Active oxygen scavenger

Abstract

To provide an active oxygen scavenger capable of effectively scavenging active oxygen.SOLUTION: Glycyrrhizic acids (glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and / or salts thereof) have an excellent active oxygen scavenging action and can be used in an active oxygen scavenger.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an active oxygen scavenger. [Background technology]

[0002] When we breathe in oxygen from the air, reactive oxygen species (ROS) are generated within the body. ROS are released from white blood cells and play a vital role in fighting off bacteria and viruses within the body with their powerful bactericidal properties. Essentially, they play an important role in maintaining biological functions. However, their production is stimulated by external environmental factors such as ultraviolet light. A sustained excess of ROS can damage healthy cells and genes, leading to various symptoms and diseases. For example, persistent excess ROS in skin tissue is known to induce skin aging, sagging, dullness, acne, and pimples. Excessive ROS has also been reported to contribute to atopic dermatitis, rheumatism, and stiff shoulders.

[0003] Various topical skin preparations capable of scavenging active oxygen generated in skin tissue have been reported. For example, L-ascorbic acid, fullerene, tocopherol acetate, astaxanthin, anthocyanin, coenzyme Q10, lutein, etc., have the ability to scavenge active oxygen, and it is known that by incorporating these into topical skin preparations, they can be used to scavenge active oxygen.

[0004] It is also known that extracts of plants such as Anacyclus pyrethrum have the effect of scavenging active oxygen and can be incorporated into external compositions for the purpose of scavenging active oxygen (see Patent Document 1).

[0005] On the other hand, in recent years, consumer demands for improvements in the functionality and feel of topical skin preparations have increased, and there is a need to develop formulations that can meet these demands. Therefore, in the field of topical compositions used for scavenging active oxygen, there is a need to find new ingredients that can scavenge active oxygen and to develop new formulations that can be used for scavenging active oxygen. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Japanese Patent Application Laid-Open No. 2013-224318 Summary of the Invention [Problem to be solved by the invention]

[0007] An object of the present invention is to provide an active oxygen scavenger capable of effectively scavenging active oxygen. [Means for solving the problem]

[0008] The present inventors have conducted extensive research to solve the above problems and have found that glycyrrhizic acids (glycyrrhizic acid, glycyrrhetinic acid, their derivatives, and / or their salts) have excellent active oxygen scavenging activity. Furthermore, the present inventors have found that when glycyrrhizic acids are used in combination with heparinoids, the interaction between them dramatically improves the active oxygen scavenging activity. The present invention was completed through further research based on these findings.

[0009] That is, the present invention provides the following aspects. Item 1. An active oxygen scavenger containing at least one glycyrrhizinic acid selected from the group consisting of glycyrrhizinic acid, glycyrrhetinic acid, derivatives thereof, and salts thereof. Item 2. The active oxygen scavenger according to Item 1, wherein the glycyrrhizinic acid compound is glycyrrhizinic acid and / or a salt thereof. Item 3. The active oxygen scavenger according to Item 1 or 2, further comprising a heparinoid. Item 4. The active oxygen scavenger according to any one of Items 1 to 3, which is an external preparation for skin. [Effects of the Invention]

[0010] The reactive oxygen scavenger of the present invention can eliminate reactive oxygen generated in the body and improve or avoid the condition in which excessive reactive oxygen exists, and is therefore effective, for example, in preventing or treating skin diseases or skin symptoms caused by the generation of excessive reactive oxygen. [Brief explanation of the drawings]

[0011] [Figure 1] FIG. 1 shows the results of evaluating the active oxygen scavenging rate for each test substance in Test Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0012] 1. Active oxygen scavenger The active oxygen scavenger of the present invention is characterized by containing at least one glycyrrhizic acid compound selected from the group consisting of glycyrrhizinic acid, glycyrrhetinic acid, derivatives thereof, and salts thereof. The active oxygen scavenger of the present invention will be described in detail below.

[0013] Glycyrrhizic acids As will be shown in the test examples below, glycyrrhizic acids have been found to have excellent active oxygen scavenging properties.

[0014] Glycyrrhizic acid is a known drug known to have anti-inflammatory and anti-allergic effects.

[0015] The derivatives of glycyrrhizinic acid are not particularly limited as long as they are pharmaceutically acceptable, and specific examples include methyl glycyrrhizinate, stearyl glycyrrhizinate, etc. These derivatives of glycyrrhizinic acid may be used alone or in combination of two or more.

[0016] The salts of glycyrrhizinic 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, potassium salts, and dipotassium salts; ammonium salts, etc. These salts of glycyrrhizinic acid and its derivatives may be used alone or in combination of two or more.

[0017] Glycyrrhetinic acid is a known drug known to have anti-inflammatory and anti-allergic effects.

[0018] The derivatives of glycyrrhetinic acid are not particularly limited as long as they are pharmaceutically acceptable, but specific examples include pyridoxine glycyrrhetinate, stearyl glycyrrhetinate, glyceryl glycyrrhetinate, glycyrrhetinic acid monoglucuronide, etc. These derivatives of glycyrrhetinic acid may be used alone or in combination of two or more.

[0019] The 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, etc. These salts of glycyrrhetinic acid and its derivatives may be used alone or in combination of two or more.

