JPWO2019082873A1 - Topical film forming agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an external preparation for forming a film, which suppresses adhesion to clothes or the like and has a long-lasting medicinal effect by forming a film which does not give a sense of discomfort immediately after application. SOLUTION: An oil-in-water emulsion-type film-forming external preparation containing a medicinal ingredient and an acid of a long-chain hydrocarbon, an alcohol of a long-chain hydrocarbon, an ester of a long-chain hydrocarbon and / or a salt thereof. provide. [Selection diagram] None

Description

The present invention relates to a film-forming external preparation useful for treating skin diseases and maintaining and improving the skin environment.

External preparations such as ointments, creams, lotions and gels have excellent features such as the ability to directly administer medicinal ingredients to areas with severe irregularities such as skin and mucous membranes and diseased areas that expand and contract. There is.
However, on the other hand, there is a problem that the application site comes into contact with the clothes or the like and adheres to the clothes or the like, which not only stains the clothes but also reduces the medicinal properties of the application site and the sustainability of the effect is poor.

As a solution to such a problem, for example, a film-forming external preparation (Patent Document 1) has been proposed. It is said that this liquid agent contains a copolymer of methacrylic acid and ethyl acrylate or methyl methacrylate to form a strong film, and the effect is maintained without being wiped off by clothes or the like.

However, in the liquid preparation disclosed in Patent Document 1, addition of a lower alcohol is essential for solubilization of the copolymer, and the total amount (% by weight) of ethanol and isopropanol in the composition is 40.98%, 52.5. %, 55.25% and 74.98% examples are shown. Furthermore, the formed film needs to be washed off with soap. In skin diseases, the skin is sensitive to irritation, and it is desirable to avoid the use of high-concentration lower alcohols and washing with soap, and there is a problem in applying the solution to skin diseases.

Patent Document 2 proposes an external preparation in which a film is formed by an emulsion-type adhesive component or a latex-type adhesive component. However, the external preparation has a drawback that it is extremely inconvenient because a strong film remains to be confirmed even 24 hours after application and a drying time for waiting for evaporation of water is required to form the film.

Japanese Unexamined Patent Publication No. 9-2943 Japanese Unexamined Patent Publication No. 2004-123633

The present invention has been made in view of the above-mentioned problems of the prior art, and an object of the present invention is to form a film that does not cause discomfort immediately after application without irritating diseases of the skin and mucous membranes, thereby making clothes and the like. It is an object of the present invention to provide a film-forming external preparation having a long-lasting medicinal effect while suppressing the adhesion of the skin.

As a result of diligent studies, the present inventors have suppressed adhesion to clothes and the like by including long-chain hydrocarbon acids, long-chain hydrocarbon alcohols, long-chain hydrocarbon esters and / or salts thereof. It has been found that a film that can be easily washed away with water is formed, thereby maintaining the effect of the medicinal ingredient, and the present invention has been completed.

Examples of the oil-in-water emulsion-type film-forming external preparation of the present invention include creams, lotions, sprays, liquids and the like, and preferably creams and lotions.

