α-Tocotrienol nicotinol succinate; N-Glc-T3: α-Tocotrienol glycol nicotinate; NQ: Not quantifiable. *Trace amounts of nicotinol were detected, insufficient for quantification.

[0137] In one implementation, the amount of modified tocotrienol or modified tocopherol compound present in the skin is quantified at the end of the permeation experiment. For this purpose, at the end of the permeation experiment with a donor solution concentration of 10% m / m, skin samples are collected, residual formulation present in the Franz diffusion cell donor chamber is removed, and the samples are thoroughly washed with distilled water. The skin samples are extracted with three volumes of 5 mL acetonitrile, these volumes are combined, and the modified compound is then quantified by HPLC according to the analytical conditions described above for determining compound purity. The amount of modified compound was found to be comparable across different molecules, approximately 0.600 mg / cm³. 2 skin.

[0138] In one embodiment, the highest levels of nicotinic acid were found in the permeate solution of α-tocotrienol nicotinate in the linkerless molecule. The highest levels of nicotinic acid were found in the permeate solution of α-tocotrienol glycyl nicotinate in the linker-containing molecule.

[0139] In one implementation, the chemical stability of the modified molecule is evaluated in an accelerated degradation assay. For this purpose, the test molecule is formulated into a cosmetic-related preparation and its degradation is evaluated over a 3-month period.

[0140] In one embodiment, the cosmetic formulation may comprise water, jojoba seed oil, butylene glycol, squalane, sodium hyaluronate, cetearyl alcohol, and carbomer.

[0141] In one embodiment, the cosmetic formulation may include more ingredients suitable for obtaining more desired properties in the cosmetic formulation.

[0142] In one embodiment, the test molecule was added to the cosmetic formulation at a level of 0.1% m / m, thoroughly homogenized to ensure uniform dispersion, and stored in a sealed glass vial in an oven at 45°C for 3 months. To assess homogeneity and stability, three samples were collected from random locations immediately after preparation, and evaluation was performed at each time point. Quantification of the test molecule was performed by HPLC.

[0143] In one embodiment, a mixture for evaluating stability was prepared according to the following experimental protocol. The compound was weighed and dissolved in 2-(2-ethoxyethoxy)ethanol (also weighed), and added to a known mass of moisturizing product. The mixture was homogenized, and three samples were collected to confirm the uniform distribution and initial concentration of the modified molecules. The mixture was then stored in an oven at 45°C for 3 months (Table IV).

[0144] In one embodiment, the stability of test molecules in cosmetic formulations was determined. Test mixtures were sampled in triplicate from a random area. Samples were prepared for analysis by dissolving the samples in acetonitrile, and modified and unmodified tocopherols and tocotrienols were quantified by HPLC. The percentages of the initial compounds are shown in Table IV. Modified tocotrienols did not degrade during storage, while unmodified tocotrienols degraded to approximately half or less of their initial amount. Modified α-tocotrienols with linkers exhibited different behaviors depending on the molecule. α-Tocotrienol glycyl nicotinate, α-tocotrienol glycolonicotinate, and α-tocotrienol nicotinol succinate exhibited excellent stability, while α-tocotrienol feruloyl nicotinate was unstable even under refrigeration.

[0145] Table IV - Percentage of the initial compound after 3 months of storage in an oven at 45°C.

[0146]

[0147]

[0148] The term “comprising” as used herein is intended to indicate the presence of the said feature, whole, step, or component, but does not exclude the presence or addition of one or more other features, wholes, steps, components, or groups thereof.

[0149] If an element or feature is used in the singular form in the description of the claims, the plural form is also included, and vice versa, unless expressly excluded. For example, the terms "a compound" or "the compound" also include the plural forms "compounds" or "the compounds," and vice versa. In the claims, articles such as "a" or "this" may indicate one or more unless indicated to the contrary or obvious from the context. For claims or descriptions containing "or" among one or more members of a group, a claim is deemed satisfied as long as one, more, or all of the group members are present in, applied to, or related to the given product or method, unless indicated to the contrary or obvious from the context. This disclosure includes embodiments in which exactly one member of the group is present in, applied to, or related to the given product or method. This disclosure also includes embodiments in which more than one or all of the group members are present in, applied to, or related to the given product or method.

[0150] Furthermore, it should be understood that this disclosure covers all variations, combinations, and arrangements in which one or more limitations, elements, clauses, descriptive terms, etc., of one or more claims or related portions of a claim are incorporated into another claim. For example, any claim referencing another claim may be modified to include one or more limitations found in any other claim referencing the same basic claim.

[0151] Furthermore, if a composition is listed in the claims, it should be understood to include methods of using the composition for any purpose described herein, as well as methods of preparing the composition according to any preparation method disclosed herein or methods known in the art, unless otherwise stated or unless obvious to a person skilled in the art.

[0152] Where a range is given, the endpoints are included. Furthermore, it should be understood that, unless otherwise stated or clearly apparent from the context and / or understanding of someone skilled in the art, a value represented as a range may have any specific value within the range specified in different embodiments, up to one-tenth of the unit of the lower limit of that range, unless the context expressly specifies otherwise. It should also be understood that a value represented as a range may have any subranges within a given range, wherein the endpoints of the subranges are represented with the same precision as one-tenth of the unit of the lower limit of the range, unless otherwise stated or clearly apparent from the context and / or understanding of someone skilled in the art.

