JP7262227B2 - film-forming agent for external use - Google Patents

Description

TECHNICAL FIELD 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 severely uneven surfaces such as the skin and mucous membranes, as well as disease areas that stretch and contract. there is
On the other hand, however, there is a problem that when the application site comes into contact with clothes, etc., it adheres to the clothes, staining the clothes, and in addition, the medicinal ingredients in the application site are reduced, resulting in poor durability of the effect.

As a solution to such problems, for example, a film-forming external liquid preparation (Patent Document 1) has been proposed. This solution is said to form a strong film by blending a copolymer of methacrylic acid and ethyl acrylate or methyl methacrylate, and to maintain its effect without being wiped off with clothes.

However, the liquid agent disclosed in Patent Document 1 requires the addition of a lower alcohol to solubilize the copolymer, and the total amount (% by weight) of ethanol and isopropanol in the composition is 40.98% and 52.5%. %, 55.25% and 74.98% examples are shown. Furthermore, the formed film must be washed off with soap. In skin diseases, the skin is sensitive to irritation, and it is desirable to avoid using high-concentration lower alcohols and washing with soap.

Patent Document 2 proposes an external preparation in which a film is formed with an emulsion adhesive component or a latex adhesive component. However, this topical preparation has the disadvantage that a firm film remains recognizable even after 24 hours of application, and that it is extremely inconvenient because it requires a drying time to wait for moisture to evaporate in order to form the film.

JP-A-9-2943 JP-A-2004-123633

The present invention has been made in view of the above-mentioned problems of the prior art, and its object is to form a coating that does not cause discomfort immediately after application without giving irritation to diseases of the skin and mucous membranes, and to apply it to clothes and the like. To provide a film-forming external preparation which suppresses the adhesion of phlegm and has a sustained efficacy.

As a result of intensive studies, the present inventors found that the inclusion of long-chain hydrocarbon acids, long-chain hydrocarbon alcohols, long-chain hydrocarbon esters and/or salts thereof suppresses adhesion to clothes and the like. The inventors have found that a film that can be easily washed off with water is formed, thereby maintaining the effect of the medicinal ingredient, and have completed the present invention.

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

That is, the present invention
(1) An oil-in-water emulsion film-forming external preparation containing the following components (A) and (B):
(A) Medicinal ingredient (B) One or two or more ingredients selected from long-chain hydrocarbon acids, long-chain hydrocarbon alcohols, long-chain hydrocarbon esters and salts thereof.
(2) The oil-in-water emulsion film-forming external preparation according to (1), wherein the component (A) is a component that acts locally.
(3) The component (A) is a moisturizer, an adrenocortical hormone agent, a therapeutic agent for psoriasis, a therapeutic agent for acne, a therapeutic agent for ringworm, a therapeutic agent for atopic dermatitis, a therapeutic agent for herpes, a therapeutic agent for alopecia, and a therapeutic agent for skin ulcers. The oil-in-water emulsion film-forming external preparation according to (1) and (2), which is one or more selected from a skin disease treatment agent, a debridement agent and a local anesthetic.
(4) The oil-in-water emulsion film-forming external preparation according to (1) to (3), wherein the component (A) is water-soluble.
(5) The oil-in-water emulsion 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, cetostearyl alcohol/sodium cetostearyl sulfate mixture, sodium cetostearyl sulfate, cetostearyl alcohol, stearyl alcohol and cetanol. , (5).
(7) The oil-in-water emulsion film-forming topical preparation according to (6), containing 0.1 to 40% by weight of the component (B).
(8) The oil-in-water emulsion film-forming external preparation according to (7), containing 2.5 to 30% by weight of component (B).
(9) The oil-in-water emulsion film-forming external preparation according to (8), containing 5 to 15% by weight of the component (B).
(10) The oil-in-water emulsion film-forming external preparation according to (1) to (3), wherein the component (A) is fat-soluble.
(11) The oil-in-water emulsion 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, cetostearyl alcohol/sodium cetostearyl sulfate mixture, sodium cetostearyl sulfate, cetostearyl alcohol, stearyl alcohol and cetanol. , (11).
(13) The oil-in-water emulsion film-forming external preparation according to (12), containing 0.1 to 40% by weight of the component (B).
(14) The oil-in-water emulsion film-forming topical preparation according to (13), containing 2.5 to 30% by weight of component (B).
(15) The oil-in-water emulsion film-forming external preparation according to (14), containing 5 to 15% by weight of the component (B).
related to.