That is, the present invention
(1) An oil-in-water emulsion-type film-forming external preparation containing the following components (A) and (B):
(A) Medicinal component (B) One or more components selected from long-chain hydrocarbon acids, long-chain hydrocarbon alcohols, long-chain hydrocarbon esters and salts thereof.
(2) The oil-in-water emulsion-type film-forming external preparation according to (1), wherein the component (A) is a component that acts locally.
(3) The component (A) is a moisturizing agent, a corticosteroid agent, a psoriasis treatment agent, a psoriasis treatment agent, a tinea treatment agent, an atopic dermatitis treatment agent, a herpes treatment agent, an alopecia treatment agent, and a skin ulcer treatment. The oil-in-water emulsion-type film-forming external preparation according to (1) and (2), which is one or more selected from agents, skin disease therapeutic agents, necrotic tissue removers and local anesthetics.
(4) The oil-in-water emulsion-type film-forming external preparation according to (1) to (3), wherein the component (A) is water-soluble.
(5) The oil-in-water emulsion-type film-forming external preparation according to (4), wherein the component (B) is one or two selected from fatty acids, fatty alcohols, fatty acid esters and salts thereof.
(6) The component (B) is one or more selected from stearic acid, potassium stearate, a mixture of cetostearyl alcohol and sodium cetostearyl sulfate, sodium cetostearyl sulfate, cetostearyl alcohol, stearyl alcohol and cetanol. , (5). The oil-in-water emulsion-type film-forming external preparation.
(7) The oil-in-water emulsion-type film-forming external preparation according to (6), which contains 0.1 to 40% by weight of the component (B).
(8) The oil-in-water emulsion-type film-forming external preparation according to (7), which contains 2.5 to 30% by weight of the component (B).
(9) The oil-in-water emulsion-type film-forming external preparation according to (8), which contains 5 to 15% by weight of the component (B).
(10) The oil-in-water emulsion-type film-forming external preparation according to (1) to (3), wherein the component (A) is fat-soluble.
(11) The oil-in-water emulsion-type film-forming external preparation according to (10), wherein the component (B) is one or two selected from fatty acids, fatty alcohols, fatty acid esters and salts thereof.
(12) The component (B) is one or more selected from stearic acid, potassium stearate, a mixture of cetostearyl alcohol and sodium cetostearyl sulfate, sodium cetostearyl sulfate, cetostearyl alcohol, stearyl alcohol and cetanol. , (11). The oil-in-water emulsion-type film-forming external preparation.
(13) The oil-in-water emulsion-type film-forming external preparation according to (12), which contains 0.1 to 40% by weight of the component (B).
(14) The oil-in-water emulsion-type film-forming external preparation according to (13), which contains 2.5 to 30% by weight of the component (B).
(15) The oil-in-water emulsion-type film-forming external preparation according to (14), which contains 5 to 15% by weight of the component (B).
Related to.

The oil-in-water emulsion-type film-forming external preparation of the present invention forms a film that does not have a firm feeling immediately after application and cannot be visually confirmed. By forming a film, adhesion to clothes and the like is suppressed, the preparation stays on the skin for a long time, and the medicinal effect can be enhanced and maintained. It does not irritate the skin or mucous membranes and is also convenient because it can be easily rinsed with water as needed without peeling it off after use.

FIG. 1 is a photograph showing a coating film confirmed by the method described in Test Example 1.

The medicinal ingredient according to the present invention is not particularly limited, and examples thereof include an ingredient that acts on the skin and mucous membranes used in human medicine, quasi-drugs and cosmetics, and preferably an ingredient that exerts an effect locally after administration. The moisturizing component is particularly preferable.

Ingredients that are locally effective include, for example, moisturizers, corticosteroids, psoriasis treatments, acne treatments, tinea treatments, atopic dermatitis treatments, herpes treatments, alopecia treatments, and skin. Examples thereof include an ulcer therapeutic agent, a necrotizing tissue treatment agent, a local anesthetic agent, and the like, and these can be used alone or in combination of two or more.

The components of the moisturizer are preferably heparin analogs, hyaluronic acid, collagen, elastin, glycerin, macrogol, 1,3-butylene glycol, urea, propylene glycol, hydrolyzed yeast extract, ethylene glycol, hexylene glycol, diethylene glycol. , Diglycerin, sodium pyrrolidone carboxylate, sodium lactate, glucose, maltose, xylitol, sorbitol, sphingolipid, soy lecithin, natural moisturizing factor, ceramide, more preferably heparin analogs, hyaluronic acid, collagen, elastin, glycerin. , Macrogol, 1,3-butylene glycol, urea, propylene glycol, more preferably heparin analog, glycerin.

The corticosteroids are preferably dexamethasone, betamethasone, prednisolone, hydrocortisone, amcinonide, triamcinonide acetonide, fluosinolone acetonide, fludroxycortide, clobetazone, fluoroxinone, diflorazone, diflucortron, mometazone furancarboxylic acid ester. , Diflupredonato, alcromethasone or salts or esters thereof, more preferably dexamethasone valerate, betamethasone butyrate propionate.