[0020] As the glycyrrhizic acid, one may be selected and used from glycyrrhizic acid, salts of glycyrrhizic acid, derivatives of glycyrrhizic acid, salts of derivatives of glycyrrhizic acid, glycyrrhetinic acid, salts of glycyrrhetinic acid, derivatives of glycyrrhetinic acid, and salts of derivatives of glycyrrhetinic acid, or two or more may be used in combination.Among these glycyrrhizic acids, from the viewpoint of exhibiting a more excellent active oxygen scavenging effect, preferably glycyrrhizic acid, salts of glycyrrhizic acid, derivatives of glycyrrhizinic acid, more preferably salts of glycyrrhizinic acid, particularly preferably dipotassium glycyrrhizinate.

[0021] The content of glycyrrhizic acids in the active oxygen scavenger of the present invention may be appropriately determined depending on the level of active oxygen scavenging activity to be imparted, the formulation, etc., and may be, for example, 0.02 to 8 wt% in total of glycyrrhizic acids. From the viewpoint of exerting a more excellent active oxygen scavenging activity, the total amount of glycyrrhizic acids is preferably 0.02 to 5 wt%, more preferably 0.02 to 3 wt%.

[0022] Heparinoids The active oxygen scavenger of the present invention may further contain a heparinoid. Although it has not been reported that heparinoids have an active oxygen scavenging activity, the active oxygen scavenging activity can be dramatically improved by using heparinoids in combination with glycyrrhizic acids or glycyrrhizic acids and ascorbic acids.

[0023] Heparinoids are polysulfated mucopolysaccharides such as chondroitin polysulfate. The origin of the heparinoids used in the present invention is not particularly limited, and examples include those obtained by polysulfating mucopolysaccharides and those extracted from tissues of edible animals (e.g., lungs containing tracheal cartilage from cattle, pigs, etc.). In the active oxygen scavenger of the present invention, heparinoids listed in the Japanese Pharmacopoeia Non-Drug Standards are preferably used as the heparinoids.

[0024] When the active oxygen scavenger of the present invention contains a heparinoid, its content may be appropriately determined depending on the level of active oxygen scavenging activity to be imparted, the formulation, etc., and may be, for example, 0.05 to 1% by weight. From the viewpoint of further effectively improving the active oxygen scavenging activity, the content of the heparinoid is preferably 0.05 to 0.3% by weight, more preferably 0.1 to 0.3% by weight.

[0025] When the active oxygen scavenger of the present invention contains a heparinoid, the ratio of the heparinoid to the glycyrrhizinic acids is determined depending on the content of each of the above-mentioned components, but may be, for example, 0.5 to 1000 parts by weight of the heparinoid per 100 parts by weight of the total amount of glycyrrhizinic acids. From the viewpoint of further effectively improving the active oxygen scavenging effect, 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 glycyrrhizinic acids.

[0026] 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, its derivatives, and salts thereof. When an ascorbic acid is contained, the active oxygen scavenging effect can be improved by using it in combination with a glycyrrhizinic acid or a glycyrrhizinic acid and a heparinoid.

[0027] 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 monoalkyl esters such as ascorbic acid monostearate, ascorbic acid monopalmitate, and ascorbic acid monooleate; ascorbic acid monoesters such as ascorbic acid monophosphate and its magnesium salt; ascorbic acid dialkyl esters such as ascorbic acid distearate, ascorbic acid dipalmitate, and ascorbic acid dioleate; ascorbic acid diphosphate and its Examples of ascorbic acid diesters include ascorbic acid salts; trialkyl esters such as ascorbic acid tristearate, ascorbic acid tripalmitate, and ascorbic acid trioleate; ascorbic acid triesters such as ascorbic acid triphosphate; 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, and 3-O-ethyl, 6-beherminoyl ascorbic acid. These ascorbic acids and derivatives thereof may be in either the L- or D-form, with the L-form being preferred.

[0028] Furthermore, salts of ascorbic acid and its derivatives are not particularly limited as long as they are pharmaceutically or cosmetically acceptable, and examples thereof include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and the like.

[0029] As the ascorbic acid, one selected from ascorbic acid, ascorbic acid derivatives, salts of ascorbic acid, and salts of ascorbic acid derivatives may be used alone or in combination of two or more. Among these ascorbic acids, from the viewpoint of more effectively improving the active oxygen scavenging activity, preferred are ascorbic acid derivatives, and more preferred is ascorbic acid 2-glucoside.

[0030] When the active oxygen scavenger of the present invention contains ascorbic acids, the content thereof may be appropriately determined depending on the level of active oxygen scavenging activity to be imparted, the formulation, etc., and may be, for example, 0.1 to 10% by weight in total of ascorbic acids. From the viewpoint of further effectively improving the active oxygen scavenging activity, the total amount of ascorbic acids is preferably 0.3 to 8% by weight, more preferably 0.5 to 7% by weight.

[0031] When the active oxygen scavenger of the present invention contains ascorbic acids, the ratio of the ascorbic acids to the glycyrrhizic acids is determined depending on the content of each of the above-mentioned components, but may be, for example, 1 to 10,000 parts by weight of ascorbic acids per 100 parts by weight of glycyrrhizic acids. From the viewpoint of further effectively improving the active oxygen scavenging effect, 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 glycyrrhizic acids.

