JP7153429B2 - Active oxygen scavenging agent - Google Patents

Description

The present invention relates to an active oxygen scavenger. The present invention also relates to a composition for external use having excellent active oxygen scavenging activity.

When oxygen in the air is taken into the body by breathing, active oxygen is generated in the body. Reactive oxygen is released from white blood cells and plays a role in repelling bacteria and viruses in the body with its strong bactericidal power, and originally plays an important function in maintaining biological functions. On the other hand, the generation of active oxygen is promoted by external environmental factors such as ultraviolet rays, and if the state of excessive active oxygen persists, it damages normal cells and genes, inducing various symptoms and diseases. . For example, it is known that when a state in which active oxygen is excessively present in skin tissue continues, symptoms such as skin aging, sagging, dullness, acne, and pimples are induced. In addition, it has been reported that excessive active oxygen is involved in the induction of atopic dermatitis, rheumatism, stiff neck, and the like.

Conventionally, various reports have been made on topical skin preparations capable of scavenging active oxygen generated in skin tissues. For example, L-ascorbic acid, fullerene, tocopherol acetate, astaxanthin, anthocyanin, coenzyme Q10, lutein, etc., have the effect of scavenging active oxygen, and by blending them in external skin preparations, they can be used for scavenging active oxygen. known to be available.

In addition, it is also known that extracts of plants such as Anachiculus pyrethrum also have the effect of scavenging active oxygen, and can be used by blending them in external compositions and the like for the purpose of scavenging active oxygen (see Patent Document 1). ).

On the other hand, in recent years, there has been an increasing demand from consumers for improving the functionality and feeling of use of external preparations for skin, and there is a demand for the development of pharmaceutical formulations that can meet the demands of consumers. Therefore, in the field of topical compositions used for the purpose of scavenging active oxygen, there is a demand for finding new ingredients capable of scavenging active oxygen and developing new pharmaceutical formulations that can be used for scavenging active oxygen.

JP 2013-224318 A

An object of the present invention is to provide an active oxygen scavenger that can effectively scavenge active oxygen.

The present inventors conducted intensive studies to solve the above problems, and found that heparin analogues have a higher active oxygen scavenging activity than ascorbic acid 2-glucoside. Furthermore, the present inventors have found that the combined use of a heparin analogue and ascorbic acid and/or its derivatives dramatically improves the active oxygen scavenging action. In addition, the present inventors have found that heparin analogues, ascorbic acids (ascorbic acid, derivatives thereof, and/or salts thereof), and glycyrrhizic acids (glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and/or salts thereof) It was found that the active oxygen scavenging action is dramatically improved by using together with. The present invention has been completed through further studies based on these findings.

That is, the present invention provides inventions in the following aspects.
Section 1. An active oxygen scavenging agent containing a heparinoid.
Section 2. Item 2. The active oxygen scavenging agent according to Item 1, further comprising at least one ascorbic acid compound selected from the group consisting of ascorbic acid, derivatives thereof, and salts thereof.
Item 3. Item 3. The active oxygen scavenging agent according to Item 2, wherein the ascorbic acid is ascorbic acid 2-glucoside.
Section 4. Item 4. The active oxygen scavenging agent according to Item 2 or 3, further comprising at least one glycyrrhizic acid compound selected from the group consisting of glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and salts thereof.
Item 5. Item 5. The active oxygen scavenging agent according to Item 4, wherein the glycyrrhizic acid is glycyrrhizic acid and/or a salt thereof.
Item 6. Item 6. The active oxygen scavenging agent according to any one of Items 1 to 5, which is an external preparation for skin.
Item 7. a heparin analogue,
at least one ascorbic acid selected from the group consisting of ascorbic acid, derivatives thereof, and salts thereof;
at least one glycyrrhizic acid selected from the group consisting of glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and salts thereof;
A topical composition containing

According to the active oxygen scavenging agent of the present invention, the active oxygen generated in the body can be eliminated, and the state of excessive active oxygen can be improved or avoided. It is effective for the prevention or treatment of skin diseases and skin symptoms.