Psoriasis therapeutic agents preferably include corticosteroids, retinoids, and vitamin D3 derivatives, more preferably calcipotriol, calcipotriol, tacalcitol, maxacalcitol, pefcalcitol, tretinoin tocopheryl, isotretinoin, etretinate. , Adaparene, tazarotene, acitretin, alitretinoin, bexarotene, and more preferably maxacalcitol and pefcalcitol.

Examples of the therapeutic agent for acne include antibacterial agents and retinoids, and more preferably tretinointocopheryl, isotretinoin, etretinate, adapalene, tazarotene, acitretin, alitretinoin, bexarotene, ozenoxacin, nadifloxacin, benzoyl peroxide, and pharopenem. Examples include sodium, more preferably adapalene, ozenoxacin, benzoyl peroxide and sodium faropenem.

The therapeutic agent for ringworm preferably includes an antifungal agent, and more preferably miconazole nitrate, sulconazole nitrate, oxyconazole nitrate, bifonazole, ketoconazole, lanoconazole, luriconazole, amorolfine hydrochloride, terbinazole hydrochloride, butenafin hydrochloride, Effie. Examples thereof include naconazole, and more preferably, lanoconazole and amorolfine hydrochloride.

The therapeutic agent for atopic dermatitis preferably includes a corticosteroid agent and an immunosuppressive agent, more preferably cyclosporine, tacrolimus, sirolimus and everolimus, and further preferably cyclosporine and tacrolimus.

The herpes therapeutic agent preferably includes an anti-herpes agent, more preferably vidarabine, acyclovir, valacyclovir, famciclovir, amenamevir, and further preferably famciclovir, amenamevir.

Preferred examples of the therapeutic agent for alopecia include minoxidil, carpronium chloride, and immunosuppressants.

Examples of the skin ulcer therapeutic agent preferably include mixed killed bacteria, tretinointocopheryl, iodine, and sodium bucladecine, and more preferably mixed killed bacteria and iodine.

Preferred examples of the necrotic tissue treatment agent include bromelain and metronidazole.

Preferred local anesthetics include lidocaine, lidocaine hydrochloride and propitocaine.

As the medicinal ingredient used in the present invention, either a water-soluble component or a fat-soluble component can be used.

The water-soluble medicinal component used in the present invention is a "slightly soluble", "easily soluble", and "extremely soluble" component defined by the Japanese Pharmacy in water, and is a heparin-like substance, glycerin, and neticonazole hydrochloric acid. Salt, Tetracycline Hydrochloride, Oxytetracycline Hydrochloride, Clindamycin Phosphate, Gentamycin Sulfate, Fradiomycin Sulfate, Polymixin B Sulfate, Faropenem Sodium, Baracyclovir Hydrochloride, Carpronium Chloride, Bucladecin Sodium, Al Examples thereof include prostadil alfadex, bromeline, lidocaine hydrochloride, prokine hydrochloride, dibucaine hydrochloride and the like.

The fat-soluble medicinal ingredients used in the present invention are "slightly insoluble", "difficult to dissolve", "extremely insoluble" and "almost insoluble" as defined by the Japanese Pharmacy, and are dexamethasone and dexamethasone. Miconazole ester, dexamethasone propionate, betamethasone valerate, betamethasone dipropionate, betamethasone butyrate propionate, prednisolone, prednisolone valerate acetate, hydrocortisone butyrate, hydrocortisone butyrate, amiconazole , Fluosinolone acetonide, fludroxycortide, clobetazone butyrate, clobetazol propionate, fluoronide, diflorazone acetate, diflucortron valerate, mometasone furancarboxylic acid ester, difluprednisolone, alkromethasone propion Acid ester, calcipotriol, calcipotriene, tacalcitol, maxacalcitol, pefcalcitol, tretinointocopheryl, isotretinoin, etretinate, adaparene, tazarotene, acitretine, alitretinoin, dexamethasone, miconazole nitrate, sulconazole nitrate, oxyconazole nitrate , Bihonazole, ketoconazole, lanoconazole, luriconazole, amorolphin hydrochloride, terbinafine hydrochloride, butenafin hydrochloride, efinaconazole, ozenoxacin, nadifloxacin, benzoyl peroxide, metronidazole, ibuprofenpiconol, ufenamate, sprofane, sprofane Examples thereof include cyclovir, amenamevir, imikimod, cyclosporin, tachlorimus, silolims, everolims, miconazole, mixed killed bacteria, trethinointocopheryl, iodine, lidocaine, propitokine and the like.

