JP7329910B2 - Skin topical composition - Google Patents

Description

TECHNICAL FIELD The present invention relates to an external skin composition containing diphenhydramine and/or a salt thereof and having an improved antipruritic effect.

Diphenhydramines such as diphenhydramine hydrochloride are known to be capable of suppressing the action of histamine, which causes allergic symptoms such as itching of the skin, and are used as antihistamines in pharmaceuticals or quasi-drugs for topical skin preparations. . For example, Patent Document 1 discloses therapeutic effects on eczema, dermatitis, insect bites, itching, heat rash, rashes, hives, etc. containing prednisolone valerate acetate and an antihistamine such as diphenhydramine and its salts as active ingredients. A topical skin preparation having

Ufenamate is used as a non-steroidal anti-inflammatory agent by being blended in pharmaceuticals or quasi-drugs for external use on the skin. For example, Patent Document 2 discloses that an emulsified composition for external use on the skin in which heparin is blended with ufenamate exhibits an excellent anti-inflammatory effect.

JP-A-2002-356430 JP 2015-199709 A

A topical skin preparation containing a diphenhydramine compound has an effect on skin itching due to its antihistaminic effect (hereinafter simply referred to as "antipruritic effect", and the property of producing an antipruritic effect is also referred to as "antipruritic"). However, there is a demand for the development of other useful means with a further enhanced antipruritic effect.

An object of the present invention is to provide a composition for external use on the skin with a further enhanced antipruritic effect.

As a result of intensive studies, the present inventor found that ufenamate was added to an external composition for skin containing diphenhydramine and/or a salt thereof (hereinafter also referred to as "diphenhydramines"). A surprising finding was found that the antipruritic effect is improved although it is not an ingredient. The present invention was completed by further studies based on this finding.

That is, the present invention provides inventions in the following aspects.
Section 1. An external skin composition containing (A) diphenhydramine and/or a salt thereof and (B) ufenamate.
Section 2. Item 1. The external composition for skin according to Item 1, which is used for antipruritic purposes.
Item 3. (A) A method for improving an antipruritic effect in an external skin composition containing diphenhydramine and/or a salt thereof,
A method for improving an antipruritic effect, comprising blending (B) ufenamate together with the component (A) in a composition for external use on the skin.

The antipruritic effect of the external skin composition of the present invention can be improved by blending ufenamate with diphenhydramines.

4 shows the results of the pruritus test in Test Example 1. FIG.

1. External Skin Composition The external skin composition of the present invention comprises (A) diphenhydramines (hereinafter also referred to as "(A) component") and (B) ufenamate (hereinafter also referred to as "(B) component"). It is characterized by containing The composition for external use on skin of the present invention will be described in detail below.

(A) Diphenhydramine and/or its salt The composition for external use on skin of the present invention contains diphenhydramine and/or its salt as component (A). Diphenhydramine is a known drug known to have antihistamine properties. Since component (A) alone takes time to develop an antipruritic effect, it does not produce an effective antipruritic effect in the initial stage after application of the composition for external use to the skin, and even worsens itching. can rapidly exhibit effective pruritic properties.

The salt of diphenhydramine is not particularly limited as long as it is pharmaceutically acceptable. Specific examples include hydrochloride, citrate, succinate, tartrate, fumarate, maleate, and salicylate. , diphenyldisulfonate, tannate, lauryl sulfate, and acid addition salts such as sulfate. These salts may be used singly or in combination of two or more.

In the composition for external use on skin of the present invention, one of diphenhydramine and salts thereof may be selected and used, or two or more thereof may be used in combination.

The content of the component (A) in the composition for external use on the skin of the present invention may be appropriately set according to the efficacy to be imparted. to 3% by weight, more preferably 0.1 to 2% by weight.

(B) Ufenamate The external composition for skin of the present invention contains ufenamate as the component (B). Ufenamate, also called butyl flufenamate, is an ingredient known as a fat-soluble non-steroidal anti-inflammatory drug. Ufenamate by itself does not exert an effective antipruritic effect, and rather has an effect of exacerbating the antipruritic effect in the initial stage after application. Due to this, the drawback of component (A) alone (that is, it takes time to develop an antipruritic effect, does not produce effective antipruritic properties at the initial stage of application of the external composition for skin, and rather exacerbates itching. It is possible to quickly exhibit effective pruritic properties.

In the external composition for skin of the present invention, the content of ufenamate is appropriately set according to the efficacy to be imparted, and is, for example, 1 to 20% by weight. is preferably 2 to 10% by weight, and more preferably 3 to 7% by weight, from the viewpoint of more effectively exhibiting.

