Stabilization of mycosporine-like amino acid

Abstract

Provided are: a MG-stabilized composition which comprises mycosporine-glycine (MG) and is acidic to weakly alkaline; a MG-stabilized composition which comprises MG and at most 10 parts by weight of 4-DG; and a MAA-stabilized composition which comprises MAA and at least one selected from among a base forming a nucleic acid, a nucleoside, a glycine, and a tranexamic acid.

Description

Stabilization of mycosporine-like amino acids

[0001] The present invention relates to a composition in which mycosporine-like amino acids (hereinafter referred to as "MAAs") are stabilized, and a method for stabilizing MAAs.

[0002] Ultraviolet (UV) rays are known to induce acute skin reactions such as erythema, skin aging, and skin cancer. The ultraviolet rays contained in sunlight are classified into three types based on their wavelength: UV-A (320-400 nm), UV-B (280-320 nm), and UV-C (200-280 nm). Of these, only UV-A and UV-B have an effect on living organisms, while UV-C is not a problem because it cannot normally pass through the atmosphere.

[0003] UV-B is the main cause of sunburn outdoors and is known to have relatively more energy than UV-A. When absorbed by the skin, it reaches the stratum corneum and epidermis, causing acute skin pigmentation such as age spots and freckles. It is also known to cause immunosuppression, which is involved in aging and the development of skin cancer.

[0004] UV-A has less energy than UV-B but a longer wavelength, and is known to penetrate deeper into the skin than UV-B, reaching the dermis. As a result, it not only causes acute skin pigmentation such as age spots and freckles, but also causes a decrease in dermal elasticity (actinic elastosis), leading to premature skin aging such as wrinkles and sagging. Furthermore, in recent years, it has been found that UV-A also causes immunosuppression and is involved in the development of precancerous skin lesions and skin cancer.

[0005] While the amount of UV-B varies depending on the season, weather, latitude, etc., a constant amount of UV-A reaches the earth's surface throughout the year. Therefore, it is important to protect the skin from not only UV-B but also UV-A.

[0006] Current UV protection agents can be classified into UV absorbers and UV scattering agents. UV absorbers convert UV energy into heat energy and release it, and examples of such agents include synthetic organic compounds such as 4-tert-butyl-4'-methoxydibenzoylmethane. UV scattering agents contain inorganic particles such as titanium oxide (TiO2) and zinc oxide (ZnO), and when applied to the skin, the inorganic particles present on the skin surface act as a barrier that reflects UV rays.

[0007] UV absorbers have the following problems: (1) they are easily decomposed by light and are therefore unstable; (2) they cause molecular excitation and promote melanin production, which can cause itching and allergies; and (3) they are synthetic chemicals, which can give a negative impression to users. UV scattering agents have the following problems: (1) they tend to turn white when applied to the skin and can make the skin feel heavy; (2) they cause the production of active oxygen; and (3) they can clog skin pores and cause concerns about inhibiting the function of exocrine glands. Due to these problems, there is growing demand for safe, naturally derived UV absorbers.

[0008] MAA is a natural UV-absorbing substance that is known to be widely present in aquatic organisms, such as corals, red algae, fish innards, and microalgae. MAA has high UV-A and UV-B absorption capabilities. MAA also has excellent antioxidant properties. For these reasons, MAA is used in cosmetics and skin care compositions.

[0009] Although MAA is an extremely useful substance, it is prone to decomposition, and the decomposition products tend to be colored. Therefore, studies have been conducted on stabilizing MAA (Patent Document 1).

[0010] JP 2017-197475 A

[0011] There is a need to stabilize MAA and further enhance its utility.

[0012] The present inventors have conducted extensive research into substances and conditions for stabilizing MAA, and have found substances and conditions suitable for stabilizing MAA, thereby completing the present invention.