1 is a diagram showing the results of evaluating the active oxygen scavenging rate for each test substance in Test Example 1. FIG.

1. Active Oxygen Scavenging Agent The active oxygen scavenging agent of the present invention is characterized by containing a heparin-like substance. The active oxygen scavenger of the present invention is described in detail below.

Heparin-like substances Heparin-like substances are polysulfated mucopolysaccharides such as chondroitin polysulfate. As shown in Test Example 1, which will be described later, it has been found that heparin analogues have an active oxygen scavenging effect superior to that of ascorbic acid 2-glucoside.

The origin of the heparin-like substance used in the present invention is not particularly limited, but examples include those obtained by polysulfating mucopolysaccharides, tissues of edible animals (e.g., tracheal cartilage of bovine, porcine, etc.). (including lungs), and the like. In the active oxygen scavenging agent of the present invention, a heparin analogue listed in the Japanese Pharmaceutical Standards outside the Pharmacopoeia is preferably used as the heparin analogue.

The content of the heparin-like substance in the active oxygen scavenging agent of the present invention may be appropriately set according to the degree of active oxygen scavenging action to be imparted, the formulation form, etc., but for example, 0.05 to 1% by weight. mentioned. From the viewpoint of exhibiting the active oxygen scavenging action more effectively, the content of the heparinoid is preferably 0.05 to 0.3% by weight, more preferably 0.1 to 0.3% by weight. be done.

Ascorbic Acids The active oxygen scavenger of the present invention may further contain at least one ascorbic acid selected from the group consisting of ascorbic acid, derivatives thereof, and salts thereof. When ascorbic acids are contained, the active oxygen scavenging action can be dramatically improved.

Ascorbic acid and derivatives thereof used in the present invention are not particularly limited as long as they are pharmaceutically or cosmetically acceptable. Examples include ascorbic acid; ascorbic acid 2-glucoside; ascorbic acid monostearate Ascorbic acid monoalkyl esters such as ascorbic acid monopalmitate and ascorbic acid monooleate; Ascorbic acid monoesters such as ascorbic acid monophosphate and its magnesium salt; Ascorbic acid distearate, ascorbic acid dipalmitate, ascorbic acid dioleate and the like acid dialkyl esters; ascorbic acid diesters such as ascorbyl diphosphate and salts thereof; trialkyl esters such as ascorbyl tristearate, ascorbyl tripalmitate, and ascorbyl trioleate; Ascorbic acid triesters; 3-O-ethyl, 6-acetyl-ascorbic acid, 3-O-ethyl, 6-butyl ascorbic acid, 3-O-ethyl, 6-lauroyl ascorbic acid, 3-O-ethyl, 6 -palmitoyl ascorbic acid, 3-O-ethyl, 6-oleoyl ascorbic acid, 3-O-ethyl, 6-stearoyl ascorbic acid, 3-O-ethyl, 6-behelminoyl-ascorbic acid and the like. These ascorbic acids and their derivatives may be either L-isomers or D-isomers, preferably L-isomers.

In addition, the salts of ascorbic acid and its derivatives are not particularly limited as long as they are pharmaceutically or cosmetically acceptable. Examples include alkali metal salts such as sodium salts and potassium salts; calcium salts and magnesium salts; and alkaline earth metal salts such as

As ascorbic acids, one of ascorbic acid, ascorbic acid derivatives, salts of ascorbic acid, and salts of ascorbic acid derivatives may be selected and used alone, or two or more may be used in combination. . Among these ascorbic acids, ascorbic acid derivatives are preferred, and ascorbic acid 2-glucoside is more preferred, from the viewpoint of more effectively improving the active oxygen scavenging action.

When ascorbic acids are contained in the active oxygen scavenging agent of the present invention, the content thereof may be appropriately set according to the degree of the active oxygen scavenging action to be imparted, the formulation form, etc. For example, ascorbic acids A total amount of 0.1 to 10% by weight may be mentioned. From the viewpoint of more effectively improving the active oxygen scavenging action, the total amount of ascorbic acids is preferably 0.3 to 8% by weight, more preferably 0.5 to 7% by weight.