In the composition for external use on skin of the present invention, the ratio of component (B) to component (A) is determined according to the respective contents of component (A) and component (B). Component (B) is, for example, 0.5 to 30 parts by weight per part by weight. From the viewpoint of exhibiting antipruritic properties more effectively, the amount is preferably 0.8 to 20 parts by weight, more preferably 1 to 15 parts by weight, per 1 part by weight of component (A).

Other Ingredients The composition for external use on skin of the present invention may contain other pharmacological ingredients in addition to the ingredients described above, if necessary. Examples of such pharmacological components include antihistamines (chlorpheniramine maleate, etc.), local anesthetics (lidocaine, dibucaine, procaine, tetracaine, bupipacaine, mepipacaine, chloroprocaine, proparacaine, meprilcaine or salts thereof, benzoic acid, Alkyl esters (e.g. ethyl aminobenzoate, diethylaminoethyl p-butylaminobenzoate hydrochloride), orthocaine, oxethazein, oxypolyethoxydecane, rot extract, percaminepase, tecittodecitin, etc.), anti-inflammatory agents (glycyrrhetinic acid, glycyrrhetinate, allantoin, Salicylic acid, glycol salicylate, methyl salicylate, indomethacin, felbinac, diclofenac sodium, loxoprofen sodium, etc.), fungicides (zinc oxide, benzalkonium chloride, decalinium chloride, benzethonium chloride, cetylpyridinium chloride, isopropylmethylphenol, chlorhexidine hydrochloride, gluconic acid) chlorhexidine, aqueous ammonia, sulfadiazine, lactic acid, phenol, etc.), antipruritic agents (crotamiton, thianthol, etc.), skin protectants (collodion, castor oil, etc.), blood circulation-promoting ingredients (nonylic acid vanillylamide, benzyl nicotinate, capsaicin, red pepper extract) etc.), cooling agents (menthol, camphor, etc.), vitamins (vitamins A, B, C, D, etc.), mucopolysaccharides (sodium chondroitin sulfate, hyaluronic acid, etc.) and the like.

Among these other pharmacological ingredients, it is preferable not to contain crotamiton from the viewpoint of preventing rashes and/or from the viewpoint of preventing exacerbation of pruritus due to a slight burning sensation (warm sensation) upon application. From the viewpoint of effectively obtaining the antipruritic effect of component B), it is preferred that glycyrrhetinic acid and glycyrrhetinate are not included.

In addition to the components described above, other bases and additives commonly used for external preparations for skin may be included, if necessary. Such base materials and additives are not particularly limited as long as they are pharmaceutically acceptable. , 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, vaseline, 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-ethylhexane Oily bases such as glyceryl acid, cetyl 2-ethylhexanoate, silicone oil (dimethylpolysiloxane, cyclic silicone, etc.); POE (10 to 50 mol) phytosterol ether, POE (10 to 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) Polyoxyethylene alkyl such as behenyl ether, POE (5-30 mol) polyoxypropylene (5-30 mol) 2-decyltetradecyl ether, POE (10-50 mol) polyoxypropylene (2-30 mol) cetyl ether 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 to 30 mol) glyceryl monostearate, POE (20 to 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) ), 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 ( methylparaben, propylparaben, benzoic acid, sodium benzoate, sorbic acid, etc.), flavoring agents (citral, 1,8-cionell, 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.), thickeners (carboxyvinyl polymer, hypromellose, polyvinylpyrrolidone, sodium alginate, ethyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, xanthan gum, carrageenan, etc.), pH adjuster (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 acid, sodium sulfite, sulfur dioxide, chlorogenic acid, catechin, rosemary extract, etc.), antioxidants, UV absorbers, chelating agents, adhesives, buffers, solubilizers, solubilizers, preservatives, etc. Additives are included.

Properties, Formulations, etc. The properties of the composition for external use on the skin of the present invention are not particularly limited, and include aqueous liquid compositions, aqueous gel compositions, oily gel compositions, emulsion compositions, and the like. Among these, from the viewpoint of formulation stability, preferred are aqueous gel compositions, oily gel compositions, and emulsion compositions, and more preferred are emulsion compositions. The emulsified state of the emulsified composition may be either an oil-in-water type or a water-in-oil type, but the oil-in-water type is preferred from the viewpoint of feeling during use such as suppression of stickiness.

The formulation form of the external composition for skin of the present invention is not particularly limited, and examples thereof include lotions, emulsions, ointments, creams and the like. Among these, emulsions and creams are preferred from the viewpoint of formulation stability.