[0013] That is, the present invention provides the following: (1) A composition in which mycosporine-glycine (MG) is stabilized, which comprises MG and is weakly acidic to weakly alkaline. (2) The composition according to (1), which has a pH of 5.4 to 8.0. (3) A method for stabilizing MG, which comprises placing MG under weakly acidic to weakly alkaline conditions. (4) The method for stabilization according to (3), which has a pH of 5.4 to 8.0. (5) A composition in which MG is stabilized, which comprises (a) MG, and (b) 10 parts by weight or less of 4-deoxygadusol (4-DG). (6) The composition according to (5), which comprises 1.5 to 10 parts by weight of 4-DG. (7) The composition according to (5) or (6), which is weakly acidic to weakly alkaline. (8) The composition according to (7), which has a pH of 5.4 to 8.0. (9) A method for stabilizing MG, comprising mixing MG with 10 parts by weight or less of 4-DG. (10) A composition in which the mycosporine-like amino acid (MAA) is stabilized, comprising (a) an MAA, and (b) one or more bases constituting nucleic acids, nucleosides, glycine, and tranexamic acid. (11) The composition according to (10), wherein the MAA is one or more MAAs selected from MG, shinorine, mycosporine-glycine-alanine, and porphyra-334. (12) The composition according to (10) or (11), wherein the MAA is one or more MAAs selected from MG, mycosporine-glycine-alanine, and shinorine. (13) The composition according to any one of (10) to (12), wherein the composition is weakly acidic to weakly alkaline. (14) The composition according to (13), wherein the pH of the composition is 5.4 to 8.0. (15) A method for stabilizing an MAA, comprising mixing the MAA with one or more selected from a base constituting a nucleic acid, a nucleoside, glycine, and tranexamic acid. (16) The method according to (15), wherein the MAA is one or more selected from MG, shinorine, mycosporine-glycine-alanine, and porphyra-334. (17) The method according to (15) or (16), wherein the MAA is one or more selected from MG, mycosporine-glycine-alanine, and shinorine.

[0014] According to the present invention, a composition in which MAA is stabilized and a method for stabilizing MAA are provided. The present invention is applicable to a wide range of MAAs and can enhance their value. Using the present invention and MAA, cosmetics, dermatological compositions, etc. that have long-lasting effects such as UV absorption ability and excellent shelf life can be produced.

[0015] The left panel of Figure 1 is a graph showing the results of investigating the effect of pH on MG stability. The right panel of Figure 1 is a graph showing the results of investigating the effect of pH on the coloration of MG solutions. The top panel of Figure 2 is a graph showing the results of investigating the effect of 4DG ratio on MG stability. The bottom panel of Figure 2 is a table showing the results of investigating the effect of 4DG ratio on the coloration of MG solutions. The left panel of Figure 3 is a graph showing the results of investigating the shinorine stabilizing effect of several compounds. The right panel of Figure 3 is a graph showing the results of investigating the MG stabilizing effect of several compounds that constitute nucleic acids. The left panel of Figure 4 is a graph showing the results of investigating the mycosporine-glycine-alanine (MGA) stabilizing effect of several bases that constitute nucleic acids. The top right panel of Figure 4 is a graph showing the results of investigating the MG stabilizing effect of several bases that constitute nucleic acids (after 20 days). The bottom right panel of Figure 4 is a graph showing the results of investigating the MG stabilizing effect of several compounds (after 49 days).

[0016] In one aspect, the present invention provides a composition containing MG, which is weakly acidic to weakly alkaline and in which MG is stabilized.

[0017] MG (Mycosporine-Glycine) is a compound having the following structure (Formula 1): MG has the characteristics of having high UV-A and UV-B absorption capacity and excellent antioxidant properties.

[0018] By adjusting the pH of the composition of the present invention from weakly acidic to weakly alkaline, MG in the composition is stabilized and decomposition is suppressed, which can also suppress coloration of the composition.

[0019] In the composition of this embodiment, stabilization of MG means that decomposition of MG is inhibited. The stabilization of MG may be determined, for example, by using the residual rate of MG after a certain period of time as an index. For example, in an experiment in which MG is left in the composition at 60°C for 4 days, the residual rate of MG may be about 80% or more, preferably about 84% or more, and more preferably about 88% or more after 4 days compared to the rate at the start of the experiment.

[0020] The pH of the composition being weakly acidic to weakly alkaline means, for example, that the pH is about 5.0 to about 9.0. Preferably, the pH is about 5.4 to about 8.8, and may be, for example, about 5.4 to about 8.0, about 5.9 to about 8.8, or about 5.9 to about 8.0.

[0021] For example, the pH of the composition can be maintained at a desired value by using known buffers.

[0022] In this specification, when "about" is added before a numerical value, it means a range of the numerical value ±20%, preferably ±10%, more preferably ±5%.

[0023] The concentration of MG in the composition of this embodiment may be any.