The oil-in-water emulsion type film-forming topical preparation of the present invention forms a film that does not give a firm feeling immediately after application and cannot be visually confirmed. By forming a film, adhesion to clothes etc. is suppressed, the formulation stays on the skin for a long time, and the efficacy can be enhanced and maintained. Since it can be easily washed off with water as needed without peeling off after use, it does not irritate the skin or mucous membranes and is highly convenient.

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

The medicinal ingredient according to the present invention is not particularly limited, but includes, for example, ingredients that act on the skin and mucous membranes used in human medicines, quasi-drugs, and cosmetics, and preferably ingredients that exhibit effects at the local site of administration. Moisturizing ingredients are particularly preferred.

Ingredients exhibiting effects at the site of administration include, for example, moisturizing agents, adrenal corticosteroids, therapeutic agents for psoriasis, therapeutic agents for acne, therapeutic agents for ringworm, therapeutic agents for atopic dermatitis, therapeutic agents for herpes, therapeutic agents for alopecia, skin Ulcer treatment agents, necrotic tissue treatment agents, local anesthetics and the like can be mentioned, and these can be used alone or in combination of two or more.

Moisturizing agents preferably include heparinoids, hyaluronic acid, collagen, elastin, glycerin, macrogol, 1,3-butylene glycol, urea, propylene glycol, hydrolyzed yeast extract, ethylene glycol, hexylene glycol, and diethylene glycol. , diglycerin, sodium pyrrolidone carboxylate, sodium lactate, glucose, maltose, xylitol, sorbitol, sphingolipids, soybean lecithin, natural moisturizing factor, ceramide, more preferably heparinoid, hyaluronic acid, collagen, elastin, glycerin , macrogol, 1,3-butylene glycol, urea and propylene glycol, more preferably heparin analogues and glycerin.

Adrenal corticosteroids, preferably dexamethasone, betamethasone, prednisolone, hydrocortisone, amcinonide, triamcinolone acetonide, fluocinolone acetonide, fludroxycortide, clobetasone, fluocinonide, diflorazone, diflucortolone, mometasone furoate , difluprednate, alclomethasone or salts or esters thereof, more preferably dexamethasone valerate, betamethasone butyrate propionate.

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

Anti-acne agents preferably include antibacterial agents and retinoids, and more preferably tretinoin tocopheryl, isotretinoin, etretinate, adapalene, tazarotene, acitretin, alitretinoin, bexarotene, ozenoxacin, nadifloxacin, benzoyl peroxide, and faropenem. sodium, more preferably adapalene, ozenoxacin, benzoyl peroxide, faropenem sodium.

The therapeutic agent for ringworm is preferably an antifungal agent, more preferably miconazole nitrate, sulconazole nitrate, oxiconazole nitrate, bifonazole, ketoconazole, lanoconazole, luliconazole, amorolfine hydrochloride, terbinafine hydrochloride, butenafine hydrochloride, efficacious naconazole, more preferably lanoconazole and amorolfine hydrochloride.

The therapeutic agent for atopic dermatitis preferably includes adrenocorticosteroids and immunosuppressants, more preferably cyclosporine, tacrolimus, sirolimus and everolimus, and still more preferably cyclosporine and tacrolimus.

Herpes therapeutic agents preferably include anti-herpes agents, more preferably vidarabine, acyclovir, valacyclovir, famciclovir and amenamevir, and still more preferably famciclovir and amenamevir.

Alopecia therapeutic agents preferably include minoxidil, carpronium chloride, and immunosuppressants.

The therapeutic agent for skin ulcers preferably includes mixed killed bacteria, tretinoin tocopheryl, iodine and bucladesine sodium, more preferably mixed killed bacteria and iodine.

Preferred necrotic tissue treatment agents include bromelain and metronidazole.

Local anesthetics preferably include lidocaine, lidocaine hydrochloride and propitocaine.

Both water-soluble and fat-soluble ingredients can be used as the medicinal ingredient used in the present invention.