[0032] Other ingredients The active oxygen scavenger of the present invention may contain, in addition to the above-mentioned components, other pharmacological components, if necessary. Examples of such pharmacological ingredients include antihistamines (diphenhydramine, diphenhydramine hydrochloride, etc.), local anesthetics (procaine, tetracaine, bupipacaine, mepipacaine, chloroprocaine, proparacaine, meprylcaine or salts thereof, orthocaine, oxethazaine, oxypolyethylenediamine, Scopolia extract, percaminpase, tesitdesitin, etc.), anti-inflammatory agents (indomethacin, felbinac, diclofenac sodium, loxoprofen sodium, etc.), skin protectants (collodion, castor oil, etc.), blood circulation promoting ingredients (nonylic acid vanillylamide, nicotinic acid benzyl ester, capsaicin, chili pepper extract, etc.), cooling agents (menthol, camphor, etc.), vitamins (vitamin A, etc.), mucopolysaccharides (chondroitin sulfate sodium, glucosamine, etc.), etc.

[0033] Furthermore, the active oxygen scavenger of the present invention may contain base materials or additives as necessary to obtain a desired formulation. Such base materials and additives are not particularly limited as long as they are pharmaceutically acceptable, and examples thereof include aqueous bases such as 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 oils (liquid paraffin, paraffin, gelled hydrocarbon, petrolatum, etc.), waxes (beeswax, carnauba wax, candelilla wax, ceresin, rice wax, microcrystalline wax, etc.), ester oils (isopropyl myristate, azide), and the like. oily bases such as isopropyl pinate, 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, glyceryl tri-2-ethylhexanoate, cetyl 2-ethylhexanoate, silicone oil (dimethylpolysiloxane, cyclic silicone, etc.);Polyoxyethylene alkyl ethers such as 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, and their phosphoric acid salts (e.g., sodium POE cetyl ether phosphate), POE (20-60 mol) sorbitan monooleate, and POE (10-60 mol) sorbitan monoisostearate Surfactants such as 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 glycol monopalmitate, 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 esters (glycerin monostearate, etc.), hydrogenated soybean phospholipids, and hydrogenated lanolin alcohol;Cooling agents (menthol, camphor, borneol, peppermint water, peppermint oil, etc.), preservatives (methylparaben, propylparaben, benzoic acid, sodium benzoate, sorbic acid, etc.), flavoring agents (citral, 1,8-sionel, citronellal, farnesol, etc.), coloring agents (tar dyes (Brown No. 201, Blue No. 201, Yellow No. 4, Yellow No. 403, etc.), cocoa pigments, chlorophyll, aluminum oxide, etc.), thickeners (carboxyvinyl polymer, hypromellose, polyvinylpyrrolidone, sodium alginate, ethyl cellulose, sodium carboxymethylcellulose, xanthan gum, carrageenan, etc.), pH adjusters (phosphoric acid, hydrochloric acid, citric acid, sodium citrate) Examples of additives include cellulose, succinic acid, tartaric acid, sodium hydroxide, potassium hydroxide, triethanolamine, triisopropanolamine, etc.), wetting agents (sodium dl-pyrrolidonecarboxylate solution, D-sorbitol solution, macrogol, etc.), stabilizers (dibutylhydroxytoluene, butylhydroxyanisole, sodium edetate, sodium metaphosphate, L-arginine, L-aspartic acid, DL-alanine, glycine, sodium erythorbate, propyl gallate, sodium sulfite, sulfur dioxide, chlorogenic acid, catechin, rosemary extract, etc.), antioxidants, UV absorbers, chelating agents, adhesives, buffers, solubilizers, solubilizers, and preservatives;

[0034] The active oxygen scavenger of the present invention may be in the form of any of external preparations for skin and internal preparations, but from the viewpoint of effectively exerting the active oxygen scavenging action, external preparations for skin are preferred.

[0035] When the active oxygen scavenger of the present invention is used as a skin external preparation, its form is not particularly limited as long as it can be applied transdermally, and examples thereof include liquid, solid, and semi-solid forms (gel, ointment, paste, etc.).

[0036] In addition, when the active oxygen scavenger of the present invention is used as a topical skin preparation, its formulation is not particularly limited as long as it can be applied transdermally, and examples thereof include topical skin medicines, topical skin quasi-drugs, cosmetics, skin cleansers, etc. Specific examples of the formulation forms when the active oxygen scavenger of the present invention is used as a topical skin preparation include topical skin medicines such as creams, lotions, gels, emulsions, liquids, patches, aerosols, ointments, packs, etc.; topical skin quasi-drugs such as creams, lotions, gels, emulsions, liquids, patches, aerosols, ointments, packs, etc.; cosmetics such as creams, lotions, gels, emulsions, liquids, ointments, packs, etc.; skin cleansers such as body shampoos, hair shampoos, rinses, etc. Among these formulation forms, preferred are topical skin medicines, more preferred are creams, lotions, gels, emulsions, and packs.

