JP6495706B2 - Skin external composition - Google Patents

Description

  The present invention relates to an external composition for skin. More specifically, the present invention relates to an emulsified external composition for skin having good usability and exhibiting excellent anti-inflammatory action.

  Conventionally, steroidal anti-inflammatory drugs and non-steroidal anti-inflammatory drugs have been widely used for the treatment of inflammatory skin diseases such as eczema, atopic dermatitis, and dry dermatitis. Although steroidal anti-inflammatory drugs have excellent anti-inflammatory effects themselves, they may cause side effects such as skin atrophy, telangiectasia, and infectivity, and attention must be paid to the amount and period of use. Yes. In addition, non-steroidal anti-inflammatory drugs have the advantage that side effects such as those seen with steroidal anti-inflammatory drugs are unlikely to occur, but they have the disadvantage of having a lower anti-inflammatory effect than steroidal anti-inflammatory drugs.

  Thus, various prescriptions that enhance the anti-inflammatory effect by using a combination of a nonsteroidal anti-inflammatory drug and a water-soluble drug have been studied. For example, Patent Document 1 reports that an external composition for skin containing a non-steroidal anti-inflammatory drug and a heparin-like substance can exert an excellent therapeutic effect on inflammatory skin diseases.

  On the other hand, in order to exert a therapeutic effect in a composition for external use of skin, it is extremely important that the drug has a high transdermal absorbability. If the transdermal absorbability is low, a sufficient therapeutic effect cannot be expected. Therefore, it is necessary to design the pharmaceutical formulation of the composition for external use for skin so that the transdermal absorbability of the drug is enhanced according to the type of the drug used.

  Conventionally, the percutaneous absorption of drugs includes "the affinity between the base and the skin" (ease of compatibility of the base with the skin) and "the affinity between the base and the drug" (the solubility of the drug to the base). (Non-patent document 1) is known to have a great influence on easiness), and in consideration of these balances, a pharmaceutical formulation of an external composition for skin is designed. Specifically, as shown in Table 1, depending on whether the drug is water-soluble or fat-soluble, or whether the base of the external preparation for skin is water-soluble or oily, the transdermal absorbability of the drug Is known to change significantly (Non-Patent Document 1). For example, in the case of a water-soluble drug, when an oleaginous base is used, “percutaneous absorbability due to affinity between base and skin” and “percutaneous absorbability due to affinity between base and drug” However, when a water-soluble base is used, both “percutaneous absorption due to affinity between base and skin” and “percutaneous absorption due to affinity between base and drug” are reduced. It is known to do. In the case of a fat-soluble drug, use of an oleaginous base improves “transdermal absorbability due to the affinity between the base and the skin”, whereas “passing due to the affinity between the base and the drug”. “Skin absorbability” decreases, and when a water-soluble base is used, “percutaneous absorbability due to affinity between base and skin” decreases, but “percutaneous absorbability due to affinity between base and drug” Is known to improve.

  In addition, when a water-soluble drug and a fat-soluble drug are used in combination, as is apparent from Table 1, the use of an oil-based base indicates that the water-soluble drug “percutaneous absorbability due to the affinity between the base and the skin” Although both “percutaneous absorption due to affinity between base and drug” are improved, a decrease in “transdermal absorption due to affinity between base and drug” of fat-soluble drug is expected. In addition, the use of a water-soluble base can only be expected to improve the “percutaneous absorption by the affinity between the base and the drug” of the fat-soluble drug. It is expected that both “percutaneous absorbability” and “percutaneous absorbability due to affinity between base and drug” will decrease. Thus, when using a water-soluble drug and a fat-soluble drug in combination, it is necessary to design the formulation according to the type of the water-soluble drug and the fat-soluble drug used in order to improve the absorbability of both. It becomes.

  On the other hand, the composition for external use of the skin is required to have a good feeling in use as well as the selection of the drug and its transdermal absorbability. Oily ointment can repel water and can be expected to protect the skin. However, it has a drawback that it is oily and sticky and has a poor feeling of use. On the other hand, it is known that an emulsified preparation has little oiliness and stickiness, a refreshing feeling of use is obtained, and the disadvantage of the feeling of use of an oily ointment can be solved.