The water-soluble medicinal ingredients used in the present invention are "slightly soluble", "easily soluble", and "extremely soluble" ingredients defined in the Japanese Pharmacopoeia in water, such as heparinoids, glycerin, neticonazole hydrochloride. salt, tetracycline hydrochloride, oxytetracycline hydrochloride, clindamycin phosphate, gentamicin sulfate, fradiomycin sulfate, polymyxin B sulfate, faropenem sodium, valacyclovir hydrochloride, carpronium chloride, bucladesine sodium, alcohol Examples include prostadil alfadex, bromelain, lidocaine hydrochloride, procaine hydrochloride, dibucaine hydrochloride and the like.

The fat-soluble medicinal ingredient used in the present invention is a component that is "slightly soluble", "slightly soluble", "extremely soluble", and "almost insoluble" as defined in the Japanese Pharmacopoeia in water. Valerate, Dexamethasone Propionate, Betamethasone Valerate, Betamethasone Dipropionate, Betamethasone Butyrate Propionate, Prednisolone, Prednisolone Valerate Acetate, Hydrocortisone Butyrate Propionate, Hydrocortisone Butyrate, Amcinonide, Triamcinolone Acetonide , fluocinolone acetonide, fludroxycortide, clobetasone butyrate, clobetasol propionate, fluocinonide, diflorazone acetate, diflucortolone valerate, mometasone furoate, difluprednate, alclomethasone propionate Acid esters, calcipotriol, calcipotriene, tacalcitol, maxacalcitol, pefcalcitol, tretinoin tocopheryl, isotretinoin, etretinate, adapalene, tazarotene, acitretin, alitretinoin, bexarotene, miconazole nitrate, sulconazole nitrate, oxiconazole nitrate , bifonazole, ketoconazole, lanoconazole, luliconazole, amorolfine hydrochloride, terbinafine hydrochloride, butenafine hydrochloride, efinaconazole, ozenoxacin, nadifloxacin, benzoyl peroxide, metronidazole, ibuprofenpiconol, ufenamate, suprofen, vidarabine, acyclovir, valacyclovir, fam Cyclovir, amenamevir, imiquimod, cyclosporine, tacrolimus, sirolimus, everolimus, minoxidil, mixed killed bacteria, tretinoin tocopheryl, iodine, lidocaine, propitocaine and the like can be exemplified.

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. It has a carboxyl group, a sulfonic acid group, a phosphate group, or a hydroxyl group as a group, and includes pharmaceutically or cosmetically acceptable salts thereof.

Those having a carboxyl group are generally called higher fatty acids, and saturated or unsaturated straight-chain or branched fatty acids having 10 to 24 carbon atoms are preferred. Specifically, capric acid, lauric acid, myristic acid, pentadecyl acid, palmitic acid, palmitoleic acid, margaric acid, stearic acid, oleic acid, vaccenic acid, linoleic acid, linolenic acid, eleostearic acid, arachidic acid, mead acid, arachidonic acid, behenic acid, lignoceric acid and the like.

Those having a hydroxyl group are generally called higher alcohols, and saturated or unsaturated linear or branched alcohols having 10 to 24 carbon atoms are preferred. Specifically, capric alcohol, undecyl alcohol, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetanol, palmitoleyl alcohol, heptadecanol, stearyl alcohol, isostearyl alcohol, elaidyl alcohol, oleyl alcohol, linoleyl alcohol, elaide linoleyl alcohol, ricinoleyl alcohol, nonadecyl alcohol, arachidyl alcohol, heneicosanol, behenyl alcohol, erucyl alcohol, lignoceryl alcohol and the like.

Esters of long-chain hydrocarbons according to the present invention are esters of those having a carboxyl group, a sulfonic acid group, a phosphoric acid group, or a hydroxyl group, and are not particularly limited, but are preferably glycerin, polyglycerin, sorbitan, and propylene glycol. , sucrose, ethylene glycol, polyethylene glycol, polyoxyethylene glycerin, polyoxyethylene sorbitan, and esters with sulfuric acid. More preferred are polyethylene glycol stearate and sodium cetostearyl sulfate.

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

Since topical preparations applied to the skin, mucous membranes, etc. are desired to have a good feeling when used, they are adjusted to have appropriate hardness and spreadability. In the present invention, the content of component (B) is not particularly limited, but from the viewpoint of the feeling of use such as the hardness of the external preparation and the ease of spreading, the content in the film-forming external preparation of the present invention is 0.1. % to 40% by weight, more preferably 2.5% to 30% by weight, even more preferably 3.5% to 20% by weight, most preferably 5% to 15% by weight.
Within this range, the medicinal ingredients are continuously supplied to the application site by forming a good film, the medicinal effect is maintained, and the feeling of use as an emulsifiable external preparation is also excellent.