[0037] Use / dose The reactive oxygen scavenger of the present invention can scavenge reactive oxygen generated in vivo and inhibit the persistence of excessive reactive oxygen in vivo. Therefore, the reactive oxygen scavenger of the present invention is effective in preventing or treating diseases or symptoms caused in part by the generation of excessive reactive oxygen. For example, diseases or symptoms caused in part by the generation of excessive reactive oxygen that can be expected to be improved by transdermal application include skin aging, sagging, dullness, acne, pimples, atopic dermatitis, rheumatism, stiff shoulders, etc.

[0038] The dose of the active oxygen scavenger of the present invention may be appropriately determined depending on the dosage form, preparation form, the degree of active oxygen scavenging effect to be imparted, etc. For example, when the active oxygen scavenger of the present invention is used as a skin external preparation, an example of the dose is 100mg / 10 ... 2 The total amount of glycyrrhizinic acids is about 0.005 to 0.3 mg per dose, and the frequency is about once to several times a day. [Example]

[0039] The present invention will be explained in more detail below by showing examples, but the present invention is not limited to these examples.

[0040] Test Example 1: Hyaluronic acid fragmentation inhibition test The active oxygen scavenging activity of the test substance was evaluated by a hyaluronic acid fragmentation inhibition test. In this test, active oxygen is generated in an ascorbic acid-iron (III) system in the presence of the test substance, and the active oxygen fragments hyaluronic acid. The remaining hyaluronic acid is then complexed with albumin and detected, thereby evaluating the active oxygen scavenging activity of the test substance. The specific test method is as follows.

[0041] 0.5 ml of 0.3 M phosphate buffer containing a predetermined amount of test substance was added to 0.3 M phosphate buffer (pH 5.3) containing 0.04 wt% sodium hyaluronate. The type of test substance used and the concentration of the test substance after addition are shown in Table 1. Next, 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 sampled and 2 ml of acetate buffer (pH 3.75) containing 0.1 wt% albumin was added to form a complex between hyaluronic acid and albumin, and the turbidity at 600 nm (Esr) was measured. Furthermore, the test was conducted under the same conditions as above, except that ascorbic acid and ferric chloride were not added, and the turbidity at 600 nm (Eso) was measured. Furthermore, the test was conducted under the same conditions as above, except that sodium hyaluronate was not added, and the turbidity at 600 nm (Eb) was measured. The active oxygen inhibition rate (%) was calculated from each turbidity value obtained according to the following formula: In this test, turbidity was measured six times under each condition, and the average value was substituted into the following formula to calculate the active oxygen inhibition rate (%).

[0042]

number

[0043] [Table 1]

[0044] The results obtained are shown in Figure 1. As a result, it was confirmed that dipotassium glycyrrhizinate has an excellent active oxygen scavenging effect (Example 1). Furthermore, when dipotassium glycyrrhizinate was used in combination with a heparinoid (Examples 2 and 4), the active oxygen scavenging effect was dramatically enhanced. Note that, although the active oxygen scavenging effect of heparinoids has not been reported previously, the results of Reference Example 3 confirmed that heparinoids also have an active oxygen scavenging effect superior to that of ascorbic acid 2-glucoside.

[0045] Prescription example Lotions (Formulation Examples 1 to 13) shown in Table 2, creams (Formulation Examples 14 to 26) shown in Table 3, gels (Formulation Examples 27 to 44) shown in Table 4, and emulsions (Formulation Examples 45 to 57) shown in Table 5 were prepared. As in Test Example 1, these preparations are expected to have excellent active oxygen scavenging activity and are effective for scavenging active oxygen.

[0046] [Table 2]

[0047] [Table 3]

[0048] [Table 4]

[0049] [Table 5]

[0050] In addition to the above-mentioned active oxygen scavenger, the present invention also provides, as a second invention, a pharmaceutical composition for excreting foreign substances. [Technical field]

[0051] The second present invention (hereinafter simply referred to as "the present invention") relates to a pharmaceutical composition for excreting foreign bodies. [Background technology]

[0052] Cold symptoms caused by viral infections are said to account for more than half of all colds in adults. Common cold symptoms include fever, cough, phlegm, and sore throat, and antipyretics, anti-inflammatory drugs, expectorants, and the like are commonly used to treat these cold symptoms. However, the use of these medicines is limited to symptomatic treatment (Non-Patent Document 1).

[0053] In addition, in medical settings, there are cases where antibiotics are prescribed to patients complaining of cold symptoms. However, it has been pointed out that the emergence of resistant bacteria due to overuse of antibiotics has already caused many adverse effects, and that antibiotics are not expected to be effective against viruses, so it has been pointed out that the use of antibiotics for colds needs to be reconsidered (Non-Patent Document 2).

[0054] On the other hand, inhibition of viral proliferation has been investigated as a way to treat cold symptoms (Patent Document 1, Non-Patent Document 3). [Prior art document] [Patent documents]

[0055] [Patent Document 1] Japanese Patent Application No. 2006-531959 [Non-patent literature]

[0056] [Non-patent document 1] Journal of the Japan Society of Cardiology 98: 424-428, 2009 [Non-patent document 2] Journal of the Japan Society of Cardiology 97: 190-199, 2008 [Non-patent document 3] Eur Respir J 2002; 19: 952-958 [Summary of the Invention] [Problem to be solved by the invention]

[0057] In order to more effectively prevent the worsening of cold symptoms, it is desirable not only to use symptomatic treatments or to suppress viral proliferation, but also to promote the expulsion of foreign substances that have entered the body through the mouth and / or nose.