The long-chain hydrocarbon acid and the long-chain hydrocarbon alcohol according to the present invention have a saturated or unsaturated linear or branched monovalent hydrocarbon group having 8 to 30 carbon atoms in the molecule and are hydrophilic. As a group, those having a carboxyl group, a sulfonic acid group, a phosphoric acid group or a hydroxyl group, and containing salts thereof which are pharmaceutically or cosmetically acceptable.

Those having a carboxyl group are also generally called higher fatty acids, and saturated or unsaturated linear or branched fatty acids having 10 to 24 carbon atoms are preferable. Specifically, capric acid, lauric acid, myristic acid, pentadecylic acid, palmitic acid, palmitic acid, margaric acid, stearic acid, oleic acid, vaccenic acid, linoleic acid, linolenic acid, eleostearic acid, arachidonic acid, and mead. Acids, arachidonic acid, behenic acid, lignoseric acid and the like can be mentioned.

The alcohol having a hydroxyl group is also generally called a higher alcohol, and a saturated or unsaturated linear or branched alcohol having 10 to 24 carbon atoms is preferable. Specifically, caprin alcohol, undecyl alcohol, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, setanol, palmitrail alcohol, heptadecanol, stearyl alcohol, isostearyl alcohol, ellaidyl alcohol, oleyl alcohol, Examples thereof include linoleil alcohol, eride linoleil alcohol, ricinorail alcohol, nonadecil alcohol, arachidyl alcohol, heneicosanol, behenyl alcohol, elcil alcohol, lignoceryl alcohol and the like.

The ester of a long-chain hydrocarbon according to the present invention is an ester having a carboxyl group, a sulfonic acid group, a phosphoric acid group or a hydroxyl group, and is not particularly limited, but is preferably glycerin, polyglycerin, sorbitan or propylene glycol. , Esters with sucrose, ethylene glycol, polyethylene glycol, polyoxyethylene glycerin, polyoxyethylene sorbitan, sulfuric acid and the like. More preferably, polyethylene glycol stearate and sodium cetostearyl sulfate can be mentioned.

In the present invention, the salt is not particularly limited as long as it forms a pharmaceutically or cosmetically acceptable salt. Specific examples thereof include, but are not limited to, alkali metal salts (for example, sodium salt, potassium salt, etc.), alkaline earth metal salts (for example, calcium salt, etc.) and the like.

Since it is desired that the external preparation to be applied to the skin, mucous membrane, etc. has a good usability, it is adjusted to have an appropriate hardness and ease of spreading. In the present invention, the content of the component (B) is not particularly limited, but is 0.1 as the content in the film-forming external preparation of the present invention from the viewpoint of usability such as hardness of the external preparation and ease of spreading. % To 40% by weight is preferable, 2.5% to 30% by weight is more preferable, 3.5 to 20% by weight is further preferable, and 5 to 15% by weight is most preferable.
Within the above range, by forming a good film, the medicinal ingredient is continuously supplied to the application site, the medicinal effect is maintained, and the good usability as an emulsion external preparation is also excellent.

The film-forming external preparation of the present invention requires the above-mentioned components, but other components usually blended in pharmaceuticals, quasi-drugs, cosmetics, etc., for example, surfactants, as long as the effects of the present invention are not impaired. Agents, oily components, and aqueous components can be appropriately blended.

Examples of the surfactant include a cationic surfactant, an anionic surfactant, an amphoteric surfactant, and a nonionic surfactant, and these can be used alone or in combination.
Specific examples of the cationic surfactant include cetyltrimethylammonium chloride, lauryldimethylbenzylammonium chloride, tetrabutylammonium chloride, dioctadecyldimethylammonium chloride and the like.
Examples of the anionic surfactant include sodium alkylbenzene sulfonate, sodium dodecyl sulfate, sodium coconut alcohol ethoxysulfate, sodium α-olefin sulfonate and the like.
Examples of the nonionic surfactant include polyoxyethylene alkyl ether and polyoxyethylene alkyl phenol ether.
Examples of the amphoteric surfactant include N-alkyl-N, N-dimethylammonium betaine, imidazoline-type amphoteric surfactant and the like.