When the active oxygen scavenging agent of the present invention contains ascorbic acids, the ratio of ascorbic acids to heparinoids is determined according to the content of each component described above. The total amount of ascorbic acids is 20 to 20,000 parts by weight. The total amount of ascorbic acids is preferably 500 to 4,000 parts by weight, more preferably 1,500 to 2,500 parts by weight, per 100 parts by weight of the heparin analogous substance from the viewpoint of more effectively improving the active oxygen scavenging action.

Glycyrrhizic Acids The active oxygen scavenger of the present invention may further contain at least one glycyrrhizic acid selected from the group consisting of glycyrrhizic acid, glycyrrhizic acid, derivatives thereof, and salts thereof. Glycyrrhizic acids have not been reported to have an active oxygen scavenging effect, but when used in combination with a heparin analogue, or in combination with a heparin analogue and ascorbic acids, the active oxygen scavenging effect is effectively improved. can be made

Glycyrrhizic acid is a known drug known to have anti-inflammatory effects, anti-allergic effects, and the like.

The derivative of glycyrrhizic acid is not particularly limited as long as it is pharmaceutically acceptable, and specific examples include methyl glycyrrhizinate and stearyl glycyrrhizinate. These derivatives of glycyrrhizic acid may be used singly or in combination of two or more.

Salts of glycyrrhizic acid and its derivatives are not particularly limited as long as they are pharmacologically acceptable, and specific examples thereof include alkali metal salts such as sodium salt, potassium salt and dipotassium salt; ammonium salts and the like. . These salts of glycyrrhizic acid and derivatives thereof may be used singly or in combination of two or more.

Glycyrrhetinic acid is a known drug known to have anti-inflammatory effects, anti-allergic effects, and the like.

The derivative of glycyrrhetinic acid is not particularly limited as long as it is pharmaceutically acceptable, and specific examples include pyridoxine glycyrrhetinate, stearyl glycyrrhetinate, glyceryl glycyrrhetinate, and monoglucuronide glycyrrhetinate. These derivatives of glycyrrhetinic acid may be used singly or in combination of two or more.

Salts of glycyrrhetinic acid and its derivatives are not particularly limited as long as they are pharmacologically acceptable, and specific examples include alkali metal salts such as sodium salts and potassium salts; ammonium salts and the like. These salts of glycyrrhetinic acid and derivatives thereof may be used singly or in combination of two or more.

As glycyrrhizic acids, one selected from glycyrrhizic acid, salts of glycyrrhizic acid, derivatives of glycyrrhizic acid, salts of derivatives of glycyrrhizic acid, glycyrrhetinic acid, salts of glycyrrhetic acid, derivatives of glycyrrhetic acid, and salts of derivatives of glycyrrhetinic acid. may be selected and used, or two or more may be used in combination. Among these glycyrrhizic acids, glycyrrhizic acid, a salt of glycyrrhizic acid, a derivative of glycyrrhizic acid, more preferably a salt of glycyrrhizic acid, and particularly preferably glycyrrhizin, from the viewpoint of further effectively improving the action of scavenging active oxygen. and dipotassium acid.

When the active oxygen scavenging agent of the present invention contains glycyrrhizic acids, the content thereof may be appropriately set according to the degree of active oxygen scavenging action to be imparted, the formulation form, etc. For example, glycyrrhizic acids A total amount of 0.02 to 8% by weight may be mentioned. From the viewpoint of more effectively improving the active oxygen scavenging action, the total amount of glycyrrhizic acids is preferably 0.02 to 5% by weight, more preferably 0.02 to 3% by weight.

When the active oxygen scavenging agent of the present invention contains glycyrrhizic acids, the ratio of glycyrrhizic acids to the heparin analogue is determined according to the content of each component described above. The total amount of glycyrrhizic acids is 10 to 1600 parts by weight. From the viewpoint of more effectively improving the active oxygen scavenging action, the total amount of glycyrrhizic acids is preferably 10 to 500 parts by weight, more preferably 50 to 200 parts by weight, per 100 parts by weight of the heparinoid.