The film-forming topical preparation of the present invention essentially contains the above-mentioned ingredients, but other ingredients usually blended in pharmaceuticals, quasi-drugs, cosmetics, etc., such as surface active Agents, oily components and water-based components can be appropriately blended.

Surfactants include cationic surfactants, anionic surfactants, amphoteric surfactants, and nonionic surfactants, and these can be used alone or in combination.
Specific examples of cationic surfactants include cetyltrimethylammonium chloride, lauryldimethylbenzylammonium chloride, tetrabutylammonium chloride, dioctadecyldimethylammonium chloride and the like.
Examples of anionic surfactants include sodium alkylbenzenesulfonate, sodium dodecylsulfate, sodium coconut alcohol ethoxysulfate, and sodium α-olefinsulfonate.
Examples of nonionic surfactants include polyoxyethylene alkyl ethers and polyoxyethylene alkylphenol ethers.
Amphoteric surfactants include, for example, N-alkyl-N,N-dimethylammonium betaine, imidazoline type amphoteric surfactants and the like.

Oily components include, for example, hydrocarbons, oils and fats, waxes and the like. These oily components can be blended in an appropriate combination depending on the purpose of use.
Examples of hydrocarbons include liquid paraffin, squalane, synthetic squalane, white petrolatum, ceresin wax, solid paraffin, and microstarin wax.
Examples of fats and oils include olive oil, soybean oil, camellia oil, palm oil, castor oil, and diethyl sebacate.
Specific examples of waxes include beeswax, carnauba wax, Japanese wax, liquid lanolin, hard lanolin and the like.

The aqueous component can be used without particular limitation as long as it is an aqueous component that is usually used in an oil-in-water emulsified formulation such as water, alcohol, thickener, pH adjuster, etc., and can be appropriately combined according to the purpose of use. can be compounded.

Examples of alcohols include monohydric alcohols such as butanol and propanol, dihydric 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 moisture in the stratum corneum evaporates at the same time, resulting in rapid dryness. The amount (% by weight) in the composition is preferably less than 40%, more preferably less than 10%, most preferably less than 5% to avoid irritation and dryness.

Examples of thickeners include carboxyvinyl polymer, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, carrageenan, xanthan gum, gelatin and the like.

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

The emulsion-type external preparation according to the present invention refers to an external preparation in which an oily component and an aqueous component are emulsified with a surfactant. An oil-in-water emulsion is a general term for emulsions in which the outermost phase is an aqueous phase, and includes complex emulsifiers such as water-in-oil-in-water emulsifiers. preferable.

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

The film according to the present invention was suppressed from adhering to clothes and the like. When the film-forming external preparation of the present invention is applied to artificial leather, a cotton cloth is brought into contact immediately after application, and the amount of adhesion to the cotton cloth is evaluated, the film-forming external preparation of the present invention forms a film. It had a characteristic that the amount of adhesion to cotton cloth was low compared to the formulation without.

Furthermore, when the film-forming external preparation of the present invention is applied to artificial leather, allowed to stand for a certain period of time, and then rubbed with a cotton cloth to evaluate the amount of adhesion to the cotton cloth, the film-forming external preparation of the present invention forms a film. Therefore, it had a characteristic that the amount of adhesion to cotton cloth was lower than that of formulations that did not form a film.

A medicinal ingredient 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 mucosa. Although the active ingredient is contained in the coating, surprisingly, the effect is maintained by releasing the active ingredient from the coating to the application site over time.

The film-forming preparation for external use according to the present invention does not cause irritation even when applied to affected areas of skin diseases that are more sensitive to stimulation than normal skin. This skin disease refers to a disease of the layer covering the surface of a living body such as skin, mucous membrane, nail or scalp, such as atopic dermatitis, psoriasis, eczema/dermatitis group, prurigo group, palmoplantar pustulosis. , insect bites, drug eruption, erythroderma, scar, keloid, lichen, mycosis fungoides, sebum deficiency, herpes simplex, herpes zoster, acne, ringworm, impetigo, vitiligo, molluscum, alopecia , pemphigus, pemphigoid, pigmentation disorder, seborrheic dermatitis, and the like.