Examples of the oily component include hydrocarbons, fats and oils, waxes and the like. These oily components can be appropriately combined and blended according to the purpose of use.
Examples of the hydrocarbon include liquid paraffin, squalane, synthetic squalane, white petrolatum, ceresin wax, solid paraffin, microstalin wax and the like.
Examples of fats and oils include olive oil, soybean oil, camellia oil, palm oil, castor oil, diethyl sebacate and the like.
Specific examples of waxes include beeswax, carnauba wax, mokuro, liquid lanolin, hard lanolin and the like.

The aqueous component can be used without particular limitation as long as it is an aqueous component usually used in oil-in-water emulsified preparations such as water, alcohol, thickeners, pH adjusters, etc., and may be appropriately combined according to the purpose of use. Can be blended.

Examples of the alcohol include monohydric alcohols such as butanol and propanol, divalent alcohols such as ethylene glycol and propylene glycol, and glycerin. However, lower alcohols such as methanol, ethanol, and propanol irritate the skin, and when they volatilize, the water in the stratum corneum also evaporates at the same time, resulting in a rapid dry state, so a large amount of compounding becomes a problem. In order to avoid irritation and drying, the amount (% by weight) in the composition is preferably less than 40%, more preferably less than 10%, and most preferably less than 5%.

Examples of the thickener include carboxyvinyl polymer, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, carrageenan, xanthan gum, gelatin and the like.

Examples of the pH adjuster include diisopropanolamine, triisopropanolamine, triethanolamine, potassium hydroxide, sodium hydroxide, sodium citrate, phosphoric acid, tartaric acid, dl-malic acid, glacial acetic acid and the like.

The emulsion external preparation according to the present invention refers to an external preparation obtained by emulsifying an oily component and an aqueous component with a surfactant. The oil-in-water emulsion type is a general term for emulsions having an aqueous phase as the outermost phase, and includes a composite emulsifier type such as a water-in-water emulsifier type in water, and is not particularly limited, but is not a composite emulsifier type. preferable.

The coating film according to the present invention is one that does not give a firm feeling to the skin or mucous membrane, fits into the skin without being peeled off like a residue, and disappears naturally without being peeled off. There is no discomfort to the extent that its presence can be detected on the skin, and it is visually detected as a film by the method described in Test Example 1.

The coating film according to the present invention was prevented from adhering to clothes and the like. When the film-forming external preparation according to the present invention is applied to the artificial leather, the cotton cloth is brought into contact immediately after the application, and the amount of adhesion to the cotton cloth is evaluated, the film-forming external agent according to the present invention forms a film, so that a film is formed. It had the property that the amount of adhesion to cotton cloth was lower than that of non-prepared preparations.

Further, when the amount of adhesion to the cotton cloth when the artificial leather is coated with the film-forming external agent according to the present invention, allowed to stand for a certain period of time, and then rubbed with the cotton cloth, the film-forming external agent according to the present invention forms a film. Therefore, it has a characteristic that the amount of adhesion to the cotton cloth is lower than that of the preparation which does not form a film.

The medicinal component is included in the film-forming external preparation of the present invention, and the film-forming external preparation forms a film when applied to the skin or mucous membrane. The medicinal ingredient is included in the coating, but surprisingly, the effect is maintained by releasing the medicinal ingredient from the coating to the application site over time.

The film-forming external preparation according to the present invention does not cause irritation even when applied to an affected area of a skin disease that is more sensitive to irritation than normal skin. This skin disease refers to a disease of the layer covering the surface of the living body such as the skin, mucous membrane, nail or scalp, and for example, atopic dermatitis, psoriasis, eruption / dermatitis group, pruritus group, palmoplantar pustulosis. , Insect bites, drug eruption, erythema, scars, keloids, lichen, fungal cyst, seborrheic deficiency, simple blisters, pemphigus, pemphigus, psoriasis, pustulosis, leukoplakia, soft tumor, alopecia , Pemphigus, pemphigus, pigmentation abnormality, seborrheic dermatitis, etc.