Other Ingredients The active oxygen scavenging agent of the present invention may optionally contain other pharmacological ingredients in addition to the ingredients described above. Examples of such pharmacological components include antihistamines (diphenhydramine, diphenhydramine hydrochloride, etc.), local anesthetics (procaine, tetracaine, bupipacaine, mepipacaine, chloroprocaine, proparacaine, meprilcaine or salts thereof, orthocaine, oxethazein, oxypolyethoxylate, Decane, Rohto extract, percamimpase, tecit decitin, etc.), anti-inflammatory agents (indomethacin, felbinac, diclofenac sodium, loxoprofen sodium, etc.), skin protective agents (collodion, castor oil, etc.), blood circulation-promoting ingredients (nonylic acid vanillylamide, benzyl nicotinate) , capsaicin, red pepper extract, etc.), cooling agents (menthol, camphor, etc.), vitamins (vitamin A, etc.), mucopolysaccharides (sodium chondroitin sulfate, glucosamine, etc.), and the like.

In addition, the active oxygen scavenging agent of the present invention may contain base materials and additives as necessary in order to obtain a desired formulation form. Such bases and additives are not particularly limited as long as they are pharmaceutically acceptable. Examples include water, lower alcohols (ethanol, isopropanol, etc.), polyhydric alcohols (glycerin, propylene glycol, dipropylene glycol, 1,3-butylene glycol, etc.); Oils (olive oil, safflower oil, soybean oil, camellia oil, corn oil, rapeseed oil, sunflower oil, cottonseed oil, peanut oil, lard, squalane, fish oil, etc.) ), mineral oil (liquid paraffin, paraffin, gelatinized hydrocarbon, petroleum jelly, etc.), waxes/waxes (beeswax, carnauba wax, candelilla wax, ceresin, rice wax, microcrystalline wax, etc.), ester oil (isopropyl myristate) , isopropyl adipate, diethyl sebacate, isopropyl sebacate, isopropyl palmitate, cetyl palmitate, ethyl oleate, etc.), fatty acid alkyl esters, fatty acids (stearic acid, oleic acid, palmitic acid, behenic acid, linoleic acid, lanolin, etc.) ), fatty acid esters (cetyl palmitate, isopropyl palmitate, ethyl linoleate, etc.), higher alcohols (stearyl alcohol, cetanol, behenyl alcohol, myristyl alcohol, oleyl alcohol, hexadecyl alcohol, lanolin alcohol, etc.), cholesterol, tri-2-ethyl Oily bases such as glyceryl hexanoate, cetyl 2-ethylhexanoate, silicone oil (dimethylpolysiloxane, cyclic silicone, etc.); POE (10-50 mol) phytosterol ether, POE (10-50 mol) dihydrocholesterol ether, POE (10-50 mol) 2-octyldodecyl ether, POE (10-50 mol) decyltetradecyl ether, POE (10-50 mol) oleyl ether, POE (2-50 mol) cetyl ether, POE (5-50 mol) ) behenyl ether, POE (5-30 mol) polyoxypropylene (5-30 mol) 2-decyltetradecyl ether, POE (10-50 mol) polyoxypropylene (2-30 mol) cetyl ether, etc. Alkyl ethers, phosphoric acids and phosphates thereof (POE cetyl ether sodium phosphate, etc.), POE (20-60 mol) sorbitan monooleate, POE (10-60 mol) sorbitan monoisostearate, POE (10- 80 mol) glyceryl monoisostearate, POE (10-30 mol) glyceryl monostearate, POE (20-100 mol) polyoxypropylene-modified silicone, POE alkyl-modified silicone, polyethylene glycol monolaurate, polyethylene monopalmitate Glycol, polyethylene glycol monostearate, polyethylene glycol dilaurate, polyethylene glycol dipalmitate, polyethylene glycol distearate, polyethylene glycol dioleate, polyethylene glycol diricinoleate, polyoxyethylene hydrogenated castor oil (5-100), polysorbate (20 ~85), surfactants such as glycerin fatty acid esters (glyceryl monostearate, etc.), hydrogenated soybean phospholipids, hydrogenated lanolin alcohol; cooling agents (menthol, camphor, borneol, peppermint water, peppermint oil, etc.), preservatives agents (methylparaben, propylparaben, benzoic acid, sodium benzoate, sorbic acid, etc.), flavoring agents (citral, 1,8-cioneal, citronellal, farnesol, etc.), coloring agents (tar pigments (brown No. 201, blue No. 201 , Yellow No. 4, Yellow No. 403, etc.), cacao pigment, chlorophyll, aluminum oxide, etc.), thickener (carboxyvinyl polymer, hypromellose, polyvinylpyrrolidone, sodium alginate, ethylcellulose, carboxymethylcellulose sodium, xanthan gum, carrageenan, etc.), pH Adjusting agent (phosphoric acid, hydrochloric acid, citric acid, sodium citrate, succinic acid, tartaric acid, sodium hydroxide, potassium hydroxide, triethanolamine, triisopropanolamine, etc.), wetting agent (dl-sodium pyrrolidonecarboxylate solution, D -sorbitol solution, macrogol, etc.), stabilizers (dibutylhydroxytoluene, butylhydroxyanisole, sodium edetate, sodium metaphosphate, L-arginine, L-aspartic acid, DL-alanine, glycine, sodium erythorbate, gallic acid propyl, sodium sulfite, sulfur dioxide, chlorogenic acid, catechin, rosemary extract, etc.), antioxidants, UV absorbers, chelating agents, adhesives, buffers, solubilizers, solubilizers, preservatives, etc. agents.