[0058] Therefore, an object of the present disclosure is to provide a pharmaceutical product that promotes the excretion of foreign bodies. [Means for solving the problem]

[0059] As a result of extensive research, the present inventors have newly discovered that specific compound 1 has the effect of promoting the excretion of foreign substances. Furthermore, the present inventors have further discovered that the effect of promoting the excretion of foreign substances is dramatically improved by the combined use of at least one of specific compound 2, compound 3, and compound 4. The present invention was completed through further research based on these findings.

[0060] That is, the present disclosure provides the inventions of the following aspects. Item 1. A pharmaceutical composition for expelling foreign bodies, comprising a compound represented by the following formula (1) or a salt thereof: [ka] (In formula (1), X is independently a halogen group). Item 2. The pharmaceutical composition according to Item 1, further comprising an ingredient selected from the group consisting of a compound represented by the following formula (2) and a salt thereof, a compound represented by the following formula (3) and a salt thereof, and a compound represented by the following formula (4): [ka] [ka] [ka] (In formula (2), R is hydrogen or an alkyl group, and in formula (3), Y is a halogen group.) Item 3. The pharmaceutical composition according to Item 1 or 2, which is used for the excretion of rhinovirus. Item 4. The pharmaceutical composition according to any one of Items 1 to 3, which does not contain at least any one of an antipyretic analgesic and an expectorant other than the compound (1). Item 5. The pharmaceutical composition according to any one of Items 1 to 4, which is in the form of granules, fine granules, powders, capsules, lozenges, or tablets. [Effects of the invention]

[0061] The pharmaceutical composition of the present disclosure can promote the expulsion of foreign substances that have entered the body through the mouth and / or nose. [Mode for Carrying Out the Invention]

[0062] The pharmaceutical composition of the present disclosure is characterized by containing a specific compound and being used to excrete foreign bodies. The pharmaceutical composition of the present disclosure will be described in detail below. In this specification, a numerical range indicated by two numbers followed by "to" includes the two numbers as the lower and upper limits. For example, the expression "2 to 15% by weight" means 2% by weight or more and 15% by weight or less.

[0063] Compound (1) The pharmaceutical composition of the present disclosure contains, as an active ingredient, a compound represented by the following formula (1) (hereinafter also referred to as "compound (1)") and / or a salt thereof. [ka]

[0064] In formula (1), X is independently a halogen group (such as a fluoro group, a chloro group, a bromo group, or an iodo group).

[0065] The salt of compound (1) is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include inorganic acid salts such as hydrochloride, hydrobromide, and phosphate; and organic acid salts such as acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, and carbonate.

[0066] In the pharmaceutical composition of the present disclosure, as compound (1), one of the above compounds may be used alone, or multiple compounds may be used in combination. Preferably, compound (1) in the pharmaceutical composition of the present disclosure is a compound represented by the following formula (1a) (hereinafter also referred to as "compound (1a)"), in which all Xs in formula (1) are bromo groups, or a salt thereof, more preferably a salt of compound (1a), even more preferably an inorganic acid salt of compound (1a), and even more preferably a hydrochloride salt of compound (1a). [ka]

[0067] The content of compound (1) in the pharmaceutical composition of the present disclosure is not particularly limited and may be appropriately determined depending on the degree of foreign body expulsion effect to be imparted, the dosage form, etc., and may be, for example, 0.1 to 10 wt %, preferably 0.2 to 5 wt %, 0.3 to 3 wt %, more preferably 0.4 to 2 wt %, and even more preferably 0.4 to 1.5 wt %.

[0068] Compound (2) In order to enhance the foreign body excretion effect, the pharmaceutical composition of the present disclosure may further contain, as an active ingredient, a compound represented by the following formula (2) (hereinafter also referred to as "compound (2)") and / or a salt thereof. [ka]

[0069] In formula (2), R is hydrogen or an alkyl group, and the alkyl group is specifically an alkyl group having 1 to 4 carbon atoms (methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, sec-butyl group, or tert-butyl group). When R in formula (2) is an alkyl group, examples of compound (2) include those in which R preferably has 1 to 3 carbon atoms, more preferably has 1 or 2 carbon atoms, and even more preferably has an alkyl group having 1 carbon atom, and salts thereof.

[0070] The salt of compound (2) is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include inorganic acid salts such as hydrochloride, hydrobromide, and phosphate; and organic acid salts such as acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, and carbonate.

[0071] In the pharmaceutical composition of the present disclosure, as compound (2), one of the above compounds may be used alone, or multiple compounds may be used in combination. Particularly preferred compound (2) in the pharmaceutical composition of the present disclosure includes a compound represented by the following formula (2a) in which R in formula (2) is hydrogen (hereinafter also referred to as "compound (2a)") or a salt thereof, and a compound represented by the following formula (2b) in which R in formula (2) is a methyl group (hereinafter also referred to as "compound (2b)") or a salt thereof, more preferably compound (2b) or a salt thereof, even more preferably a salt of compound (2b), even more preferably an inorganic acid salt of compound (2b), and particularly preferably a hydrochloride salt of compound (2b).

