JP2019006697A - Active oxygen scavenger - Google Patents

Abstract

To provide an active oxygen scavenger that can effectively scavenge active oxygen.SOLUTION: A glycyrrhizinic acid (glycyrrhizinic acid, glycyrrhetinic acid, derivatives thereof, and/or salts thereof) has an excellent active oxygen scavenging action, and can be used for an active oxygen scavenger.SELECTED DRAWING: None

Description

  The present invention relates to an active oxygen scavenger.

  When oxygen in the air is taken into the body by breathing, active oxygen is generated in the body. Active oxygen is released from leukocytes 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 production of active oxygen is promoted by external environmental factors such as ultraviolet rays, and if the state of excessive presence of active oxygen persists, it damages normal cells and genes and induces various symptoms and diseases . For example, it is known that symptoms such as skin aging, sagging, dullness, acne, and pimples are induced when a state in which active oxygen is excessively present in the skin tissue continues. It has been reported that excessive active oxygen is also involved in the induction of atopic dermatitis, rheumatism, stiff shoulders, and the like.

  Conventionally, various skin external preparations that can eliminate active oxygen generated in skin tissue have been reported. For example, L-ascorbic acid, fullerene, tocopherol acetate, astaxanthin, anthocyanin, coenzyme Q10, lutein, and the like have an action of scavenging active oxygen. It is known that it can be used.

  It is also known that plant extracts such as Anakikurusu and Pireturum have an action of scavenging active oxygen and can be used by blending with an external composition for the purpose of scavenging active oxygen (see Patent Document 1). ).

  On the other hand, in recent years, consumer demand for improvements in functionality, usability, etc. of external preparations for skin has increased, and development of a pharmaceutical formulation capable of following consumer demands has been demanded. Accordingly, in the field of compositions for external use used for the purpose of eliminating active oxygen, a new ingredient capable of eliminating active oxygen has been found, and development of a new pharmaceutical formulation that can be used for the purpose of eliminating active oxygen has been demanded.

JP 2013-224318 A

  An object of the present invention is to provide an active oxygen scavenger capable of effectively scavenging active oxygen.

  As a result of intensive studies to solve the above problems, the present inventors have found that glycyrrhizic acids (glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof and / or salts thereof) have an excellent active oxygen scavenging action. I found. Furthermore, the present inventors have found that when glycyrrhizic acids and heparin-like substances are used in combination, the active oxygen scavenging action is dramatically improved by these interactions. The present invention has been completed by further studies based on these findings.

That is, this invention provides the invention of the aspect hung up below.
Item 1. An active oxygen scavenger containing at least one glycyrrhizic acid selected from the group consisting of glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and salts thereof.
Item 2. Item 2. The active oxygen scavenger according to Item 1, wherein the glycyrrhizic acids are glycyrrhizic acid and / or a salt thereof.
Item 3. Item 3. The active oxygen scavenger according to Item 1 or 2, further comprising a heparin-like substance.
Item 4. Item 4. The active oxygen scavenger according to any one of Items 1 to 3, which is a skin external preparation.

  According to the active oxygen scavenger of the present invention, the active oxygen generated in the body can be erased, and the state where the active oxygen is excessively present can be improved or avoided. For example, the generation of excess active oxygen is one of the factors. It is effective for the prevention or treatment of skin diseases and skin symptoms.

In Experiment 1, it is a figure which shows the result of having evaluated the active oxygen elimination rate about each test substance.

1. Active oxygen scavenger The active oxygen scavenger of the present invention contains at least one glycyrrhizic acid selected from the group consisting of glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and salts thereof. Hereinafter, the active oxygen scavenger of the present invention will be described in detail.

Glycyrrhizic acids As shown in the test examples described later, glycyrrhizic acids have been found to have an excellent active oxygen scavenging action.

  Glycyrrhizic acid is a known drug known to have an anti-inflammatory action, an antiallergic action, 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 glycyrrhizic acid derivatives may be used alone or in combination of two or more.

  The salt of glycyrrhizic acid and its derivative is not particularly limited as long as it is pharmacologically acceptable, and specific examples include alkali metal salts such as sodium salt, potassium salt, dipotassium salt; ammonium salt and the like. . These salts of glycyrrhizic acid and its derivatives may be used alone or in combination of two or more.

  Glycyrrhetinic acid is a known drug known to have an anti-inflammatory action, an antiallergic action, 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, monoglucuronide glycyrrhetinate, and the like. These glycyrrhetinic acid derivatives may be used alone or in combination of two or more.