The active oxygen scavenging agent of the present invention may be in any dosage form such as an external skin preparation or an internal preparation, but from the viewpoint of effectively exerting the active oxygen scavenging action, a skin external preparation is preferable. .

When the active oxygen scavenging agent of the present invention is used as a skin preparation for external use, its shape is not particularly limited as long as it can be applied transdermally. paste) and the like.

In addition, when the active oxygen scavenging agent of the present invention is used as a skin external preparation, the formulation form is not particularly limited as long as it can be applied transdermally. and skin cleansing agents. When the active oxygen scavenging agent of the present invention is used as an external preparation for skin, specific formulation forms include creams, lotions, gels, emulsions, liquids, patches, aerosols, ointments, packs, and the like. external skin pharmaceuticals; creams, lotions, gels, emulsions, liquids, patches, aerosols, aerosols, ointments, packs, and other skin external quasi-drugs; creams, lotions, gels, emulsions , liquids, ointments, and packs; skin cleansers such as body shampoos, hair shampoos, and rinses; Among these formulation forms, pharmaceuticals for external use on the skin are preferred, and creams, lotions, gels, milky lotions and packs are more preferred.

Use/dosage The active oxygen scavenging agent of the present invention can eliminate active oxygen generated in the body and suppress the continuation of the state in which the active oxygen is excessively present in the body. Therefore, the active oxygen scavenging agent of the present invention is effective in preventing or treating diseases and symptoms in which excessive generation of active oxygen is one of the factors. For example, diseases and symptoms in which excessive generation of active oxygen is one of the factors and whose improvement can be expected by transdermal application include skin aging, sagging, dullness, acne, pimples, and atopic skin. Inflammation, rheumatism, stiff neck, etc. can be mentioned.

The dose of the active oxygen scavenging agent of the present invention may be appropriately set according to the dosage form, formulation form, degree of active oxygen scavenging action to be imparted, and the like. For example, when the active oxygen scavenging agent of the present invention is used as an external preparation for skin, an example of the dosage is about 0.01 to 0.08 mg of the heparinoid per 1 cm ² of skin per application. In terms of amount, the frequency may be about once to several times a day.