JP 2000-38352 A

Supervised by Michiteru Otani, “Savings of Nursing Drugs vol.1”, [online], Maruho Co., Ltd., [March 3, 2014 search], Internet <URL: http://www.maruho.co.jp/ medical / academic / infostore / vol01 / 05.html>

  Considering the percutaneous absorbability of the drugs shown in Table 1, in the composition for external use with a combination of a fat-soluble nonsteroidal anti-inflammatory drug and a water-soluble drug, an oily base is used due to the balance of the transdermal absorbability of both. (For example, oily ointment) tends to be employed. However, such an oily ointment has a drawback that the feeling of use is poor as described above. On the other hand, it is possible to improve the feeling of use by formulating an external preparation composition containing a fat-soluble non-steroidal anti-inflammatory drug and a water-soluble drug as an emulsified preparation. It will be damaged and the medicinal effect will be reduced. That is, in an emulsified preparation, the fat-soluble drug is localized in the oil-based base (oil phase), and the water-soluble drug tends to be localized in the water-soluble base (aqueous phase). Changing the design of an oily ointment containing a drug to an emulsified formulation results in a decrease in the transdermal absorbability of the water-soluble drug due to the affinity between the base and the drug. It will cause a decline. Furthermore, in the case of an emulsified preparation, the drug present in the droplet does not directly contact the skin, so that the drug present in the droplet is absorbed percutaneously, It is also necessary to distribute (move) to (non-patent document 1). As described above, in the case of an emulsified preparation, the transdermal absorbability of the drug is also entrusted to the dispersibility of the drug in the droplets, so that the drug effect inherent to the drug may not be sufficiently exhibited.

  For this reason, it is difficult for the conventional technology to formulate into an emulsified form having a good feeling of use in a composition for external use containing a fat-soluble non-steroidal anti-inflammatory drug and a water-soluble drug, and exhibit an excellent anti-inflammatory action. Met.

  Accordingly, an object of the present invention is to provide a composition for external use on skin, which contains a fat-soluble non-steroidal anti-inflammatory drug and a water-soluble drug, and can exhibit an excellent anti-inflammatory action while being in an emulsified form. .

  As a result of diligent studies to solve the above-mentioned problems, the present inventors have found that a combination of ufenamate and a heparin-like substance from among countless combinations of fat-soluble non-steroidal anti-inflammatory drugs and water-soluble drugs. It has been found that by preparing this into an emulsified form, it can be provided with a good feeling of use and can exhibit a particularly excellent anti-inflammatory effect. The present invention has been completed by further studies based on such knowledge.

That is, this invention provides the skin external composition of the aspect hung up below.
Item 1. An external composition for skin comprising ufenamate and a heparin-like substance and being in an emulsified state.
Item 2. Item 2. The external composition for skin according to Item 1, wherein 0.1 to 20 parts by weight of a heparin-like substance is contained per 100 parts by weight of ufenamate.
Item 3. Item 3. The external composition for skin according to Item 1 or 2, which is an oil-in-water emulsified state.
Item 4. Item 4. The external composition for skin according to any one of Items 1 to 3, which is used for anti-inflammatory purposes.
Item 5. Item 5. The external composition for skin according to any one of Items 1 to 4, which is used for IL-1α production suppression.
Item 6. Item 6. The external composition for skin according to any one of Items 1 to 5, which is a cream.

  The composition for external use of the skin of the present invention contains a fat-soluble ufenamate and a hydrophilic heparin-like substance, and can exhibit a remarkably excellent anti-inflammatory effect even though it is formulated in an emulsified state. From the prior art, considering that a combination of a fat-soluble drug and a water-soluble drug is formulated into an emulsified state, a decrease in transdermal absorbability (that is, a decrease in medicinal effect) is predicted. This is extremely unexpected.

  Furthermore, since the composition for external use of the present invention can provide a skin barrier function to an applied skin affected part, it can be remarkably applied to a skin affected part that is scratched or a damaged skin layer. An excellent therapeutic effect can be achieved. Conventionally, preparations in an emulsified state are generally known to be inferior in terms of skin barrier function compared to oily ointments, but the composition for external use of the skin of the present invention has a skin barrier function that surpasses oily ointments while being in an emulsified state. The effects of the present invention are beyond the scope assumed from the prior art.