[0024] The composition is typically in the form of a solution, but may also be in the form of a semisolid such as a cream or a paste, or a solid such as a gel. In the case of a solution, the solvent may be water, an organic solvent such as ethanol, or a mixture of water and an organic solvent. The composition may be, for example, a cosmetic composition (e.g., sunscreen cream or lotion, whitening cosmetics, etc.), a dermatological composition (e.g., liquid, spray, ointment, cream, paste, gel, patch, etc.), etc. Bases, carriers, and excipients for producing these compositions are known.

[0025] The composition may contain components other than MG, such as pH adjusters (buffers), salts, flavorings, coloring agents, preservatives, or compounds that improve the stabilization of MG (described below).

[0026] In another aspect, the present invention provides a method for stabilizing MG, which comprises placing MG under weakly acidic to weakly alkaline conditions.

[0027] The stabilization of MG, the pH range from weakly acidic to weakly alkaline, is as explained above.

[0028] Placing MG under weakly acidic to weakly alkaline conditions typically refers to mixing MG into a neutral or weakly alkaline solution composition, but MG may also be mixed into a weakly acidic to weakly alkaline semi-solid or solid composition. For example, weakly acidic to weakly alkaline conditions can be created by using a known buffer.

[0029] The present inventors have found for the first time the range of the content of 4-DG in a composition that can stabilize MG in the composition. Accordingly, in a further aspect, the present invention provides the following: a composition in which MG is stabilized, comprising: (a) MG, and (b) 10 parts by weight or less of 4-DG.

[0030] 4-DG (4-Deoxygadusol) is a compound having the following structure (Formula 2):

[0031] The amount of 4-DG in the composition of this embodiment (sometimes referred to as the 4-DG ratio) is expressed in parts by weight relative to MG. The amount of 4-DG in the composition of this embodiment may be any concentration that provides the desired MG stabilization effect, for example, about 12 parts by weight or less, preferably about 11 parts by weight or less, more preferably about 10 parts by weight or less, such as about 0.5 parts by weight to about 12 parts by weight, about 1.0 parts by weight to about 11 parts by weight, or about 1.5 parts by weight to about 10 parts by weight.

[0032] The pH of the composition of this embodiment is preferably from slightly acidic to slightly alkaline, and such pH ranges are as explained above.

[0033] In the composition of this embodiment, stabilization of MG means that decomposition of MG is inhibited. The stabilization of MG can be determined, for example, by using the residual rate of MG after a certain period of time as an index. For example, in an experiment in which MG is placed in a composition at 60°C and pH 7 for 57 days, the residual rate of MG after 57 days may be about 71% or more, preferably about 73% or more, and more preferably about 75% or more, compared to the rate at the start of the experiment.

[0034] The composition is as described above.

[0035] The concentration of MG in the composition of this embodiment may be any.

[0036] In yet another aspect, the present invention provides a method for stabilizing MG, which comprises mixing MG with 10 parts by weight or less of 4-DG.

[0037] The stabilization of 10 parts by weight or less of 4-DG and MG is as described above. 4-DG and MG may be mixed in solution. 4-DG and MG may also be kneaded in a semi-solid such as cream or pasta. Alternatively, a mixed solution of 4-DG and MG may be gelled by a known method.

[0038] The present inventors have found for the first time that MAA can be stabilized in a composition by adding one or more compounds selected from the group consisting of nucleic acid bases, nucleosides, glycine, and tranexamic acid to the composition. Therefore, in yet another aspect, the present invention provides the following: a composition in which MAA is stabilized, comprising: (a) MAA, and (b) one or more compounds selected from the group consisting of nucleic acid bases, nucleosides, glycine, and tranexamic acid.

[0039] MAA is a general term for compounds in which an amino acid is bound to a cyclohexenone or cyclohexenimine skeleton which may have a substituent.

[0040] Examples of MAAs include, but are not limited to, shinorine (formula 3), porphyra-334 (formula 4), asterina-330 (formula 5), ​​palythene (formula 6), palythine (formula 7), mycosporine-glycine (formula 8), mycosporine-glycine-valine (formula 9), mycosporine-glycine-alanine (formula 10), mycosporine serinol (formula 11), and the like.