Specific examples of the composition for external use on the skin of the present invention include pharmaceuticals, quasi-drugs, cosmetics and the like. Among these dosage forms, pharmaceuticals and quasi-drugs are preferred.

Method of use The external composition for skin of the present invention can be used for antipruritic purposes, and is used by applying it to the part of the skin where itching is felt or the part of the skin where itching is to be prevented. There are no particular limitations on the skin symptoms at the skin site to which the composition for external use of the present invention is applied, as long as it causes itching, but it is preferably applied to redness and eczema. Such redness and eczema are preferably skin symptoms caused by dampness, friction/irritation, weight bearing, and the like.

The site of the skin to which the composition for external use of the present invention is applied is not particularly limited as long as it is a site accompanied by itching, preferably the site where the aforementioned redness or eczema is likely to occur. Specific examples include the buttocks and thighs, more preferably the vicinity of the boundary between the buttocks and thighs, which are likely to be repeatedly subjected to stuffiness, friction/irritation, weight bearing, and the like.

The composition for external use on the skin of the present invention can be applied by applying, for example, 0.1 to 0.5 g per 100 cm ² of skin once or twice a day.

On the skin site to which the composition for external use of the present invention is applied, an antipruritic effect is rapidly produced, and furthermore, along with preventing the itching stimulus, together with the anti-inflammatory effect originally possessed by ufenamate, itchy skin symptoms can be improved. can.

2. Method for Improving Antipruritic Effect Further, the present invention provides a method for improving the antipruritic effect of an external composition for skin containing diphenhydramines. The improvement of the antipruritic effect means that the antipruritic effect is expressed at an earlier stage than when diphenhydramine and / or a salt thereof is contained alone, and / or, at least, after the application of the external skin composition. In the initial stage (for example, within 15 minutes, preferably within 10 minutes, more preferably within 5 minutes), it means that the antipruritic effect is enhanced as compared with the case of containing diphenhydramine and/or a salt thereof alone.

Specifically, the method for improving antipruritic effect of the present invention is characterized by blending (B) ufenamate together with (A) diphenhydramine and/or a salt thereof in an external composition for skin. In the method for improving the antipruritic effect of the present invention, the types and amounts of ingredients used, the properties and formulation forms of the composition for external use on the skin, the method of use, etc. are as described in the section "1. Composition for external use on the skin" above. is.

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
An external skin composition having the composition shown in Table 1 was prepared and applied to a pruritus model mouse prepared by administering a pruritus-inducing substance to conduct a pruritus test. In the scratch test, the antipruritic effect was evaluated by counting the number of scratching movements of the mice. The details of the pruritus model mouse, the method of application, and the method of counting the number of scratching movements are as follows.

・Pruritus model mouse Animal used Species Mouse strain Slc: ICR
Age: 5 weeks Source: Japan SLC Co., Ltd.
Administration of prurigenic substance Prurigenic substance Compound 48/80
Available from Sigma-Aldrich Co.;
Route of administration Intradermal administration Dose 50 μg/site
Administration method A glass syringe (Top Co., Ltd.) and a 30G needle (Dentronics Co., Ltd.) were used to administer to the back immediately after shaving and applying the composition for external use to the skin.
Dosing frequency 1 time

- Application of topical skin composition Route of administration Application Dose 100 mg/mouse Administration method Immediately before administration of the pruritus, the composition was spread over the entire shaved back with a rubber-gloved finger.
Dosing frequency 1 time

・Count of scraping motions
The behavior of the mouse was observed during video images using Windows Media Player (version: 12.0.7601.23517), and the scratching behavior of the mouse's hind limbs on the back of the mouse was observed from immediately after administration of the pruritus to 5 minutes after administration of the pruritus. , from immediately after administration of the pruritus to 15 minutes after the administration of the pruritus, the number of times was counted. The number of scratching motions was set to 1 when the mouse completed a series of motions in which the hind leg was raised to scratch, the scratching behavior was performed, and the hind leg was lowered again. A multi-tally counter (DS-404: Takano Keiki Co., Ltd.) was used for counting, and it was confirmed by the timer display in the video that the video was not interrupted. Table 1 and FIG. 1 show the results of counting the scratching motions.

As shown in Table 1 and FIG. 1, in the case of diphenhydramine alone (Comparative Example 1), although diphenhydramine itself is a component that produces an antipruritic effect, the number of scratching movements was reduced within a short period of 5 minutes after the induction. In many cases, the antipruritic effect could not be exhibited. Also, when ufenamate was used alone (Comparative Example 2), the number of scratching movements was large, and the antipruritic effect could not be exhibited. When lidocaine, a local anesthetic with an antipruritic effect, was combined with diphenhydramine (Comparative Example 3), the number of scratching movements was slightly reduced, but the degree was not sufficient. In addition, in all of Comparative Examples 1 to 3, the number of scratching movements was greater than in the case of applying petroleum jelly instead of the composition for external use as a control, and the itching worsened.