[0153] This disclosure should not be construed as limiting in any way to the described embodiments, and those skilled in the art will foresee many possibilities for modification thereto.

[0154] The above implementation schemes are combinable.

[0155] References

[0156] 1. Muller, L., K. Theile, and V. Bohm, In vitro antioxidant activity oftocopherols and tocotrienols and comparison of vitamin E concentration and lipophilic antioxidant capacity in human plasma. Mol Nutr Food Res, 2010.54(5):p.731-42.

[0157] 2.Yoshida,Y.,E.Niki,and N.Noguchi,Comparative study on the action oftocopherols and tocotrienols as antioxidant:chemical and physicaleffects.Chem Phys Lipids,2003.123(1):p.63-75.

[0158] 3.Guo,M.,et al.,Inhibitory effects of Schisandra chinensis extract onacne-related inflammation and UVB-induced photoageing.Pharm Biol,2016.54(12):p.2987-94.

[0159] 4.Shibata,A.,et al.,Suppression of gamma-tocotrienol on UVB inducedinflammation in HaCaT keratinocytes and HR-1 hairless mice via inflammatorymediators multiple signaling.J Agric Food Chem,2010.58(11):p.7013-20.

[0160] 5.Colombo,M.L.,An update on vitamin E,tocopherol and tocotrienol-perspectives.Molecules,2010.15(4):p.2103-13.

[0161] 6.Manor,D.,Morley,S.,Theα-Tocopherol Transfer Protein.In Vitamins&Hormones,Academic Press:2007;Vol.76,p.45-65.

[0162] 7.Gee,P.T.,Unleashing the untold and misunderstood observations onvitamin E.Genes Nutr,2011.6(1):p.5-16.

[0163] 8.Parkhurst,R.M.and W.A.Skinner,Chromanols and Tocopherols,inChemistry of Heterocyclic Compounds(eds G.P.Ellis and I.M.Lockhart).2008.p.59-137.

[0164] 9.Heymann,E.,et al.,Organophosphate sensitive and insensitivecarboxylesterases in human skin.Chem Biol Interact,1993.87(1-3):p.217-26.

[0165] 10.Montagna,W.,Histology and cytochemistry ofhuman skin.IX.Thedistribution of non-specific esterases.J Biophys Biochem Cytol,1955.1(1):p.13-6.

[0166] 11.Khodaeiani,E.,et al.,Topical 4%nicotinamide vs.1%clindamycin inmoderate inflammatory acne vulgaris.Int J Dermatol,2013.52(8):p.999-1004.

[0167] 12.Walocko,F.M.,et al.,The role of nicotinamide in acnetreatment.Dermatol Ther,2017;30:e12481.

[0168] 13.Rolfe,H.M.,A review of nicotinamide:treatment of skin diseases andpotential side effects.J Cosmet Dermatol,2014.13(4):p.324-8.

Claims

1. A compound of the following general formula (I) ###0001### wherein (I) R1, R2, R3, R4 are independently selected from each other; R1 is H or CH3; R2 is H or CH3; R3 is H or CH3; R4 is selected from the following list: R5 is a glycolate diester residue, a succinate diester residue or a glycine amide ester residue. ; ; 2. The compound according to claim 1, wherein the compound is selected from the following list:

3. Use of a compound according to any of the preceding claims 1 or 2 for the manufacture of a pharmaceutical preparation for the prevention or treatment of a skin disease. ; ; 。 4. Use of a compound according to any of the preceding claims 1 or 2 for the manufacture of a pharmaceutical preparation for the prevention or treatment of a skin inflammatory disease or a skin disorder. Said use is a use in a pharmaceutical preparation for the prevention or treatment of acne, rosacea, or seborrhea.

5. Use of a compound according to claim 3, characterized in that, 6. Non-therapeutic use of a compound according to any of the claims 1 to 2 in cosmetics, said compound being used as an anti-aging agent.

7. A pharmaceutical or cosmetic composition comprising at least one compound according to claim 1 and at least one pharmaceutically or cosmetically acceptable excipient.

8. The pharmaceutical or cosmetic composition according to claim 7, wherein said composition comprises at least one compound according to claim 1 in a quantity of up to 20% by mass with respect to the total mass of the composition.

9. The pharmaceutical or cosmetic composition according to the preceding claim 8, wherein said composition comprises at least one compound according to claim 1 in a quantity of from 0.01 % to 10% by mass with respect to the total mass of the composition.

10. The pharmaceutical or cosmetic composition according to the preceding claim 9, wherein said composition comprises at least one compound according to claim 1 in a quantity of from 0.1 % to 5% by mass with respect to the total mass of the composition.

11. The pharmaceutical or cosmetic composition according to the preceding claim 10, wherein said composition comprises at least one compound according to claim 1 in a quantity of from 0.1 % to 2% by mass with respect to the total mass of the composition.

12. The pharmaceutical or cosmetic composition according to claim 7, wherein the composition is a topical composition.

13. The pharmaceutical or cosmetic composition according to claim 12, wherein the topical composition is in the form of a gel, a cream, an emulsion, a serum, a paste or a foam.

14. The pharmaceutical or cosmetic composition according to claim 13, wherein the topical composition is in the form of an ointment.

15. A patch comprising a compound according to any of the claims 1 to 2 or a composition according to any of the claims 7 to 14. ​

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