2. External Composition The present invention further provides an external composition comprising a heparinoid, ascorbic acids, and glycyrrhizic acids. The composition for external use of the present invention can exhibit a remarkably excellent active oxygen scavenging action through the interaction of these ingredients.

The types and contents of heparinoids, ascorbic acids, and glycyrrhizic acids used in the composition for external use of the present invention are as described in the section "1. Active oxygen scavenger".

In the composition for external use of the present invention, the types and contents of other ingredients that can be blended, and the formulation form are also as described in the section "1. Active oxygen scavenger".

In addition, the application of the composition for external use of the present invention is not particularly limited, and it may be used for any purpose as long as the effect can be recognized by transdermal application of the composition for external use of the present invention. Since the composition for external use of the present invention has dramatically improved active oxygen scavenging action, it can be suitably used for scavenging active oxygen. Specific aspects of the active oxygen scavenging application are as described in the section "1. Active oxygen scavenging agent" above.

EXAMPLES The present invention will be described in more detail with reference to examples below, but the present invention is not limited to these.

Test Example 1 Hyaluronic Acid Fragmentation Suppression Test Active oxygen scavenging activity was evaluated by a hyaluronic acid fragmentation inhibition test. In this test, active oxygen is generated in the ascorbic acid-iron (III) system in the presence of the test substance, hyaluronic acid is fragmented by the active oxygen, and residual hyaluronic acid is complexed with albumin and detected. This test method evaluates the active oxygen scavenging action of a substance. A specific test method is as follows.

To 0.3 M phosphate buffer (pH 5.3) containing 0.04% by weight of sodium hyaluronate, 0.5 ml of 0.3 M phosphate buffer containing a predetermined amount of test substance was added. Table 1 shows the type of test substance used and the concentration of the test substance after addition. Then, ascorbic acid was added to 1 mM and ferric chloride to 50 μM, and the mixture was incubated at 37° C. for 24 hours. After incubation, 0.2 ml of the solution was collected, and 2 ml of acetate buffer (pH 3.75) containing 0.1% by weight of albumin was added to form a complex of hyaluronic acid and albumin to obtain a turbidity of 600 nm (Esr ). Further, the test was conducted under the same conditions as above except that ascorbic acid and ferric chloride were not added, and the turbidity (Eso) at 600 nm was determined. Furthermore, except that sodium hyaluronate was not added, the test was conducted under the same conditions as above, and the turbidity (Eb) at 600 nm was determined. From the obtained turbidity values, the active oxygen suppression rate (%) was obtained according to the written calculation formula. In this test, the turbidity was measured six times under each condition, and the average value was substituted into the following formula to obtain the active oxygen suppression rate (%).

The results obtained are shown in FIG. As a result, it was confirmed that the heparin analogue (Example 1) has a superior active oxygen scavenging effect to ascorbic acid 2-glucoside (Reference Example 2). Moreover, when at least one of 2-glucoside ascorbate and dipotassium glycyrrhizinate was used in combination with the heparin analogue (Examples 2 to 4), the active oxygen scavenging action was dramatically enhanced. Although dipotassium glycyrrhizinate has not been reported to have an active oxygen scavenging effect, the results of Reference Example 3 confirmed that dipotassium glycyrrhizinate also has an active oxygen scavenging effect.

Formulation Examples Lotions shown in Table 2 (Formulation Examples 1 to 12), Creams shown in Table 3 (Formulation Examples 13 to 24), Gels shown in Table 4 (Formulation Examples 25 to 42), and emulsions shown in Table 5 Agents (formulation examples 43-54) were prepared. All of these formulations are expected to have an excellent active oxygen scavenging action, as in Test Example 1, and are effective for scavenging active oxygen. In Formulation Example 12, when sodium polyethylene sulfonate is blended in place of the heparin analogous substance, a similar active oxygen scavenging effect can be expected and is effective for scavenging active oxygen.

Claims (1)

An active oxygen scavenging agent containing a heparin-like substance as an active ingredient for scavenging active oxygen.

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