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

[Test Example 1]

1) Preparation method Using the ingredients shown in Table 1 (total 100% by weight),
Component 1 and components 2 to 7 are heated and dissolved at 70 ° C. or higher to prepare an oil phase.
Components 8 and 9 are heated and stirred at 70 ° C. or higher to prepare an aqueous phase.
Mix the oil phase and the aqueous phase and cool and stir until room temperature.
2) Evaluation method of film formation The prepared preparation was applied to a circle with a radius of 2.5 cm on a black acrylic plate, allowed to stand for 3 hours under room temperature conditions, and then immersed in a hot water bath at 40 ° C. to visually form a film. I checked the status of.
The coating amount was 4.8 mg / cm ² .
3) Evaluation criteria for film formation ・-: No film ・ ±: Confirm a film-like substance ・ ＋: Form a film only partially ・ ++: Form a thin film ・ +++: Form a strong film ・ ++++: Forming a very strong coating

Formulation Examples 1-11 containing long-chain hydrocarbon acids, long-chain hydrocarbon alcohols, long-chain hydrocarbon esters and / or salts thereof show the form of oil-in-water emulsion creams or lotions. A coating was confirmed. The coating was separated from the black acrylic plate by immersing it in a hot water bath without peeling it off. A photograph of the confirmed coating is shown in FIG.

[Test Example 2]

1) Preparation method Formulation Examples 12 to 17
Using the ingredients listed in Table 2 (100% by weight in total),
Ingredients 2 to 10 are heated and dissolved at 70 ° C. or higher to prepare an oil phase.
Ingredients 1, 12, 13 and 14 are stirred and dissolved, and heated at 70 ° C. or higher to prepare an aqueous phase. The oil phase and the aqueous phase are mixed and stirred, and cooled and stirred to room temperature.
Formulation Examples 18 to 20
Using the ingredients listed in Table 2 (100% by weight in total),
Ingredients 2 to 10 are heated and dissolved at 70 ° C. or higher to prepare an oil phase.
Ingredients 1, 11, 12, 13 and 14 (partial) are stirred and dissolved, and heated at 70 ° C. or higher to prepare an aqueous phase.
The oil phase and the aqueous phase are mixed and stirred.
Ingredients 12 and 14 (remaining amount) are added, and the mixture is cooled and stirred to room temperature.
In all of Formulation Examples 12 to 20, the forms of oil-in-water emulsion creams or lotions were shown.
2) Skin irritation The abdominal skin of a 4-week-old female guinea pig was depilated, and each preparation was uniformly applied to a concentration of 4.8 mg / cm ² . The number of cases of each preparation was five. The irritation of the skin at the administration site was evaluated before application and after application 1, 3, 6, 9 and 24 hours.
No skin irritation such as erythema or edema was observed on the skin of the administration site in all of Formulation Examples 12 to 20.
3) Moisture content of the stratum corneum The abdominal skin of a 4-week-old female guinea pig was depilated, and each preparation was uniformly applied to a concentration of 4.8 mg / cm ² . The number of cases of each preparation was five. Before application and after application 1, 3, 6, 9 and 24 hours, the conductance was measured by pressing the sensor probe of the skin surface stratum corneum water content measuring device (manufactured by Yayoi Co., Ltd .: SKICON-200EX) against the administration site. The larger the value of conductance, the higher the water content of the stratum corneum.

The numerical values in the table show the average value of 5 cases. Formulation Examples 12 to 20 contain the same amount of moisturizing ingredient as a medicinal ingredient, and the effect of the moisturizing ingredient can be confirmed as the amount of keratin water.
From Table 3, the film-forming external preparations of the present invention shown as Formulation Examples 12 to 17 were highly effective as compared with Formulation Examples 18 to 20 immediately after application, and the high effect was maintained for a long time thereafter. Even after 9 hours of application, the effect comparable to the value after 3 hours of application is maintained, and even after 24 hours, the effect of about 60% to about 90% of the value after 3 hours of application is maintained. Was confirmed.
On the other hand, in Formulation Examples 18 to 20 which do not form a film, the value 24 hours after application shows only about 30% of the value after 3 hours of application of Formulation Examples 12 to 17, and the sustainability of the effect is confirmed. There wasn't.