  Moreover, since the composition for external use of skin of this invention is an emulsified state, since there is no oiliness and stickiness and it shows the outstanding usability | use_condition, it can also be used comfortably.

In Experiment 1, it is a figure which shows the result of having measured the erythema value by administration of the composition for skin external application. In Experiment 1, it is a figure which shows the result of having measured the amount of water transpiration by administration of the composition for skin external application. In Reference Test Example 1, it is a figure which shows the result of having measured the erythema value by administration of the composition for skin external application. In the reference test example 1, it is a figure which shows the result of having measured the amount of water transpiration by administration of the composition for skin external application. In the reference test example 2, it is a figure which shows the result of having evaluated the IL-1 (alpha) production inhibitory effect.

  The external composition for skin of the present invention contains ufenamate and a heparin-like substance and is in an emulsified state. Hereinafter, the external composition for skin of the present invention will be described in detail.

[Ingredients]
Ufenamate The external composition for skin of the present invention contains ufenamate. Ufenamate is a drug known as a fat-soluble non-steroidal anti-inflammatory drug. Ufenamate is fat-soluble and is contained in the oil phase in the external composition for skin of the present invention.

  In the composition for external use of the skin of the present invention, the content of ufenamate is appropriately set according to the medicinal effect to be exhibited, for example, 1 to 10% by weight, preferably 3 to 10% by weight, more preferably 4 to 4%. 6% by weight is mentioned.

Heparin analog The composition for external use of the skin of the present invention contains a heparin analog together with ufenamate. Thus, by selecting a combination of ufenamate and heparin-like substance, it is possible to exert an excellent anti-inflammatory effect even in an emulsified state. The heparin-like substance is water-soluble, and is contained in the aqueous phase in the external composition for skin of the present invention.

  A heparin-like substance is a polysulfated mucopolysaccharide such as chondroitin polysulfate, and is a known drug known to have a moisturizing action, a blood flow increasing action, and the like. The origin of the heparin analog used in the present invention is not particularly limited. For example, it is obtained by polysulfating mucopolysaccharide, edible beast tissue (for example, lung including bovine tracheal cartilage) ) And the like extracted from the above. In the composition for external use of the present invention, a heparin-like substance that is included in the Japanese Pharmacopoeia pharmaceutical standards is suitably used as the heparin-like substance.

  In the composition for external use of the skin of the present invention, the content of the heparin-like substance is appropriately set according to the medicinal effect to be exhibited, for example, 0.01 to 1% by weight, preferably 0.01 to 0.5. % By weight, more preferably 0.05 to 0.5% by weight.

  In the composition for external use of the skin of the present invention, the ratio of ufenamate and heparin-like substance is not particularly limited, but from the viewpoint of further improving the anti-inflammatory effect, the heparin-like substance is 0.1% per 100 parts by weight of ufenamate. 1-20 weight part, Preferably it is 0.5-10 weight part, More preferably, 0.5-8 weight part is mentioned.

Oily Base The composition for external use of the skin of the present invention contains an oily base in order to form an oil phase in an emulsified state.

  The oleaginous base is not particularly limited as long as it is pharmaceutically acceptable and can form an oil phase in an emulsified state. For example, vegetable oil, animal oil, mineral oil, fatty acid alkyl ester, fatty acid, higher alcohol And silicone oil.

  Examples of vegetable oils include olive oil, wheat germ oil, rice oil, safflower oil, soybean oil, camellia oil, corn oil, rapeseed oil, sesame oil, castor oil, sunflower oil, cottonseed oil, peanut oil, jojoba oil, hydrogenated oil Avocado oil, fennel oil, clove oil, peppermint oil, eucalyptus oil, lemon oil, orange oil, carnauba wax, candelilla wax, rice bran wax, tree wax and the like. These vegetable oils may be used individually by 1 type, and may be used in combination of 2 or more type.

  Specific examples of animal oils include lard, fish oil, squalane, beeswax and the like. These animal oils may be used alone or in combination of two or more.