[0072] [ka] [ka]

[0073] In the pharmaceutical composition of the present disclosure, the ratio of compound (1) to compound (2) is not particularly limited and may be appropriately set depending on the degree of the foreign body excretion effect to be imparted, etc., but preferably, the content of compound (2) per part by weight of compound (1) is, for example, 0.05 to 40 parts by weight, preferably 0.1 to 20 parts by weight, more preferably 0.5 to 10 parts by weight, even more preferably 0.7 to 5 parts by weight, and even more preferably 1 to 2 parts by weight.

[0074] The specific content of compound (2) in the pharmaceutical composition of the present disclosure is not particularly limited and may be appropriately determined depending on the degree of foreign body expulsion effect to be imparted, the formulation, etc., and may be, for example, 0.15 to 15 wt %, preferably 0.3 to 8 wt %, 0.5 to 5 wt %, more preferably 0.65 to 3 wt %, and even more preferably 0.65 to 2.5 wt %.

[0075] Compound (3) In order to enhance the foreign body excretion effect, the pharmaceutical composition of the present disclosure may further contain, as an active ingredient, a compound represented by the following formula (3) (hereinafter also referred to as "compound (3)") and / or a salt thereof. [ka]

[0076] In formula (3), Y is a halogen group (such as a fluoro group, a chloro group, a bromo group, or an iodo group).

[0077] The salt of compound (3) is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include inorganic acid salts such as hydrochloride, hydrobromide, and phosphate; and organic acid salts such as acetate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, and carbonate.

[0078] In the pharmaceutical composition of the present disclosure, as compound (3), one of the above compounds may be used alone, or multiple compounds may be used in combination. Preferably, compound (3) in the pharmaceutical composition of the present disclosure is a compound represented by the following formula (3a) in which Y in formula (3) is a chloro group (hereinafter also referred to as "compound (3a)") or a salt thereof, more preferably a salt of compound (3a), even more preferably an organic acid salt of compound (3a), and even more preferably a maleate salt of compound (3a). [ka]

[0079] In the pharmaceutical composition of the present disclosure, the ratio of compound (1) to compound (3) is not particularly limited and may be appropriately set depending on the degree of the foreign body excretion effect to be imparted, etc., but preferably, the content of compound (3) per part by weight of compound (1) is, for example, 0.005 to 4 parts by weight, preferably 0.01 to 2 parts by weight, more preferably 0.05 to 1 part by weight, even more preferably 0.07 to 0.5 parts by weight, and even more preferably 0.1 to 0.2 parts by weight.

[0080] The specific content of compound (3) in the pharmaceutical composition of the present disclosure is not particularly limited and may be appropriately determined depending on the degree of foreign body expulsion effect to be imparted, the dosage form, etc., and may be, for example, 0.015 to 2 wt %, preferably 0.03 to 1.5 wt %, 0.05 to 1 wt %, more preferably 0.065 to 0.5 wt %, and even more preferably 0.065 to 0.35 wt %.

[0081] Compound (4) From the viewpoint of enhancing the foreign body excretion effect, the pharmaceutical composition of the present disclosure may further contain a compound represented by the following formula (4) (hereinafter also referred to as "compound (4)") as an active ingredient. [ka]

[0082] In the pharmaceutical composition of the present disclosure, the ratio of compound (1) to compound (4) is not particularly limited and may be appropriately set depending on the degree of the foreign body excretion effect to be imparted, etc., but preferably, the content of compound (4) per part by weight of compound (1) is, for example, 0.5 to 400 parts by weight, preferably 1 to 200 parts by weight, more preferably 5 to 100 parts by weight, even more preferably 7 to 50 parts by weight, and even more preferably 10 to 20 parts by weight.

[0083] The specific content of compound (4) in the pharmaceutical composition of the present disclosure is not particularly limited and may be appropriately determined depending on the degree of foreign body expulsion effect to be imparted, the dosage form, etc., and may be, for example, 1.5 to 70 wt %, preferably 3 to 60 wt %, 5 to 50 wt %, more preferably 6.5 to 40 wt %, and even more preferably 6.5 to 30 wt %.

[0084] Combination of Compounds (2) to (4) In a preferred embodiment of the pharmaceutical composition of the present disclosure, the compound to be combined with compound (1) may be one of the three compounds, compound (2), compound (3), and compound (4), but from the viewpoint of further enhancing the foreign body excretion effect, it is preferably two compounds, and more preferably three compounds.