[0041] The MAA stabilized in the composition of this embodiment may be any MAA. Preferred examples of the MAA include, but are not limited to, MG, shinorine, mycosporine-glycine-alanine, and porphyra-334. One type of MAA may be stabilized, or two or more types may be stabilized.

[0042] The MAA stabilizer used in the composition of this embodiment is selected from the group consisting of bases constituting nucleic acids, nucleosides, glycine, and tranexamic acid. The MAA stabilizer may be one type or two or more types.

[0043] Bases constituting nucleic acids include purine bases (adenine, guanine) and pyrimidine bases (cytosine, uracil, thymine). In this specification, other bases constituting nucleic acids besides those mentioned above include hypoxanthine, xanthine, 7-methylguanine, 5,6-dihydrouracil, 5-methylcytosine, 5-hydroxymethylcytosine, etc. A preferred example of a base constituting nucleic acids is adenine, but is not limited to this.

[0044] Glycine is a known naturally occurring amino acid.

[0045] Tranexamic acid is a known artificial amino acid represented by formula 12, and is used as a hemostatic agent and an anti-inflammatory agent.

[0046] The MAA stabilizer may be a nucleoside. Examples of bases constituting nucleosides include, but are not limited to, purine bases such as adenine and guanine, pyrimidine bases such as thymine, cytosine, and uracil, nicotinamide, and dimethylisoalloxazine. Examples of sugars constituting nucleosides include, but are not limited to, ribose and deoxyribose. Examples of nucleosides that can be used as MAA stabilizers include, but are not limited to, adenosine, guanosine, uridine, cytidine, 5-methyluridine, deoxyadenosine, deoxyguanosine, deoxyuridine, deoxycytidine, and thymidine.

[0047] The pH of the composition of this embodiment is preferably from slightly acidic to slightly alkaline, and such a pH range is as described above. The composition is also as described above.

[0048] In the composition of this embodiment, stabilization of MAA means that decomposition of MAA is inhibited. The stabilization of MAA may be assessed, for example, by using the MAA residual rate after a certain period of time as an index. For example, in an experiment in which MG is stored at 60°C and pH 7.5 for 60 days, the MG residual rate may be about 68% or more, preferably about 72% or more, and more preferably about 76% or more, after 60 days compared to the start of the experiment. Furthermore, for example, in an experiment in which shinorine is stored at 60°C and pH 7.5 for 3 days, the shinorine residual rate may be about 64.5% or more, preferably about 65.5% or more, and more preferably about 66.5% or more, after 3 days compared to the start of the experiment.

[0049] The concentration of MAA in the composition of this embodiment may be any concentration.

[0050] The concentration of the MAA stabilizer in the composition of this embodiment may be any concentration that provides the desired MAA stabilization effect, and may be determined taking into consideration the MAA concentration in the composition, such as about 0.05% to about 1% by weight, about 0.1% to about 0.5% by weight, or about 0.1% to about 0.2% by weight.

[0051] In yet another aspect, the present invention provides a method for stabilizing MAA, which comprises mixing MAA with one or more selected from the group consisting of bases constituting nucleic acids, nucleosides, glycine, and tranexamic acid.

[0052] Preferred examples of MAAs in this method include, but are not limited to, MG, shinorine, mycosporine-glycine-alanine, and porphyra-334. Preferred examples of bases constituting nucleic acids used in this method include, but are not limited to, adenine.

[0053] The present invention will be described in detail and specifically below with reference to examples, but the examples are not intended to limit the scope of the present invention.

[0054] The stability of MG in solution and the effect of pH on the coloration of the MG solution were investigated. The solution was adjusted to each pH using 0.1 M phosphate buffer, and phosphoric acid and NaOH as needed. The MG concentration in the solution was 0.1%. MG solutions at each pH were prepared and left at 60°C for 4 days, after which the amount of MG and the absorbance (400 nm) of the solution were measured. The residual MG rate was determined by comparing it with the amount at the start of the experiment. The results are shown in Figure 1.

[0055] It was found that the MG residual rate increased in weakly acidic to weakly alkaline conditions, and that MG was stabilized. It was also found that the coloration of the MG solution was suppressed in weakly acidic to weakly alkaline conditions. The MG residual rate was 88% or more in the pH range of 5.4 to 8.8. These results showed that the stability of MG becomes very high in the pH range of weakly acidic to weakly alkaline conditions. The absorbance of the solution was very low (0.018 or less) in the pH range of 5.4 to 8.0.

