JPH11124311A - Phototoxicity inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a phototoxicity inhibitor capable of providing more effective and practical means for controlling phototoxicity caused by the exposure of powder of a specific metal compound, etc., to sunlight and preventing skin aging and aggravation of skin symptoms, etc., in the field of medicine, quasi- medicine, cosmetic, etc. SOLUTION: This phototoxicity inhibitor comprises a combination of ascorbic acid and BHT as active ingredients widely used as an antioxidant, an antioxidant auxiliary, etc., in the field of medicine, quasi-medicine, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a phototoxicity inhibitor capable of suppressing phototoxicity mainly caused by exposure of metal oxide powder to ultraviolet light, and a phototoxicity inhibitor and a powder capable of causing phototoxicity. The invention in the technical field relates to a phototoxicity-suppressing powder composition in which the phototoxicity of the powder is suppressed, comprising: The present invention is also an invention in the technical field relating to a skin external preparation containing the phototoxicity suppressing powder composition.

[0002]

2. Description of the Related Art In the fields of pharmaceuticals, quasi-drugs, and cosmetics, powder components are actively mixed, and among them, powders of metal compounds represented by titanium oxide powder are widely used as cosmetic pigments and ultraviolet ray blocking agents. (For example, titanium oxide powder is widely used as a white pigment and an ultraviolet ray blocking agent). By the way, the ultraviolet blocking effect of the metal compound powder is such that when the metal compound powder is exposed to ultraviolet light, the energy of the ultraviolet light is absorbed by the metal compound atom when the metal compound atom is excited. The operation is based on It is known that a large amount of free electrons and holes are generated at the same time when the atoms of the metal compound enter the excited state. Although the nature of the powder of the metal compound has recently attracted attention in various fields as a so-called photocatalyst, it poses a serious problem as a component of a skin external preparation such as cosmetics.

[0003] That is, as a compounding component of a skin external preparation such as a cosmetic, a metal compound powder applied on the skin absorbs ultraviolet rays in sunlight and directly affects the skin with ultraviolet rays in sunlight. On the other hand, there are concerns about various adverse effects on skin due to active elements and free radicals derived from a large amount of free electrons and holes, that is, phototoxicity. Various diseases have been attracting attention, and various evidences that active oxygen is involved in aging have also been reported.) Therefore, as a method of protecting against phototoxicity mainly caused by active oxygen and free radicals in metal compound powder,
Surface modification and surface treatment of metal compound powders have been proposed but are not complete, and phototoxic protection means have not yet been established in the fields of pharmaceuticals, quasi-drugs, cosmetics, and the like.

[0004]

The problem to be solved by the present invention arises in the fields of pharmaceuticals, quasi-drugs, cosmetics, etc., when the powder of a specific metal compound is exposed to sunlight. An object of the present invention is to provide a more effective means for suppressing phototoxicity based on active oxygen, free radicals and the like, and preventing skin aging and deterioration of skin symptoms.

[0005]

Means for Solving the Problems The present inventor has made intensive studies to solve this problem. As a result, the present inventors have surprisingly found that by combining ascorbic acid and BHT as an active ingredient, a synergistically superior phototoxicity-inhibiting action is observed, and completed the present invention.

That is, the present invention relates to an ascorbic acid and B
Provided is a phototoxicity inhibitor comprising HT as an active ingredient.

[0007] The present invention also provides a phototoxicity-suppressing powder composition comprising the phototoxicity-inhibiting agent and a powder having the property of causing phototoxicity. In addition, a metal oxide powder having a band gap of 2.3 to 3.5 eV is more specifically a powder having the property of causing phototoxicity, and more specifically, a titanium oxide, a zinc oxide, a chromium oxide, and an iron oxide. One or more metal oxide powders selected from the group consisting of metal oxide powders, more preferably titanium oxide powders, may be selected.

Further, the present invention also provides an external preparation for skin comprising the powder composition for suppressing phototoxicity.

In the present invention, "phototoxicity" refers to toxicity due to active oxygen, free radicals, and the like generated by a large amount of free electrons and holes generated by exposing a powder component to ultraviolet rays as described above. Is meant.

[0010] As "active oxygen and free radicals", such as hydroxy radical (HO ·), superoxide radical (O ^- _2), singlet oxygen ⁽¹ O _2), hydrogen peroxide (H ₂ O _2), Lipid hydroperoxide (LOO
H), alkoxy radical (LO.), Peroxy radical (LOO.), Hydroperoxy radical (HOO)
•) etc. [Throughout this specification,
These are described as "active oxygen / free radical"].