[0085] The content ratio of compound (2), compound (3), and compound (4) may be appropriately set depending on the degree of the foreign matter expelling effect to be imparted, and examples thereof include the following. The weight ratio of the content of compound (2) to compound (3) is, for example, 0.1 to 60:0.01 to 6, preferably 0.5 to 40:0.05 to 4, more preferably 1 to 20:0.1 to 2, even more preferably 4 to 18:0.4 to 1.8, still more preferably 6 to 14:0.6 to 1.4, still more preferably 8 to 12:0.8 to 1.2, and particularly preferably 9 to 11:0.9 to 1.1. The weight ratio of the content of compound (2) to compound (4) is, for example, 0.1 to 60:1 to 600, preferably 0.5 to 40:5 to 400, more preferably 1 to 20:10 to 200, even more preferably 4 to 18:40 to 180, still more preferably 6 to 14:60 to 140, still more preferably 8 to 12:80 to 120, and particularly preferably 9 to 11:90 to 110. The weight ratio of the content of compound (3) to compound (4) is, for example, 0.01 to 6:1 to 600, preferably 0.05 to 4:5 to 400, more preferably 0.1 to 2:10 to 200, even more preferably 0.4 to 1.8:40 to 180, still more preferably 0.6 to 1.4:60 to 140, still more preferably 0.8 to 1.2:80 to 120, and particularly preferably 0.9 to 1.1:90 to 110. The weight ratio of the contents of compound (2), compound (3), and compound (4) is, for example, 0.1 to 60:0.01 to 6:1 to 600, preferably 0.5 to 40:0.05 to 4:5 to 400, more preferably 1 to 20:0.1 to 2:10 to 200, even more preferably 4 to 18:0.4 to 1.8:40 to 180, still more preferably 6 to 14:0.6 to 1.4:60 to 140, still more preferably 8 to 12:0.8 to 1.2:80 to 120, and particularly preferably 9 to 11:0.9 to 1.1:90 to 110.

[0086] Other ingredients The pharmaceutical composition of the present disclosure may or may not contain other pharmacological ingredients, as needed, in addition to the aforementioned compound (1) and, if necessary, compound (2), compound (3), and / or compound (4), as long as the effects of the present invention are not impaired. The types of pharmacological ingredients that may or may not be contained are not particularly limited, and examples thereof include antacids, stomachics, digestives, intestinal regulators, antispasmodics, mucosal repair agents, antipyretics and analgesics (e.g., acetaminophen, loxoprofen or a salt thereof, ibuprofen, ethenzamide, aspirin or a salt thereof, salicylamide, sodium salicylate, salicylamide, lactylphenetidine, sazapirin, isopropylantipyrine, meloxicam or a salt thereof, etc.), astringents, antiemetics, antitussives, expectorants (e.g., Examples of pharmacological ingredients include: anti-inflammatory enzymes (e.g., lysozyme or a salt thereof, bromelain, serratiopeptidase, semi-alkaline proteinase, etc.), sedatives, hypnotics, antihistamines, anticholinergics, cardiotonic diuretics, antibacterial agents, vasoconstrictors, vasodilators, local anesthetics, herbal powders or herbal extracts, vitamins (e.g., tocopherol and / or its derivatives (organic acid esters such as acetate ester, nicotinate ester, succinate ester, and / or linoleate ester)), etc. When these pharmacological ingredients are used, they may be used alone or in combination of two or more. The content of these pharmacological ingredients may be appropriately determined depending on the type of pharmacological ingredient used and / or the dosage form of the pharmaceutical composition.

[0087] In a preferred embodiment of the pharmaceutical composition of the present disclosure, at least one of an antipyretic analgesic and an expectorant (other than compound (1)) among the other pharmacological ingredients may be excluded.

[0088] The pharmaceutical compositions of the present disclosure may or may not contain other pharmaceutically acceptable bases and / or additives, etc., as needed to prepare them into the desired dosage form. Examples of such other bases and additives, which may or may not be present, include excipients, binders, disintegrants, lubricants, isotonicity agents, plasticizers, dispersants, emulsifiers, solubilizers, wetting agents, stabilizers, suspending agents, adhesives, coating agents, glossing agents, water, oils and fats, waxes, hydrocarbons, fatty acids, higher alcohols, esters, water-soluble polymers, surfactants, metal soaps, lower alcohols, polyhydric alcohols, pH adjusters, buffers, antioxidants, UV protection agents, preservatives, flavoring agents, fragrances, powders, thickeners, dyes, chelating agents, etc. When these bases and / or additives are used, they may be used alone or in combination of two or more. The content of these bases and / or additives may be appropriately determined depending on the type of additive used and / or the dosage form of the pharmaceutical composition.

[0089] Formulation The dosage form of the pharmaceutical composition of the present disclosure is not particularly limited and may be either a liquid or a solid, but is preferably a solid. Specific examples of solids include tablets, lozenges, capsules, powders, fine granules, and granules (including dry syrup).

[0090] To prepare the pharmaceutical composition of the present disclosure into the above-mentioned dosage form, the compound (1) and, if necessary, the compound (2), the compound (3), the compound (4), and / or other ingredients may be formulated according to a conventional formulation method employed in the pharmaceutical field.

[0091] Purpose The pharmaceutical composition of the present disclosure is used for foreign body expulsion. In the present invention, foreign body expulsion refers to so-called airway clearance, specifically, the transport and elimination of foreign bodies inhaled from the outside world through the mouth and / or nose. Generally, effects that result in foreign body expulsion include reduced mucus production (e.g., inhibition of mucin production, inhibition of goblet cell metaplasia, etc.), activation of ciliary movement, surfactant increase (Nihon Nai Kai Zasshi 101:3525-3532, 2012), and promotion of IgA production (Nihon Otolaryngol 123:1247-1252, 2020). The foreign body expulsion effect of the pharmaceutical composition of the present disclosure is also achieved by one or more of these effects combined. When the pharmaceutical composition of the present disclosure contains compound (2), compound (3), and / or compound (4), the further improved foreign body excretion effect is not limited to this speculation, but is speculated to be largely contributed by one or more of the surfactant-increasing effect, the IgA production-promoting effect, and other effects.