  Specific examples of the mineral oil include paraffin, hydrogenated polyisobutene, liquid paraffin, gelled hydrocarbon (plasty base and the like), petrolatum and the like. These hydrocarbons may be used individually by 1 type, and may be used in combination of 2 or more type.

  Examples of the fatty acid alkyl ester include esters of a fatty acid having 4 to 30 carbon atoms and an alcohol having 1 to 34 carbon atoms, specifically, diisopropyl adipate, isopropyl myristate, isopropyl palmitate, cetyl palmitate, Examples include diethyl sebacate and ethyl oleate. These fatty acid alkyl esters may be used alone or in combination of two or more.

  Examples of the fatty acid include fatty acids having 4 to 30 carbon atoms, and specific examples include lauric acid, myristic acid, palmitic acid, sebacic acid, oleic acid, linoleic acid, and the like. These fatty acids may be used alone or in combination of two or more.

  Examples of higher alcohols include monohydric alcohols having 6 to 34 carbon atoms. Specific examples include myristyl alcohol, cetyl alcohol, oleyl alcohol, stearyl alcohol, isostearyl alcohol, behenyl alcohol, hexadecyl alcohol, lanolin alcohol, and the like. Is mentioned. These higher alcohols may be used alone or in combination of two or more.

  Specific examples of the silicone oil include methylpolysiloxane, cross-linked methylpolysiloxane, cyclic silicone, alkyl-modified silicone, amino-modified silicone, polyether-modified silicone, polyglycerin-modified silicone, acrylic silicone, and phenyl-modified silicone. It is done. These silicone oils may be used alone or in combination of two or more.

  Among these oleaginous bases, animal oils, mineral oils, fatty acid alkyl esters, fatty acids, and higher alcohols are preferable from the viewpoint of more effectively improving the anti-inflammatory action.

  These oleaginous bases may be used individually by 1 type, and may be used in combination of 2 or more type.

  In the composition for external use of the skin of the present invention, the content of the oleaginous base varies depending on the type of the emulsified state and cannot be uniformly defined. For example, it is 5 to 80% by weight, preferably 5 to 75% by weight. %, More preferably 10 to 75% by weight.

Water (water-soluble base)
The external composition for skin of the present invention contains water to form an aqueous phase in an emulsified state.

  In the external composition for skin of the present invention, the water content varies depending on the type of the emulsified state and cannot be uniformly defined. For example, it is 18 to 90% by weight, preferably 20 to 90% by weight, Preferably 20 to 85 weight% is mentioned.

Surfactant It is preferable that the composition for external use of the present invention contains a surfactant in order to form an emulsified state. The surfactant is not particularly limited as long as it is pharmaceutically acceptable, and any of a nonionic surfactant, an anionic surfactant, a cationic surfactant, and an amphoteric surfactant can be used. A nonionic surfactant is preferably used from the viewpoint of stably maintaining the emulsified state. The nonionic surfactant used in the present invention may be either a lipophilic nonionic surfactant or a hydrophilic nonionic surfactant.

  Examples of the lipophilic nonionic surfactant include sorbitan fatty acid esters (for example, sorbitan monooleate, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, Sorbitan trioleate, diglycerol sorbitan penta-2-ethylhexylate, diglycerol sorbitan tetra-2-ethylhexyl); glycerin polyglycerin fatty acids (for example, mono-cotton oil fatty acid glycerin, mono-erucic acid glycerin, sesquioleate glycerin, monostearin) Glycerin acid, α, α′-oleic acid pyroglutamic acid glycerin, monostearic acid glycerin malic acid, etc.); propylene glycol fatty acid esters (for example, , Propylene glycol monostearate, etc.); hardened castor oil derivative; glycerin alkyl ether; steareth-2 and the like.