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

[Test Example 1]

1) Preparation method Using the components shown in Table 1 (total 100% by weight),
Components 1 and 2 to 7 are dissolved by heating at 70°C or higher to form an oil phase.
Components 8 and 9 are heated and stirred at 70° C. or higher to form an aqueous phase.
The oil phase and water phase are mixed and cooled to room temperature with stirring.
2) Method for evaluating film formation The prepared formulation is applied to a circle with a radius of 2.5 cm on a black acrylic plate, left to stand at room temperature for 3 hours, and then immersed in a hot water bath at 40°C to visually observe film formation. confirmed the status of
The coating amount was 4.8 mg/cm ² .
3) Criteria for evaluation of film formation -: no film ±: film-like object confirmed +: film formed only partially ++: thin film formed +++: strong film formed ++++: Forms a very strong film

Formulation Examples 1 to 11 containing long-chain hydrocarbon acids, long-chain hydrocarbon alcohols, long-chain hydrocarbon esters and/or salts thereof are in the form of oil-in-water emulsion creams or lotions, coating was confirmed. The film 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 12-17
Using the components listed in Table 2 (total 100% by weight),
Components 2 to 10 are heated and dissolved at 70° C. or higher to form an oil phase.
Components 1, 12, 13 and 14 are stirred, dissolved, and heated to 70° C. or higher to form an aqueous phase. The oil phase and water phase are mixed and stirred, cooled to room temperature and stirred.
Formulation Examples 18-20
Using the components listed in Table 2 (total 100% by weight),
Components 2 to 10 are heated and dissolved at 70° C. or higher to form an oil phase.
Components 1, 11, 12, 13 and 14 (parts) are stirred to dissolve and heated to 70°C or higher to form an aqueous phase.
The oil phase and water phase are mixed and stirred.
Add ingredients 12 and 14 (remaining amount) and stir to cool to room temperature.
Formulation Examples 12 to 20 all showed the form of an oil-in-water emulsion cream or lotion.
2) Skin Irritation Abdominal skin of 4-week-old female guinea pigs was shaved, and each formulation was uniformly applied at 4.8 mg/cm ² . The number of examples for each formulation was 5. Before application and 1, 3, 6, 9 and 24 hours after application, skin irritation at the application site was evaluated.
In all of Formulation Examples 12 to 20, skin irritation such as erythema and edema was not observed on the skin at the administration site.
3) Moisture content of stratum corneum Abdominal skin of 4-week-old female guinea pigs was shaved, and each preparation was uniformly applied so as to be 4.8 mg/cm ² . The number of examples for each formulation was 5. Before application and 1, 3, 6, 9 and 24 hours after application, conductance was measured by pressing a sensor probe of a skin surface stratum corneum water content measuring device (manufactured by Yayoi Co., Ltd.: SKICON-200EX) against the administration site. A larger conductance value indicates a higher moisture content in the stratum corneum.

Numerical values in the table indicate average values of 5 examples. 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 moisture content of stratum corneum.
From Table 3, the film-forming external preparations of the present invention shown as Formulation Examples 12 to 17 exhibited higher effects immediately after application than Formulation Examples 18 to 20, and maintained high effects for a long time thereafter. Even after 9 hours of application, an effect comparable to the value after 3 hours of application is maintained, and even after 24 hours, an 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 that do not form a film, the value after 24 hours of application shows only about 30% of the value after 3 hours of application in Formulation Examples 12 to 17, and the persistence of the effect has been confirmed. I didn't.

[Test Example 3]