[0011]

Embodiments of the present invention will be described below. A. The phototoxicity inhibitor according to the present invention (hereinafter referred to as the phototoxicity inhibitor of the present invention) is an agent containing ascorbic acid and BHT as active ingredients. In the present invention, "ascorbic acid"
Contains both L-ascorbic acid and D-ascorbic acid. Among ascorbic acids, L-ascorbic acid is another name of vitamin C which is widely used as an antioxidant and a whitening ingredient in the field of skin external preparations such as cosmetics,
Usually, it can be synthesized by a known method, and it is commercially available.

The ascorbic acid which can be added to the phototoxicity inhibitor of the present invention also includes pharmaceutically acceptable salts of ascorbic acid. Specific examples include sodium and potassium salts of ascorbic acid.

However, ascorbic acid esters such as sulfate of ascorbic acid do not show the desired phototoxicity-inhibiting effect in combination with BHT and are excluded from ascorbic acid as an active ingredient of the phototoxicity-inhibiting agent of the present invention. Is done.

The official name of BHT used as an active ingredient of the phototoxic protective agent of the present invention in combination with this ascorbic acid is 2,6-di- tert -butyl-4-methylphenol, which is a cosmetic agent as an antioxidant. It is a component widely used in the field of skin external preparations such as. Of course, this BH
T can be synthesized by a generally known method, and is commercially available.

In the phototoxicity inhibitor of the present invention, in addition to the active ingredients ascorbic acid and BHT, other ingredients,
For example, an antioxidant or an ultraviolet absorber other than these active ingredients, and especially a stabilizer for ascorbic acid, etc. can be added as required. Of course, it is also possible to mix base components and the like according to the formulation. The compounding amount of ascorbic acid and BHT in the phototoxicity inhibitor of the present invention is:
There is no particular limitation. In addition, the phototoxicity suppressor of the present invention can take not only a single agent form but also a multi-part form in consideration of stability and the like.

B. The composition according to the present invention (hereinafter, referred to as the present composition) is a composition comprising the above-mentioned phototoxic inhibitor of the present invention and a powder having a property of causing phototoxicity. "Powder having phototoxic properties" is such that when the powder is exposed to sunlight (more precisely, due to ultraviolet rays in sunlight), it becomes excited and generates free electrons and holes. The powder is not particularly limited as long as it has a property of generating active oxygen and free radicals by an oxidation reaction or a reduction reaction by the reaction and causing phototoxicity.

A metal oxide powder having a band gap of 2.3 to 3.5 eV, which is an energy width of a forbidden band, generally has the property of causing this phototoxicity. More specifically, titanium oxide, zinc oxide, Usually used as pigments and ultraviolet ray blocking agents, such as chromium oxide and iron oxide (including red iron oxide, yellow iron oxide, and black iron oxide), as powders of metal oxides.
Examples include metal compound powders used in the fields of quasi-drugs, cosmetics, and the like. In particular, while titanium oxide has attracted attention as a typical photocatalyst today, its phototoxicity is a problem, and it is a suitable metal oxide to which the present invention is applied.

The particle size of these powders is not particularly limited, and the present invention can be applied to all of the particle sizes of powders usually used for external preparations for skin such as cosmetics. Can be. More specifically, the diameter is several tens.
The present invention can be applied to particles ranging from μm particles to ultrafine particles of 100 nm or less.

Further, the present invention can be applied to powder whose surface has been subjected to chemical treatment. For example, a fat or oil treatment method that makes the powder lipophilic by adsorbing fat or oil on the powder surface or by an esterification or etherification reaction mediated by a functional group such as a hydroxyl group; using a zinc salt or a magnesium salt of a fatty acid. The present invention is applied to powders that have been subjected to a powder surface treatment method such as a metal soap treatment method; a silicone treatment method using dimethyl polysiloxane or methyl hydrogen polysiloxane; and a method of treating with a fluorine compound having a perfluoroalkyl group. be able to.

The weight ratio of these powders to the above-mentioned ascorbic acid and BHT in the composition of the present invention is such that at least ascorbic acid and BHT are each equal in weight to the powder [powder: ascorbic acid: BHT = 1: 1: 1 (weight ratio)] or more is necessary in order to sufficiently exhibit the desired phototoxicity suppressing effect.

In the composition of the present invention, in addition to the above essential components,
According to the purpose, a component capable of removing active oxygen and free radicals which are the main cause of phototoxicity can be blended.

For example, amino acids such as histidine, tryptophan, methionine, alanine, cysteine, methionine ester and the like; butylhydroxyanisole (BHA), phenoxyethanol; α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, Tocopherols such as tocopherol acetate; gallic acid esters; rosemary, pentagon, rutin, catechin, quercetin, tannins,
Plant extracts such as flavonoids and proanthocyanidins;
α-Glucosylrutin, quercetin fatty acid ester and the like and derivatives thereof; biological components such as hypotaurine, thiotaurine, bilirubin, uric acid, and ergosterol can be exemplified, but not limited to these components.