[Test Example 3]

1) Preparation method Formulation Examples 21-23
Using the ingredients listed in Table 4 (100% by weight in total),
After the components 1 and 2 are stirred and dissolved, the components 5 to 9 are added and heated to 70 ° C. or higher to prepare an oil phase.
Ingredients 11 and 12 are stirred to form an aqueous phase and heated to 70 ° C. or higher.
The aqueous phase is added to the oil phase, and after high-speed stirring, cooling and stirring is performed until room temperature is reached.
Formulation Examples 24 and 25
After the components 1 and 2 are stirred and dissolved, the components 3 or 4 are added and heated to 70 ° C. or higher to prepare an oil phase.
After stirring and dissolving components 10 and 12 (part), the mixture is heated to 70 ° C. or higher to prepare an aqueous phase.
The oil phase and the aqueous phase are mixed and stirred.
Ingredients 11 and 12 (remaining amount) are added, and the mixture is cooled and stirred to room temperature.
2) Evaluation method of film formation The prepared preparation was applied to a circle with a radius of 2.5 cm on a black acrylic plate, allowed to stand for 3 hours under room temperature conditions, and then immersed in a hot water bath at 40 ° C. to visually form a film. I checked the status of.
The coating amount was 2.8 mg / cm2.
3) Evaluation criteria for film formation ・-: No film ・ ±: Confirm a film-like substance ・ ＋: Form a film only partially ・ ++: Form a thin film ・ ++++: Form a strong film ・ ++++: Forming a very strong film In all of Preparation Examples 21 to 25, the form of an oil-in-water emulsion cream or lotion was shown, and the acid of a long-chain hydrocarbon, the alcohol of a long-chain hydrocarbon, and the long-chain hydrocarbon Films were confirmed in Formulation Examples 21-23 containing esters and / or salts thereof.
4) In vitro percutaneous absorption test / skin used: Hairless mouse back skin / device used: In vitro percutaneous absorption automatic sampling system (trade name: Microette Plus, manufactured by Hanson Research Co., Ltd.)
・ Applicable amount: 2.8 mg
-Receptor solution: PBS buffer (pH 7.4, liquid temperature 32 ° C)
-Sampling time point: 12 hours, 24 hours, 72 hours and 84 hours after the start of the test-Number of tests: 3 times for each formulation example 5) Tacrolimus measurement-Use device: LC / MS / MS device (Triple Quad 6500+) , AB SCIEX), Liquid chromatograph device (Shimadzu)
-Column: Inertsil ODS-SP (manufactured by GL Sciences)
-Mobile phase: Mobile phase A; 0.1% formic acid-containing 5 mmol / L ammonium formate aqueous solution Mobile phase B; Acetonitrile-Mobile phase flow velocity: 0.8 mL / min-Monitor ion: (Q1) m / z 822.400 , (Q3) m / z 769.300
-Solid-phase extraction plate (OASIS HLB μElution plate, manufactured by Water)

The numerical values in the table show the average values of the three cases. Formulation Examples 21 to 25 contain the same amount of tacrolimus hydrate, which is a fat-soluble compound, as a medicinal ingredient, and the effect of tacrolimus can be confirmed as an amount that has penetrated the skin. According to the package insert of Protopic Ointment containing tacrolimus hydrate as a medicinal ingredient, tacrolimus reaches the maximum blood concentration within 6 hours after application of Protopic Ointment.
From Table 5, in the present invention shown as Formulation Examples 21 to 23, the amount of skin permeation 12 hours after application, which is the early stage of skin permeation, and 12 to 24 hours after application, which is in a steady state of skin permeation, is after application. It was confirmed that the same level of maintenance could be achieved even in 72 to 84 hours.
On the other hand, in Formulation Examples 24 and 25 that do not form a film, the amount of skin permeation rapidly decreases with the passage of time, and the amount of skin permeation 72 to 84 hours after application is less than half of any time interval after application. The persistence of the effect was not confirmed.