1) Preparation method Formulation Examples 21-23
Using the components listed in Table 4 (total 100% by weight),
After stirring and dissolving components 1 and 2, components 5 to 9 are added and mixed while heating to 70° C. or higher to form an oil phase.
Ingredients 11 and 12 are stirred into the aqueous phase and warmed to 70°C or above.
The water phase is added to the oil phase, and after high-speed stirring, the mixture is cooled and stirred until it reaches room temperature.
Formulation Examples 24 and 25
After components 1 and 2 are stirred and dissolved, component 3 or 4 is added and mixed while heating to 70° C. or higher to obtain an oil phase.
After stirring and dissolving components 10 and 12 (parts), the mixture is heated to 70°C or higher to form an aqueous phase.
The oil phase and water phase are mixed and stirred.
Add ingredients 11 and 12 (remaining amount) and stir to cool to room temperature.
2) Method for evaluating film formation The prepared formulation is applied to a circle with a radius of 2.5 cm on a black acrylic plate, left to stand at room temperature for 3 hours, and then immersed in a hot water bath at 40°C to visually observe film formation. confirmed the status of
The coating amount was 2.8 mg/cm2.
3) Criteria for evaluation of film formation -: no film ±: film-like object confirmed +: film formed only partially ++: thin film formed +++: strong film formed ++++: Forms a very strong film Formulation Examples 21 to 25 all show the form of oil-in-water emulsion creams or lotions, and include long-chain hydrocarbon acids, long-chain hydrocarbon alcohols, long-chain hydrocarbon Coating was confirmed in Formulation Examples 21 to 23 containing esters and/or salts thereof.
4) In vitro percutaneous absorption test ・Skin used: back skin of hairless mouse ・Apparatus used: In vitro percutaneous absorption automatic sampling system (trade name: Microette Plus, manufactured by Hanson Research)
・Applied amount: 2.8 mg
・Receptor liquid: PBS buffer (pH 7.4, liquid temperature 32°C)
- Sampling time points: 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) Measurement of tacrolimus - Equipment used: LC / MS / MS equipment (Triple Quad 6500+ , AB SCIEX), liquid chromatograph (manufactured by Shimadzu)
・ Column: Inertsil ODS-SP (manufactured by GL Sciences)
・Mobile phase: mobile phase A; 5 mmol/L ammonium formate aqueous solution containing 0.1% formic acid mobile phase B; acetonitrile ・Mobile phase flow rate: 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)

Numerical values in the table indicate average values of three examples. Formulation Examples 21 to 25 contain the same amount of tacrolimus hydrate, which is a fat-soluble compound, as an active ingredient, and the effect of tacrolimus can be confirmed by the amount permeated through the skin. According to the package insert of Protopic ointment containing tacrolimus hydrate as a medicinal ingredient, tacrolimus reaches its maximum blood concentration within 6 hours after application of Protopic ointment.
From Table 5, the present invention, shown as Formulation Examples 21-23, shows that the amount of skin permeation at 12 hours after application, which is an early time point of skin permeation, and 12-24 hours after application, which is at a steady state of skin permeation, is It was confirmed that it could be maintained at the same level for 72 to 84 hours.
On the other hand, in Formulation Examples 24 and 25 that do not form a film, the amount of permeation through the skin rapidly decreases with the passage of time, and the amount of permeation through the skin at 72 to 84 hours after application is less than half for any time interval after application. and 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 formulation (appropriate amount for about 2% of the body surface area of an adult) in a circle with a diameter of 4 cm on artificial leather, and immediately after application, a cotton cloth covering a plastic cylinder with a diameter of 3.5 cm, The contact was made 10 times with an approach distance of 1.2 mm, and the amount of the formulation adhering to the cotton cloth was measured.
3) Friction test method 60 mg of each formulation (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 is A cotton cloth covering an arm of 3.5×1.5 cm was reciprocated 30 times at a moving speed of 1 mm per second and a moving distance of 3 cm to measure the amount of formulation adhered to the cotton cloth.

In both the contact test and the friction test, since Formulation Examples 1 to 6 form a film, compared with Formulation Example 18 which does not form a film, it was confirmed that the amount of adhesion to cotton cloth is low.

Claims (5)

An oil- in-water emulsion film-forming external preparation containing the following components (A) and (B) , wherein the component (B) is contained in an amount of 5 to 30% by weight. Oil-type emulsion film-forming preparation for external use :
(A) Medicinal ingredient (B) Three or more ingredients selected from stearic acid, cetostearyl alcohol/sodium cetostearyl sulfate mixture, sodium cetostearyl sulfate, cetostearyl alcohol, and myristyl alcohol . 2. The oil-in-water emulsion 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, an adrenocortical hormone agent, a therapeutic agent for psoriasis, a therapeutic agent for acne, a therapeutic agent for ringworm, a therapeutic agent for atopic dermatitis, a therapeutic agent for herpes, a therapeutic agent for alopecia, a therapeutic agent for skin ulcer, and skin. 3. The oil-in-water emulsion 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 debridement agent and a local anesthetic. The oil-in-water emulsion 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 film-forming external preparation according to any one of claims 1 to 4 , wherein the component (A) is fat-soluble.

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