  Examples of the hydrophilic nonionic surfactant include POE-sorbitan fatty acid esters (for example, POE-sorbitan monooleate, POE-sorbitan monostearate, POE-sorbitan tetraoleate, etc.); POE sorbite fatty acid ester (Eg, POE-sorbite monolaurate, POE-sorbite monooleate, POE-sorbite pentaoleate, POE-sorbite monostearate, etc.); POE-glycerin fatty acid esters (eg, POE-glycerin monostearate, POE-glycerin monoisostearate, POE-glycerin triisostearate, etc.); POE-fatty acid esters (for example, POE-monooleate, POE-distearate, POE-monodiolate, diss) POE-alkyl ethers (for example, POE-lauryl ether, POE-oleyl ether, POE-stearyl ether, POE-behenyl ether, POE-2-octyldodecyl ether, POE-cholestanol ether, etc.) Pluronic type (for example, pluronic and the like); POE • POP-alkyl ethers (for example, POE • POP-cetyl ether, POE • POP-2-decyltetradecyl ether, POE • POP-monobutyl ether, POE • POP−) Hydrogenated lanolin, POE / POP-glycerin ether and the like); steareth-21 and the like.

  These surfactants may be used individually by 1 type, and may be used in combination of 2 or more type.

  In the external composition for skin of the present invention, the content of the surfactant varies depending on the type of the surfactant, the type of the emulsified state, etc., but is, for example, 0.1 to 20% by weight, preferably 0.1 to 0.1% by weight. 15 weight%, More preferably, 0.5-15 weight% is mentioned.

Other Components The composition for external use of the skin of the present invention may contain a polyhydric alcohol, if necessary, in addition to the components described above, in order to have moisture retention and the like.

  The polyhydric alcohol is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include ethylene glycol, propylene glycol, isoprene glycol, diethylene glycol, dipropylene glycol and the like. These polyhydric alcohols may be used individually by 1 type, and may be used in combination of 2 or more type.

  Moreover, the external composition for skin of this invention may contain the other additive normally used for the external composition for skin other than the component mentioned above as needed. Examples of such additives include pH adjusters, buffers, solubilizers, chelating agents, preservatives, preservatives, antioxidants, stabilizers, chelating agents, thickeners, fragrances, and coloring agents. Is mentioned.

  Furthermore, the composition for external use of the present invention may contain a drug other than ufenamate and heparin-like substances, if necessary. Examples of such drugs include steroids (dexamethasone, dexamethasone hydrochloride, dexamethasone acetate, hydrocortisone hydrochloride, prednisolone valerate, prednisolone acetate, etc.), antihistamines (diphenhydramine, diphenhydramine hydrochloride, chlorpheniramine maleate, etc.), local anesthetics (Lidocaine, dibucaine, procaine, tetracaine, bupipacaine, mepipacaine, chloroprocaine, proparacaine, meprilcaine or salts thereof, benzoic acid alkyl esters (for example, ethyl aminobenzoate, diethylaminoethyl parabutylaminobenzoate hydrochloride), orthocaine, oxesasein, Oxypolyentoxydecane, funnel extract, percamin ase, tesit decite, etc.), anti-inflammatory agents (glycyrrhetinic acid, Dipotassium tyrrhizate, monoammonium glycyrrhetinate, allantoin, salicylic acid, glycol salicylate, methyl salicylate, indomethacin, felbinac, diclofenac sodium, loxoprofen sodium, etc.), bactericides (benzalkonium chloride, decalinium chloride, benzethonium chloride, cetylpyridinium chloride, Isopropylmethylphenol, chlorhexidine hydrochloride, chlorhexidine gluconate, ammonia water, sulfadiazine, lactic acid, phenol, etc.), antipruritic agents (crotamiton, thianthol, etc.), skin protectants (collodion, castor oil, etc.), blood circulation promoting ingredients (nonyl acid vanillylamide, Nicotinic acid benzyl ester, capsaicin, red pepper extract, etc.), vitamins (vitamin A, B, C, D, etc.), muco S (sodium chondroitin sulfate, glucosamine, hyaluronic acid, etc.) and the like.

[Emulsified state]
The emulsified state of the external composition for skin of the present invention may be either an oil-in-water type or a water-in-oil type, but from the viewpoint of improving the efficacy more effectively, an oil-in-water type is preferable. It is done.

[Formulation]
As long as the composition for external skin of the present invention is in an emulsified state, the formulation form is not particularly limited, and examples thereof include liquid form and cream form. From the viewpoint of improving the drug efficacy more effectively, a cream is preferable.