  The salt of glycyrrhetinic acid and its derivative is not particularly limited as long as it is pharmacologically acceptable, and specific examples include alkali metal salts such as sodium salt and potassium salt; ammonium salt and the like. These salts of glycyrrhetinic acid and its derivatives may be used alone or in combination of two or more.

  As glycyrrhizic acids, one of glycyrrhizic acid, glycyrrhizic acid salt, glycyrrhizic acid derivative, glycyrrhizic acid derivative salt, glycyrrhetinic acid, glycyrrhetinic acid salt, glycyrrhetinic acid derivative, and glycyrrhetinic acid derivative salt, one kind May be selected and used, or two or more may be used in combination. Among these glycyrrhizic acids, from the viewpoint of exerting a more excellent active oxygen scavenging action, preferably glycyrrhizic acid, a salt of glycyrrhizic acid, a derivative of glycyrrhizic acid, more preferably a salt of glycyrrhizic acid, particularly preferably glycyrrhizic acid Dipotassium is mentioned.

  The content of glycyrrhizic acids in the active oxygen scavenger of the present invention may be appropriately set according to the degree of active oxygen scavenging action to be imparted, the formulation form, etc., for example, 0.02 to 0.02 in terms of the total amount of glycyrrhizic acids 8% by weight is mentioned. From the viewpoint of exhibiting a more excellent 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.

Heparin-like substance The active oxygen scavenger of the present invention may further contain a heparin-like substance. Although heparin-like substances have not been reported to have an active oxygen scavenging action, the active oxygen scavenging action is dramatically improved by the combined use with glycyrrhizic acids, or with glycyrrhizic acids and ascorbic acids. be able to.

  A heparin-like substance is a polysulfated mucopolysaccharide such as chondroitin polysulfate. The origin of the heparin-like substance used in the present invention is not particularly limited. For example, it is obtained by polysulfating mucopolysaccharides, tissues of edible animals (for example, tracheal cartilage such as cattle and pigs) And the like extracted from the lung including In the active oxygen scavenger of the present invention, as the heparin-like substance, a heparin-like substance included in the Japanese Pharmacopoeia Pharmaceutical Standards is preferably used.

  When the active oxygen scavenger of the present invention contains a heparin-like substance, the content may be appropriately set according to the degree of active oxygen scavenging action to be imparted, the formulation form, etc. 05 to 1% by weight. From the viewpoint of more effectively improving the active oxygen scavenging action, the heparin-like substance content is preferably 0.05 to 0.3% by weight, more preferably 0.1 to 0.3% by weight. It is done.

  When the active oxygen scavenger of the present invention contains a heparin-like substance, the ratio of the heparin-like substance to the glycyrrhizic acid is determined according to the content of each component described above. For example, the total amount of glycyrrhizic acids is 100 parts by weight. The heparin-like substance per hit is 0.5 to 1000 parts by weight. From the viewpoint of further effectively improving the active oxygen scavenging action, the total amount of ascorbic acids is preferably 10 to 500 parts by weight, more preferably 50 to 200 parts by weight, per 100 parts by weight of the total amount of glycyrrhizic acids. .

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 included, the active oxygen scavenging action can be improved by using in combination with glycyrrhizic acids or using in combination with glycyrrhizic acids and heparin-like substances.

  The ascorbic acid and derivatives thereof used in the present invention are not particularly limited as long as they are pharmaceutically or cosmetically acceptable, and examples thereof include ascorbic acid; ascorbic acid 2-glucoside; ascorbic acid monostearate Ascorbic acid monopalmitate, ascorbic acid monoalkyl esters such as ascorbic acid monooleate; ascorbic acid monoesters such as ascorbic acid monophosphate and its magnesium salt; Acid dialkyl esters; ascorbic acid diesters such as ascorbic acid diphosphate and its salts; ascorbic acid tristearate, ascorbic acid tripalmitate, ascorb Trialkyl esters such as acid triolate; Ascorbic acid triesters such as ascorbic acid triphosphate; 3-O-ethyl, 6-acetyl-ascorbic acid, 3-O-ethyl, 6-butylascorbic 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-beherminoyl-ascorbic acid, etc. are mentioned. These ascorbic acid and derivatives thereof may be either L-form or D-form, and preferably L-form.

  Further, the salt of ascorbic acid and its derivatives is not particularly limited as long as it is pharmaceutically or cosmetically acceptable. For example, alkali metal salts such as sodium salt and potassium salt; calcium salt and magnesium salt And alkaline earth metal salts.