In contrast, when ufenamate was used in combination with diphenhydramine (Example 1), a significant reduction in the number of scratching movements was observed. The extent of this reduction was more pronounced than when lidocaine was combined with diphenhydramine (Comparative Example 3). In addition, the number of scratching movements in Example 1 was lower than in the case of the control, and it was confirmed that the antipruritic effect was exhibited immediately after application. In other words, the composition for external use of the present invention containing diphenhydramine in combination with ufenamate has no antipruritic effect when used alone, but the local anesthetic lidocaine, which has an antipruritic effect, is used in combination (Comparative Example 3). It was also found that the antipruritic effect can be remarkably improved, and such an effect can be exhibited immediately after application, which is an unexpected effect.

Test example 2
A skin care composition having the composition shown in Table 2 was prepared as an oil-in-water emulsified composition. The prepared composition for external use on the skin was applied to a subject complaining of skin symptoms such as redness and eczema in the vicinity of the boundary between the buttocks and the thighs, and itching at the site. The amount applied was about 0.2 g per 100 cm ² and the frequency of application was twice a day. As a result, a reduction in itchiness was felt from about 5 minutes after application. Furthermore, about 2 hours after application, a tendency toward improvement in skin symptoms such as redness and eczema was also observed.

Claims (2)

(A) diphenhydramine and/or a salt thereof, and (B) ufenamate , an external skin composition for antipruritic use containing no crotamiton (except for the following cases:
[I] If it contains glycyrrhetinic acid or its ester,
[II] If it contains allantoin and tocopherol acetate,
[III ] When containing polyoxyethylene sorbitan mono fatty acid ester, anionic surfactant, glycerin fatty acid ester and water,
[IV] When containing a polyglycerin fatty acid ester, a glycerin fatty acid ester, a fatty acid that constitutes a fatty acid soap that is neutralized by a base and functions as an anionic surfactant , the base, a water-soluble polymer, oil and water,
[V] If it contains Uwaurushi,
[VI] When containing polyoxyethylene hydrogenated castor oil having an average polyoxyethylene addition mole number of 5 to 20,
[VII] When containing at least one selected from the group consisting of isopropylmethylphenol, glycyrrhizic acid, glycyrrhetinic acid, stearyl glycyrrhetinate, lidocaine and salts thereof,
[VIII] When impregnated in a water-decomposable sheet-like substrate ,
[ IX] at least one selected from the group consisting of glycyrrhetinic acid, glycyrrhizic acid, pyridoxine glycyrrhetinate, stearyl glycyrrhetinate, glyceryl glycyrrhetinate, glycyrrhetinate monoglucuronide, methyl glycyrrhizinate, stearyl glycyrrhizinate, and salts thereof case , and
[X] when used for UV absorption ). (A) A skin external composition containing diphenhydramine and/or a salt thereof and containing no crotamiton and used for antipruritic purposes (except for the following cases:
[I] If it contains glycyrrhetinic acid or its ester,
[II] If it contains allantoin and tocopherol acetate,
[III ] When containing polyoxyethylene sorbitan mono fatty acid ester, anionic surfactant, glycerin fatty acid ester and water,
[IV] When containing a polyglycerin fatty acid ester, a glycerin fatty acid ester, a fatty acid that constitutes a fatty acid soap that is neutralized by a base and functions as an anionic surfactant , the base, a water-soluble polymer, oil and water,
[V] If it contains Uwaurushi,
[VI] When containing polyoxyethylene hydrogenated castor oil having an average polyoxyethylene addition mole number of 5 to 20,
[VII] When containing at least one selected from the group consisting of isopropylmethylphenol, glycyrrhizic acid, glycyrrhetinic acid, stearyl glycyrrhetinate, lidocaine and salts thereof,
[VIII] When impregnated in a water-decomposable sheet-like substrate ,
[ IX] at least one selected from the group consisting of glycyrrhetinic acid, glycyrrhizic acid, pyridoxine glycyrrhetinate, stearyl glycyrrhetinate, glyceryl glycyrrhetinate, glycyrrhetinate monoglucuronide, methyl glycyrrhizinate, stearyl glycyrrhizinate, and salts thereof case , and
[X] when used for ultraviolet absorption ), a method for improving the antipruritic effect,
A method for improving an antipruritic effect, comprising blending (B) ufenamate together with the component (A) in a composition for external use on the skin.