[Usage]
Since the composition for external use of the present invention exhibits an excellent anti-inflammatory action, it can be used for the treatment of inflammatory skin diseases. Examples of the inflammatory skin disease to which the external composition for skin of the present invention is applied include eczema (erythema, papule, blisters, crusts, scales, etc.), atopic dermatitis, contact dermatitis, dry dermatitis, Inflammatory keratosis, rash, rash, diaper rash, hives, insect bites and the like.

  Moreover, since the composition for external use of skin of this invention can suppress effectively the production | generation of IL-1 (alpha) which is an inflammatory cytokine deeply involved in an inflammatory reaction, it is used for IL-1 (alpha) production suppression use in an inflammatory skin disease. It can also be used. Furthermore, in addition to the excellent anti-inflammatory action, the composition for external use of the present invention can also impart a barrier function to the applied skin, so that the skin inflammation site that has been scratched, the skin inflammation site that accompanies stratum corneum damage, etc. It is also preferably used for skin inflammation sites that are required to have a barrier function.

[Production method]
The composition for external use of the skin of this invention can be manufactured in accordance with the manufacturing method of a well-known emulsion composition. As a manufacturing method of the composition for external use of skin of this invention, the method shown below is mentioned, for example. First, an oil phase is prepared by mixing ufenamate, an oleaginous base, and other fat-soluble components added as necessary. Separately, an aqueous phase is prepared by mixing a heparin-like substance, water, and other water-soluble components added as necessary. The surfactant may be mixed in either the oil phase or the aqueous phase, but is preferably mixed in the oil phase. Next, the composition for external use of the skin of the present invention is produced by mixing the obtained water phase and oil phase and emulsifying them by an emulsification technique such as a homogenizer.

  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
Compositions for external use of the skin shown in Tables 2 to 4 were prepared, and the therapeutic effect on erythema was evaluated by the following method. In addition, Example 1 is a water-in-oil emulsified cream, Example 2 is an oil-in-water emulsified cream, and Comparative Example 1 is an oily ointment.

  The operation of attaching and removing the cellophane tape to the lower arm of five subjects was performed 30 times or more, and four test sites were artificially created in which the values of erythema were aligned on the lower arm. In each test site, nothing was applied at one place, and each skin external composition of Example 1-2 and Comparative Example 1 was applied three times a day to the remaining three places. After 5 days, the erythema value and the amount of water transpiration at each test site were measured. The erythema value was measured using a multi-probe adapter manufactured by Courage + Khazaka, and the amount of water transpiration was measured using VAPO SCAN AS-VT100RS manufactured by Asahi Technolab. In addition, for healthy skin that has not been subjected to tape stripping, similarly, the erythema value and moisture transpiration amount are measured, and the erythema value and moisture transpiration amount of the test site before application of each external composition for skin are 100%, Evaluation was carried out with relative values assuming that the erythema value and the amount of water transpiration of a healthy skin site were 0%.

  The measurement result of the erythema value is shown in FIG. 1, and the measurement result of the water transpiration amount is shown in FIG. From this result, it can be seen that the compositions for external use in Examples 1 and 2 are excellent in the effect of suppressing erythema, which is an index of inflammation, and the effect of reducing the amount of water transpiration, which is an index of destruction of the barrier function of the skin. confirmed. In particular, the composition for external use in Examples 1 and 2 is in an emulsified state, and compared with the oily ointment of Comparative Example 1, the percutaneous absorbability is expected to decrease and the anti-inflammatory action is expected to be weak. On the other hand, the anti-inflammatory effect of the skin external composition of Examples 1 and 2 was far superior to the oily ointment of Comparative Example 1. Further, since the oily ointment of Comparative Example 1 has a high film effect (skin barrier function), it was predicted that the action of reducing the amount of moisture transpiration was high. The amount of moisture transpiration was far lower than that of the oily ointment, and the skin external compositions of Examples 1 and 2 had a remarkably excellent skin barrier function despite being in an emulsified form. .

  In addition, the compositions for external use in Examples 1 and 2 had no oiliness and stickiness, and were far superior to the oily ointment in Comparative Example 1 in terms of usability.