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

  When the ascorbic acids are included in the active oxygen scavenger of the present invention, the content thereof may be appropriately set according to the degree of active oxygen scavenging action to be imparted, the formulation form, etc. The total amount is 0.1 to 10% by weight. 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 scavenger of the present invention contains ascorbic acid, the ratio of ascorbic acid to glycyrrhizic acid is determined according to the content of each component described above, for example, per 100 parts by weight of the total amount of glycyrrhizic acid, Ascorbic acids are 1 to 10,000 parts by weight in total. From the viewpoint of more effectively improving the active oxygen scavenging action, the total amount of ascorbic acids is preferably 500 to 4000 parts by weight, more preferably 1500 to 2500 parts by weight per 100 parts by weight of the total amount of glycyrrhizic acids. .

Other Components The active oxygen scavenger of the present invention may contain other pharmacological components as necessary in addition to the components described above. Examples of such pharmacological components include antihistamines (diphenhydramine, diphenhydramine hydrochloride, etc.), local anesthetics (procaine, tetracaine, bupipacaine, mepipacaine, chloroprocaine, propalacaine, meprilucaine or salts thereof, orthocaine, oxesasein, oxypolyentoxy Decane, funnel extract, percaminpase, tesit decite, etc.), anti-inflammatory agents (indomethacin, felbinac, diclofenac sodium, loxoprofen sodium, etc.), skin protectants (collodion, castor oil, etc.), blood circulation promoting components (nonyl acid vanillylamide, nicotinic acid benzyl ester) , Capsaicin, pepper extract, etc.), refreshing agents (menthol, camphor, etc.), vitamins (vitamin A, etc.), mucopolysaccharides (chondroy) Sodium emission sulfate, glucosamine, etc.) and the like.

  Moreover, the active oxygen scavenger of this invention may contain the base material and the additive as needed in order to make a desired formulation form. Such bases and additives are not particularly limited as long as they are pharmaceutically acceptable. For example, water, lower alcohols (ethanol, isopropanol, etc.), polyhydric alcohols (glycerin, propylene glycol, dipropylene) Aqueous bases such as glycol and 1,3-butylene glycol; 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, gelled hydrocarbon, petroleum jelly, etc.), waxes and waxes (honey bees, carnauba wax, candelilla wax, ceresin, rice wax, microcrystalline wax, etc.), ester oil (isopropyl myristate) , Isopropyl adipate, sebacic acid Ethyl, 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 (palmitic acid) Cetyl, isopropyl palmitate, ethyl linoleate, etc.), higher alcohols (stearyl alcohol, cetanol, behenyl alcohol, myristyl alcohol, oleyl alcohol, hexadecyl alcohol, lanolin alcohol, etc.), cholesterol, glyceryl tri-2-ethylhexanoate, 2-ethyl Oily bases such as cetyl hexanoate, silicone oil (dimethylpolysiloxane, cyclic silicone, etc.); POE (10-50 mol) phytosterol ether, POE ( 0-50 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) polyoxyethylene alkyl ethers such as cetyl ether, phosphoric acid / phosphate thereof (such as POE cetyl ether sodium phosphate), 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), glycerin fatty acid ester (glyceryl monostearate, etc.), hydrogenated soybean phospholipid, hydrogenated lanoli Surfactants such as alcohol; refreshing agents (menthol, camphor, borneol, mint water, mint oil, etc.), preservatives (methylparaben, propylparaben, benzoic acid, sodium benzoate, sorbic acid, etc.), flavoring agents (citral) , 1,8-shioner, citronellal, farnesol, etc.), coloring agent (tar pigment (brown 201, blue 201, yellow 4, yellow 403, etc.), cacao pigment, chlorophyll, aluminum oxide, etc.), thickener (Carboxyvinyl polymer, hypromellose, polyvinylpyrrolidone, sodium alginate, ethyl cellulose, sodium carboxymethylcellulose, xanthan gum, carrageenan, etc.), pH adjuster (phosphoric acid, hydrochloric acid, citric acid, sodium citrate, succinic acid, tartaric acid, sodium hydroxide, Hydroxy Potassium, triethanolamine, triisopropanolamine, etc.), wetting agents (sodium dl-pyrrolidonecarboxylate, D-sorbitol, macrogol, etc.), stabilizers (dibutylhydroxytoluene, butylhydroxyanisole, sodium edetate, metalin) Acid sodium, L-arginine, L-aspartic acid, DL-alanine, glycine, sodium erythorbate, propyl gallate, sodium sulfite, sulfur dioxide, chlorogenic acid, catechin, rosemary extract, etc.), antioxidant, UV absorption Additives such as agents, chelating agents, pressure-sensitive adhesives, buffers, solubilizers, solubilizers, preservatives, etc.

  The active oxygen scavenger of the present invention may be in any dosage form such as a topical skin preparation or an internal preparation, but preferably a skin external preparation from the viewpoint of effectively exhibiting the active oxygen scavenging action. .