[Test Example 4]

1) Preparation method Formulation Examples 1 to 6 and 18 described in [Test Examples 1 and 2] were used.
2) Contact test method Apply 20 mg of each preparation (appropriate amount for about 2% of the body surface area of an adult) in a circle with a diameter of 4 cm of artificial leather, and immediately after application, apply a cotton cloth covering a plastic cylinder with a diameter of 3.5 cm. The amount of the preparation adhered to the cotton cloth was measured by contacting the cotton cloth 10 times with an approach distance of 1.2 mm.
3) Friction test method 60 mg of each preparation (appropriate amount for about 2% of the body surface area of an adult) is applied to an area of 5.2 x 7.2 cm of artificial leather, and after standing at 23 ° C. for 15 minutes, the mass is 55 g and the size. A cotton cloth covering a 3.5 × 1.5 cm arm was reciprocated 30 times at a moving speed of 1 mm per second and a moving distance of 3 cm, and the amount of the preparation adhered to the cotton cloth was measured.

In both the contact test and the friction test, since Formulation Examples 1 to 6 form a film, it was confirmed that the amount of adhesion to the cotton cloth was lower than that of Formulation Example 18 which did not form a film.

Claims (15)

An oil-in-water emulsion-type film-forming external preparation containing the following components (A) and (B):
(A) Medicinal component (B) One or more components selected from long-chain hydrocarbon acids, long-chain hydrocarbon alcohols, long-chain hydrocarbon esters and salts thereof. The oil-in-water emulsion-type film-forming external preparation according to claim 1, wherein the component (A) is a component that acts locally. The component (A) is a moisturizing agent, a corticosteroid agent, a psoriasis agent, an acne agent, a tinea agent, an atopic dermatitis agent, a herpes agent, an alopecia agent, a skin ulcer agent, and skin. The oil-in-water emulsion-type film-forming external preparation according to any one of claims 1 and 2, which is one or more selected from a disease therapeutic agent, a necrotic tissue remover, and a local anesthetic. The oil-in-water emulsion-type film-forming external preparation according to any one of claims 1 to 3, wherein the component (A) is water-soluble. The oil-in-water emulsion-type film-forming external preparation according to claim 4, wherein the component (B) is one or more selected from fatty acids, fatty alcohols, fatty acid esters and salts thereof. The claim that the component (B) is one or more selected from stearic acid, potassium stearate, a mixture of cetostearyl alcohol and sodium cetostearyl sulfate, sodium cetostearyl sulfate, cetostearyl alcohol, stearyl alcohol and cetanol. The oil-in-water emulsion-type film-forming external preparation according to 5. The oil-in-water emulsion-type film-forming external preparation according to claim 6, which contains 0.1 to 40% by weight of the component (B). The oil-in-water emulsion-type film-forming external preparation according to claim 7, which contains 2.5 to 30% by weight of the component (B). The oil-in-water emulsion-type film-forming external preparation according to claim 8, which contains 5 to 15% by weight of the component (B). The oil-in-water emulsion-type film-forming external preparation according to any one of claims 1 to 3, wherein the component (A) is fat-soluble. The oil-in-water emulsion-type film-forming external preparation according to claim 10, wherein the component (B) is one or more selected from fatty acids, fatty alcohols, fatty acid esters and salts thereof. The claim that the component (B) is one or more selected from stearic acid, potassium stearate, a mixture of cetostearyl alcohol and sodium cetostearyl sulfate, sodium cetostearyl sulfate, cetostearyl alcohol, stearyl alcohol and cetanol. 11. The oil-in-water emulsion-type film-forming external preparation according to 11. The oil-in-water emulsion-type film-forming external preparation according to claim 12, which contains 0.1 to 40% by weight of the component (B). The oil-in-water emulsion-type film-forming external preparation according to claim 13, which contains 2.5 to 30% by weight of the component (B). The oil-in-water emulsion-type film-forming external preparation according to claim 14, which contains 5 to 15% by weight of the component (B).