Further, an ultraviolet absorber may be added to the composition of the present invention to absorb ultraviolet rays in sunlight, thereby suppressing the excitation of powder atoms. As the ultraviolet absorber, those usually added to an external preparation for skin such as cosmetics can be added.

Specifically, for example, a paraaminobenzoic acid-based ultraviolet absorber such as paraaminobenzoic acid; an anthranilic acid-based ultraviolet absorber such as methyl anthranilate; a salicylic acid-based ultraviolet absorber such as octyl salicylate, phenyl salicylate and homomenthyl salicylate; Isopropyl paramethoxycinnamate, octyl paramethoxycinnamate, 2-ethylhexyl paramethoxycinnamate, glyceryl mono-2-ethylhexanoate diparamethoxycinnamate,
[4-bis (trimethylsiloxy) methylsilyl-3-
Methylbutyl] -3,4,5-trimethoxycinnamic acid esters and other cinnamic acid-based ultraviolet absorbers; 2,4-dihydroxybenzophenone, 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxybenzophenone- 5-sulfonic acid, benzophenone-based ultraviolet absorbers such as sodium 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid; urocanic acid, ethyl urocanate, 2-phenyl-5-methyl-benzoxazole, 2- (2 ^'- (Hydroxy-5'-methylphenyl) benzotriazole, 4- tert -butyl-4'-methoxydibenzoylmethane and the like can be incorporated in the composition of the present invention.

The above components selected here (active oxygen / free radical removing component and / or ultraviolet absorber)
Can be blended in the composition of the present invention, but can be blended in combination of two or more if necessary.

The composition of the present invention thus constituted suppresses phototoxicity caused by exposure of a specific powder to sunlight, thereby preventing skin aging and skin symptoms from aggravating. can do.

C. The composition of the present invention is mainly used in the fields of pharmaceuticals, quasi-drugs, and cosmetics. Specifically, by positively incorporating the composition of the present invention into an external preparation for skin, the properties of the powder in the composition of the present invention are utilized, and the phototoxicity of the powder caused by sunlight is further suppressed. Further, there is provided an external preparation for skin with significantly improved safety on the skin. In the skin external preparation of the composition of the present invention (hereinafter, referred to as
The blending amount in the skin external preparation of the present invention) should be appropriately selected according to the specific embodiment of the skin external preparation of the present invention, and is not limited.

The external preparation for skin of the present invention may contain other components in addition to the above essential components, as long as the desired effects of the composition of the present invention are not impaired, depending on the specific purpose. For example, humectants, vitamins, hormones, amino acids, anti-inflammatory agents, whitening agents, astringents, cooling agents,
Extracts from various animals and plants, oils and fats, waxes, lower alcohols, sterols, ester oils, hydrocarbon oils, silicones, surfactants, water-soluble polymers, surfactants, antibacterial agents, antioxidants, neutralizing agents , A pH adjuster, a metal sequestering agent, a fragrance, a pigment, and the like can be appropriately selected and blended in the skin external preparation of the present invention.

These components are merely examples, and the components that can be added to the external preparation for skin of the present invention are not limited to these components. These components can be combined in the external preparation for skin of the present invention in an appropriate combination according to the formulation according to the desired form.

The external preparation for skin of the present invention includes pharmaceuticals, quasi-drugs (ointments, dentifrices, etc.) and cosmetics [basic cosmetics such as facial cleansers, emulsions, creams, gels, essences (cosmetics), pack masks, etc .; Makeup cosmetics such as foundations and lipsticks; oral cosmetics, aromatic cosmetics, hair cosmetics, body cosmetics, etc.]. And
The form that the external preparation for skin of the present invention can take is not limited to these forms.

The dosage forms are aqueous solution type, solubilizing type, emulsifying type, powder type, oil liquid type, gel type, ointment type, aerosol type,
A wide range of dosage forms such as a water-oil two-layer system and a water-oil-powder three-layer system can be adopted. The specific prescription of the skin external preparation of the present invention will be described in Examples described later.

[0032]

EXAMPLES Next, the present invention will be described more specifically with reference to examples and the like, but the technical scope of the present invention should not be construed as being limited to these examples and the like. First, prior to the description of specific formulations described below, specific evaluations of the present invention will be described as test examples.

Test Example 1 Photocytotoxicity test 3.5 × 10 ⁵ human dermal fibroblasts (N
B1RGB cells) containing 10% fetal calf serum (JRH Bi
0.1 ml of RITC80-7 medium (OSCIENCE) (Kyokuto Pharmaceutical Co., Ltd.) was added to each well of a 96-well microplate, and precultured at 37 ° C. and 5% CO ₂ for 24 hours. Next, a test substance was prepared and added to each well in a dose amount. After completing the test preparation in this way, these test systems were incubated at 37 ° C. and 5% CO ₂ for 1 hour.