[0092] Examples of foreign substances include at least one of viruses, bacteria, dust, and pollen. In the present disclosure, the device is preferably used for excretion of viruses, more preferably excretion of viruses that cause colds, and even more preferably excretion of rhinoviruses. In addition, in the present disclosure, the excreted viruses or bacteria include active viruses or live cells, and inactive viruses or dead cells.

[0093] Dosage / Usage The pharmaceutical composition of the present disclosure is used by oral administration. The dosage of the pharmaceutical composition of the present disclosure is appropriately determined depending on the age, sex, constitution, severity of symptoms, etc. of the subject to be administered. For example, the amount of compound (1) per day for one human (60 kg) is about 4.5 to 90 mg, preferably about 40 to 50 mg, and may be administered 1 to 3 times a day, preferably 2 or 3 times a day. [Example]

[0094] The present invention will be explained in more detail below by showing examples, but the present invention is not limited to these examples.

[0095] Mice (BALB / cAnNCrlCrlj) were allowed to acclimate for 8 days. Human rhinovirus 1B (B632) was inoculated into 1 × 10 9 TCID 50 / mL (1 × 10 8 TCID 50 A virus solution was prepared by adjusting the volume to 0.1 mL / body. Mice were anesthetized with isoflurane by inhalation, and the prepared virus solution was inoculated into both nostrils using a micropipette to infect them. The administration samples shown in Table 6 were prepared, and the resulting administration samples were orally administered twice a day at a dose of 10 mL / kg / day (N=6 per sample). The day of virus inoculation was designated Day 0, and the administration samples were orally administered daily from Day 0 to Day 2.

[0096] Bronchoalveolar lavage fluid (BALF) was collected on days 1 and 2 after oral administration. Viral RNA was purified from the collected BALF using the QIAamp Viral RNA mini Kit. cDNA was synthesized from the purified viral RNA using the PrimeScript RT reagent Kit. The viral RNA content of the synthesized cDNA was measured using TB Green Premix Ex Tag II, and the viral shedding rate was calculated from the average value using the following formula. The average viral shedding rate is shown in Table 6. (Calculation formula) Viral excretion rate (%) = (Viral load on Day 1 - Viral load on Day 2) / Day 1 * 100

[0097] [Table 6]

[0098] As shown in Table 6, it was confirmed that the virus excretion effect was improved by Examples 1 and 2. In particular, the virus excretion effect of Example 2 was significantly more pronounced.

[0099] The amount of MUC5AC (secretory mucin) in the BALF collected on Day 1 was measured using a "Mouse Mucin-5 Subtype AC (MUC5AC) ELISA kit." As a result, the average amount of MUC5AC in the BALF was 33.44 ng / mL in Comparative Example 1, 23.54 ng / mL in Example 1, and 24.62 ng / mL in Example 2. In other words, while it is possible that the expectorant effect due to the mucin reduction (reduced viscosity of airway secretions) contributed to virus excretion in Examples 1 and 2, the difference in expectorant effect due to the suppression of mucin production was small between Examples 1 and 2, and therefore the significant improvement in virus excretion in Example 2 is due in part to the expectorant effect due to the suppression of mucin production, as well as to the contribution of another effect.

[0100] Additionally, ciliary motility was evaluated using the administered samples shown in Table 6 using an animal model of upper respiratory tract inflammation. Guinea pigs (Slc: Hartley) were exposed to high-concentration sulfur dioxide gas (700-800 ppm) for 3 hours, and then orally administered the administered samples shown in Table 6. Two hours after the end of gas exposure, the animals were anesthetized and fixed to a stationary board so that the trachea was horizontal. The trachea was then exposed and incised vertically, and a drop of dye (Evans blue, 0.2 g / ml) was injected 1 cm from the lower end of the incision. The ciliary motility enhancement effect was evaluated by measuring the dye migration distance (mm) 1 minute after dye injection (N = 8 per sample). The average dye migration distance was 2.52 mm in Comparative Example 1, 4.21 mm in Example 1, and 4.76 mm in Example 2. In other words, while it is possible that the activation of ciliary movement contributed to virus excretion in Examples 1 and 2, the difference in the activation of ciliary movement between Examples 1 and 2 was small, and therefore the significant improvement in virus excretion in Example 2 is recognized to be due in part to the activation of ciliary movement, as well as to the contribution of another effect.

Claims

1. An active oxygen scavenger containing at least one glycyrrhizic acid compound selected from the group consisting of glycyrrhizic acid, glycyrrhetinic acid, derivatives thereof, and salts thereof.

2. 2. The active oxygen scavenger according to claim 1, wherein the glycyrrhizinic acid compound is glycyrrhizinic acid and / or a salt thereof.

3. The active oxygen scavenger according to claim 1 or 2, further comprising a heparinoid.

4. The active oxygen scavenger according to any one of claims 1 to 3, which is an external preparation for skin.

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