[0056] The effect of 4-DG on stabilization of MG was investigated. Solutions containing various ratios of 4-DG to MG (0.1%) were prepared at pH 7 (in 0.1 M phosphate buffer) and left at 60°C for 57 days. The amount of MG was measured and the residual MG rate was calculated. The absorbance (400 nm) of the solution was also measured over time during the experiment. The results are shown in Figure 2.

[0057] When the 4-DG ratio was 1.5 to 11.1 parts by weight, the residual rate of MG was as high as 74% or more, indicating that MG was stabilized for a long period of time. Furthermore, when the 4-DG ratio was 1.5 to 11.1 parts by weight, the absorbance of the solution was 0.17 or less on the 57th day, indicating a high effect of inhibiting discoloration of the solution.

[0058] The effects of glycine, tranexamic acid, adenine, and uridine on the stability of shinorine and MG were investigated. A 0.1% shinorine solution (pH 7.5 with 0.1 M phosphate buffer) containing glycine (0.1%, 0.2%), tranexamic acid (0.2%), adenine (0.1%), or uridine (0.2%) was prepared. A 0.15% MG solution (pH 7.5 with 0.1 M phosphate buffer) containing glycine (0.1%, 0.2%), tranexamic acid (0.2%), adenine (0.1%), or uridine (0.2%) was prepared. After storing these solutions at 60°C for 3 days (shinorine) and 60 days (MG), the amounts of shinorine and MG were measured, and the residual percentages were calculated. The results are shown in Figure 3.

[0059] The stabilizing effects of glycine, tranexamic acid, adenine, and uridine were confirmed for both shinorine and MG.

[0060] The effects of nucleic acid bases (adenine, guanine, cytosine, uracil, and thymine) on the stability of MGA and MG were investigated. A 0.1% MGA solution (pH 7.5 in 0.1M phosphate buffer) containing adenine (0.01%), guanine (0.2%), cytosine (0.2%), uracil (0.2%), and thymine (0.2%) was prepared. A 0.1% MG solution (pH 7.5 in 0.1M phosphate buffer) containing adenine (0.01%), cytosine (0.2%), uracil (0.2%), and thymine (0.2%) was also prepared. These solutions were stored at 60°C for 3 days (MGA) and 20 and 49 days (MG), after which the amounts of MGA and MG were measured and the residual percentages were calculated. The results are shown in Figure 4.

[0061] The stabilizing effects of adenine, guanine, cytosine, uracil, and thymine on MGA were confirmed. The stabilizing effects of adenine, cytosine, uracil, and thymine on MG were also confirmed.

[0062] The present invention provides a composition for stabilizing MAA and a method for stabilizing MAA. Therefore, the present invention is useful in the fields of cosmetics, pharmaceuticals, etc. The present invention is useful in the production of cosmetics and topical skin preparations for UV protection, whitening, or antioxidant purposes.

Claims

1. (a) Mycosporine-like amino acid (MAA), and (b) one or more selected from bases, nucleosides, glycine, and tranexamic acid that constitute nucleic acids A composition comprising.

2. (a) Mycosporine-like amino acid (MAA), and (b) one or more selected from bases, nucleosides, and glycine that constitute nucleic acids A composition comprising.

3. The composition according to claim 1 or 2, wherein the MAA is one or more MAAs selected from MG, shinorine, mycosporine-glycine-alanine, and porphyrar-334.

4. The composition according to claim 3, wherein the MAA is one or more MAAs selected from MG, mycosporine-glycine-alanine, and shinorine.

5. The composition according to claim 1 or 2, wherein the composition is weakly acidic to weakly alkaline.

6. The composition according to claim 5, wherein the pH of the composition is 5.4 to 8.

0.

7. A method for stabilizing MAA, comprising mixing MAA with one or more selected from bases, nucleosides, glycine, and tranexamic acid that constitute nucleic acids.

8. A method for stabilizing MAA, comprising mixing MAA with one or more selected from bases, nucleosides, and glycine that constitute nucleic acids.

9. The method according to claim 7 or 8, wherein the MAA is one or more MAAs selected from MG, shinorine, mycosporine-glycine-alanine, and porphyrar-334.

10. The method according to claim 7 or 8, wherein the MAA is one or more MAAs selected from MG, mycosporine-glycine-alanine, and shinorine.