After culturing, these culture systems were exposed to ultraviolet light (UV
A: Irradiation with long-wave ultraviolet light (5 J / cm ² , control is not irradiated)
did. After irradiation, the test system was further heated at 37 ° C and 5% CO ₂ for 2 hours.
The cells were cultured for 4 hours. After completion of the culture, discard the medium, and add 50 μg / ml
Was added to each well, and the cells were cultured at 37 ° C. and 5% CO ₂ for 3 hours. After completion of the culture, the medium was discarded, 0.2 ml of a 1% aqueous solution of calcium chloride containing 1% formaldehyde (washing / fixing solution) was added to each well, and the mixture was left at room temperature for 1 minute.

The washing / fixing solution was discarded, and 0.1 ml of a 50% aqueous ethanol solution (extract) containing 1% glacial acetic acid was added to each well.
Stirred for minutes. Microplate reader (Bio-Rad
Was used to measure the absorbance of each well at a wavelength around 540 nm. At this time, the absorbance of the empty well was set to 0 (%),
The absorbance of the well containing only the test substance-free cells was set to 100.
(%), And the absorbance (%) of each well was calculated. By preparing or calculating a dose-response curve, the test substance concentration (EC ₅₀ % value) to be ₅₀ % was determined.

As a test substance, among the titanium oxide reference catalysts used for joint research by the Catalysis Society of Japan, JRC-T
When IO-4 was used, the EC ₅₀ value of the ultraviolet irradiation plate was around 10 μg / ml. For non-irradiated plates, 10
No cytotoxicity was observed up to 0 μg / ml. As test substances, JRC-TIO-4 and L-ascorbic acid,
Alternatively, when JRC-TIO-4 and BHT were used in equimolar amounts, the EC ₅₀ value of the ultraviolet irradiation plate was around 20 μg / ml, and the phototoxicity of JRC-TIO-4 was slightly suppressed.

However, when JRC-TIO-4, L-ascorbic acid and BHT were used in equimolar combination, no cytotoxicity was observed up to 100 μg / ml on the ultraviolet plate, and the light of JRC-TIO-4 was not observed. Toxicity was completely suppressed. From these results, it was clarified that the desired phototoxicity-suppressing action was recognized from the viewpoint of cytotoxicity by the combined use of ascorbic acid and BHT.

Hereinafter, specific formulation examples of the composition of the present invention will be shown. [Example 1] O / W emulsified liquid foundation compounding ingredients (wt%) ion-exchanged water 54.2 propylene glycol 10.0 bentonite 0.5 triethanolamine 1.0 polyethoxyethylene sorbitan monostearate (20E) .O) 0.9 Stearic acid 2.2 Self-emulsifying glyceryl monostearate 2.0 Adsorbed and purified lanolin 2.0 Liquid paraffin 8.0 Cetyl 2-ethylhexanoate 7.0 Talc 3.0 Titanium dioxide (JRC- TIO-4) 5.0 Yellow iron oxide 1.4 Black iron oxide 0.1 Bengala 0.5 Ethyl paraben 0.1 Butyl paraben 0.1 L-ascorbic acid 1.0 BHT 1.0 <Production method> , O / W emulsion type liquid foundation was prepared.

When the phototoxicity test described above was conducted on the composition of the present invention thus prepared, it was confirmed that the phototoxicity due to titanium dioxide or iron oxide was clearly suppressed.

[0040]

Industrial Applicability According to the present invention, in the fields of pharmaceuticals, quasi-drugs, cosmetics, etc., phototoxicity caused by exposure of a powder of a specific metal compound or the like to sunlight is suppressed, and skin aging and skin A more effective and practical means for preventing the deterioration of symptoms and the like beforehand is provided.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/375 ADA A61K 31/375 ADA // C07D 307/62 C07D 307/62

Claims (6)

[Claims] 1. A phototoxicity inhibitor comprising ascorbic acid and BHT as active ingredients. 2. A phototoxicity-inhibiting powder composition comprising the phototoxicity-inhibiting agent according to claim 1 and a powder having a property of inducing phototoxicity. 3. A powder having the property of causing phototoxicity,
The phototoxicity suppressing powder composition according to claim 2, which is a metal oxide powder having a band gap of 2.3 to 3.5 eV. 4. A powder having the property of causing phototoxicity,
The phototoxicity suppressing powder composition according to claim 2, which is one or more metal oxide powders selected from the group consisting of titanium oxide, zinc oxide, chromium oxide, and iron oxide. 5. A powder having the property of causing phototoxicity,
The phototoxicity suppressing powder composition according to claim 3, which is a titanium oxide powder. 6. An external preparation for skin comprising the phototoxicity-suppressing powder composition according to any one of claims 2 to 5.