  When the active oxygen scavenger of the present invention is used as a skin external preparation, its shape is not particularly limited as long as it can be applied transdermally. For example, liquid, solid, semi-solid (gel, ointment, Paste) and the like.

  In addition, when the active oxygen scavenger 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. For example, a skin external medicine, a skin external medicine, a cosmetic And skin cleansing materials. As a preparation form when the active oxygen scavenger of the present invention is used as an external preparation for skin, specifically, creams, lotions, gels, emulsions, solutions, patches, aerosols, ointments, packs, etc. Skin external medicines: creams, lotions, gels, emulsions, solutions, patches, aerosols, ointments, packs, etc .; external quasi-drugs such as creams, lotions, gels, emulsions And cosmetics such as liquids, ointments and packs; and skin cleansing agents such as body shampoos, hair shampoos and rinses. Among these preparation forms, preferably a skin external medicine, more preferably a cream, a lotion, a gel, an emulsion, or a pack.

Use / Dose The active oxygen scavenger of the present invention can eliminate active oxygen generated in the living body and suppress the persistence of the excessive presence of active oxygen in the living body. Therefore, the active oxygen scavenger of the present invention is effective for the prevention or treatment of diseases and symptoms caused by excessive generation of active oxygen. For example, skin aging, sagging, dullness, acne, pimples, atopic skin are the diseases and symptoms that are caused by the generation of excessive active oxygen and can be expected to be improved by transdermal application. Examples include flame, rheumatism, and stiff shoulders.

What is necessary is just to set suitably about the dosage of the active oxygen scavenger of this invention according to a dosage form, a formulation form, the grade of the active oxygen scavenging action which should be provided, etc. For example, when the active oxygen scavenger of the present invention is used as an external preparation for skin, as an example of the dose, the total amount of glycyrrhizic acids is about 0.005 to 0.3 mg per 1 cm ^{2 of} skin per one time. The amount is about 1 to several times a day.

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

Test Example 1: Hyaluronic acid fragmentation inhibition test The active oxygen scavenging action 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 with active oxygen, and the remaining hyaluronic acid is complexed with albumin and detected. This test method evaluates the active oxygen scavenging action of a substance. The specific test method is as follows.

  0.5 ml of 0.3 M phosphate buffer containing a predetermined amount of a test substance was added to 0.3 M phosphate buffer (pH 5.3) containing 0.04 wt% sodium hyaluronate. The types of test substances used and the concentrations of test substances after addition are as shown in Table 1. Subsequently, ascorbic acid was added to 1 mM and ferric chloride to 50 μM, and the mixture was incubated at 37 ° C. for 24 hours. 0.2 ml of the solution after the incubation 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, and a turbidity of 600 nm (Esr ) Further, a test was performed under the same conditions as described above except that ascorbic acid and ferric chloride were not added, and a turbidity (Eso) of 600 nm was obtained. Furthermore, a test was performed under the same conditions as above except that sodium hyaluronate was not added, and a turbidity (Eb) of 600 nm was obtained. From the obtained turbidity values, the active oxygen suppression rate (%) was determined according to the formula for writing. In this test, the turbidity was measured 6 times under each condition, and the average value was substituted into the following formula to determine the active oxygen suppression rate (%).

  The obtained results are shown in FIG. As a result, it was confirmed that dipotassium glycyrrhizinate has an excellent active oxygen scavenging action (Example 1). Moreover, when a heparin analog was used together with dipotassium glycyrrhizinate (Examples 2 and 4), the active oxygen scavenging action was dramatically increased. Conventionally, no active oxygen scavenging action has been reported for heparin-like substances, but the results of Reference Example 3 confirmed that heparin-like substances also have an active oxygen scavenging action that surpasses ascorbic acid 2-glucoside. .

Formulation Examples Lotions (Prescription Examples 1 to 13) shown in Table 2, Creams (Prescription Examples 14 to 26) shown in Table 3, Gels (Prescription Examples 27 to 44) shown in Table 4, and Emulsions shown in Table 5 Agents (Prescription Examples 45 to 57) were prepared. As in the case of Test Example 1, these preparations are expected to have an excellent active oxygen scavenging action and are effective for active oxygen scavenging applications.

Claims (4)

  An active oxygen scavenger containing at least one glycyrrhizic acid selected from the group consisting of glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and salts thereof.   The active oxygen scavenger according to claim 1, wherein the glycyrrhizic acids are glycyrrhizic acid and / or a salt thereof.   The active oxygen scavenger according to claim 1 or 2, further comprising a heparin-like substance.   The active oxygen scavenger according to any one of claims 1 to 3, which is a skin external preparation.