Test example 2
The external composition for skin shown in Tables 5-7 was prepared, and the therapeutic effect on erythema was evaluated in the same manner as in Test Example 1. In addition, Example 3 is an oil-in-water emulsion and Examples 4 and 5 are oil-in-water emulsion creams.

  As a result, it was confirmed that any of the compositions for external use in Examples 3 to 5 had excellent therapeutic effects against erythema and good usability as in the case of Test Example 1.

Test example 3
The skin external composition shown in Tables 8 and 9 was prepared, and the therapeutic effect on erythema was evaluated in the same manner as in Test Example 1. Examples 6 to 10 are water-in-oil creams, and Examples 11 to 15 are oil-in-water emulsified creams.

  As a result, it was confirmed that any of the compositions for external use in Examples 6 to 15 had excellent therapeutic effects against erythema and good usability as in the case of Test Example 1.

Reference test example 1
The external composition for skin shown in Tables 10-12 was prepared, and the therapeutic effect on erythema was evaluated in the same manner as in Test Example 1. Comparative Example 2 is an oily ointment, Comparative Example 3 is a water-in-oil emulsified cream, and Comparative Example 4 is an oil-in-water emulsified cream.

  The measurement result of the erythema value is shown in FIG. 3, and the measurement result of the water transpiration amount is shown in FIG. Since the composition for external use in Comparative Examples 3 and 4 is in an emulsified state, it is expected that the percutaneous absorption will be lower than that of the oily ointment in Comparative Example 1, but the anti-inflammatory action was actually weakened. Moreover, the composition for external use of skin of Comparative Examples 3-4 was inadequate also in the point of the fall effect | action of a water | moisture content. That is, the combination of a fat-soluble non-steroidal anti-inflammatory drug (glycyrrhizic acid) and a heparin-like substance, as expected from the prior art, has an insufficient anti-inflammatory effect when it is emulsified, and the amount of water transpiration is low. It was confirmed that the lowering effect was not satisfactory.

  From the above results, in Test Examples 1 and 2, the excellent anti-inflammatory action and water transpiration reduction effect observed in the emulsified external compositions of Examples 1 to 5 are the same as that of ufenamate and heparin-like substances. It was confirmed to be unique due to the combination.

Reference test example 2
The effect of the combined use of ufenamate and heparin-like substances on the production of inflammatory cytokine (IL-1α) deeply involved in the inflammatory response was evaluated by the following method.

Normal human epidermal cells were seeded in a 96-well plate at a density of 2.0 × 10 ⁴ cells / well using HuMedia KG ₂ medium. 24 hours after sowing, each test medium shown in Table 13 was replaced (pretreatment). After 24 hours of pretreatment, the cells were replaced with Hanks buffer (Ca ²⁺ , Mg ²⁺ free; HBS (−)), and the cells were irradiated with 35 mJ / cm ² of UVB. After irradiation, HBS (−) was replaced with each test medium shown in Table 13 (post treatment), and further cultured for 24 hours. The amount of IL-1α in the culture supernatant after culturing was quantified using a commercially available EIA kit (IL-1α Human ELISA kit Quantikine (R & D)). At the same time, the amount of protein in the cells was quantified using BCA Protein Assay reagent (Thermo Scientific), and the amount of IL-1α produced per unit protein was calculated. The IL1-α production inhibition rate was calculated using the IL-1α production amount per unit protein amount in the case of control as a reference (IL1-α production inhibition rate 0%).

  The obtained results are shown in FIG. As is clear from FIG. 5, although ufenamate alone has no IL-1α production inhibitory effect, the combined use of ufenamate and a heparin-like substance enhanced the IL-1α inhibitory action accordingly.

Claims (6)

  An external composition for skin comprising ufenamate and a heparin-like substance and being in an emulsified state.   The external composition for skin according to claim 1, wherein 0.1 to 20 parts by weight of a heparin-like substance is contained per 100 parts by weight of ufenamate.   The external composition for skin according to claim 1 or 2, which is in an oil-in-water emulsified state.   The external composition for skin according to any one of claims 1 to 3, which is used for anti-inflammatory purposes.   The external composition for skin according to any one of claims 1 to 4, which is used for suppressing IL-1α production.   The external composition for skin according to any one of claims 1 to 5, which is a cream.