JP7487443B2 - Composition for application to mucosal epithelium - Google Patents

Description

The present invention relates to a composition for application to mucosal epithelium, which contains an active ingredient in an oil that has been thickened and/or sol-gelled using an oil-based thickener.

Sol-gel preparations are preparations in which active ingredients are dissolved or mixed in a sol-gel base, and they provide a faster onset of efficacy than solid preparations and a longer-lasting effect than liquid preparations. Due to these characteristics, they are used in a variety of applications, including medicines, food and beverages, and cosmetics.

Conventionally, various sol-gel preparations have been developed and reported.
Patent Document 1 describes an invention relating to a gel composition (specifically, hydrogel beads (oil content 40%)) containing an active ingredient and fats and oils or polysaccharides. It is described that this invention has high sustained release properties for the active ingredient contained therein, and that by adjusting the specific gravity, it is possible to increase gastric retention when orally administered.

Patent Document 2 describes an invention relating to an internal gel composition that contains a fat-soluble active ingredient, oil, a gelling agent (agar, xanthan gum, pectin, carangeena, locust bean gum, gellan gum, etc.), a surfactant, and water. According to this invention, by forming the gel, the active ingredient dissolved in the gel that comes into contact with the oral cavity or esophagus after ingestion is quickly absorbed at the target site, and the medicinal effect is quickly exerted, and the menthol and essential oil components dissolved in the oil are gradually released, and the medicinal effect is sustained.

However, there remains a strong demand in this field for the development of a formulation that can exert its efficacy quickly and for a longer, sustained period of time.

Patent Document 3 describes an invention relating to a thickening or solidifying agent for oils and fats that is characterized by containing a polyglycerol fatty acid ester and has excellent transparency. It also states that foods containing the present invention have a good texture, excellent shape retention, and little oil floating.

JP 2000-256216 A JP 2005-047809 A JP 2018-042550 A

The present invention aims to provide a formulation that has rapid onset of efficacy and can exert its effect for a longer, sustained period.

The inventors of the present invention have conducted extensive research to solve the above problems and have found that a sol-gel preparation that is made by thickening fats and oils with an oil-based thickener and that contains an active ingredient and is substantially water-free, when applied to the mucosal epithelium, not only exhibits rapid efficacy, but also adheres to the mucosal epithelium and exerts a long-lasting effect.

The present invention is based on these findings and includes the following inventions.
[1] A composition for application to mucosal epithelium, comprising an oil-based thickener, an oil and an active ingredient, and substantially free of water.
[2] The composition according to [1], which is in the form of a sol, a gel, a paste, or a cream.
[3] The composition according to [1] or [ ² ], which has a viscosity of 100 mPa·s to 20,000 mPa·s at 25° C. and a shear rate of 10 (1/s), or a gel strength of 800 N/m ² to 51,000 N/m 2 at 25° C.
[4] The composition according to any one of [1] to [3], wherein the oil-based thickener is a polyglycerol fatty acid ester.
[5] The composition according to any one of [1] to [4], wherein the active ingredient is a fat-soluble active ingredient.
[6] The composition according to [5], wherein the fat-soluble active ingredient is menthol, vitamin E, vitamin A, vitamin K, vitamin D, shogaol, or sanshool.
[7] Any of the compositions according to [1] to [5], having a water content of 1% by mass or less.
[8] The composition according to any one of [1] to [7], wherein the mucosal epithelium is at least one mucosal epithelium selected from the group consisting of the mucosal epithelium of the eye, ear, nose, mouth, respiratory tract, digestive tract, urinary tract, and reproductive organs.
[9] The composition according to any one of [1] to [7], which is an oral composition.
[10] The composition according to [9], which is in an encapsulated or coated form.

The composition for application to mucosal epithelium of the present invention contains thickened and/or sol-gelled oils and fats together with the active ingredient, allowing for rapid onset of medicinal effects, and since it is substantially water-free and has a high oil and fat content, it can adhere to the mucosal epithelium and remain there for a long time, allowing it to exert its effects for a longer period of time.

FIG. 1 is a graph showing the results of evaluating over time the cooling sensation due to the active ingredient felt on the oral mucosa after ingesting the composition of Example 1 containing an oil-based thickener, the composition of Comparative Example 1 containing neither an oil-based thickener nor an aqueous thickener, and the composition of Comparative Example 2 containing an aqueous thickener. FIG. 2 is a graph showing the results of evaluating over time the cooling sensation due to the active ingredient felt after applying the composition of Example 2 containing an oil-based thickener, the composition of Comparative Example 3 containing neither an oil-based thickener nor an aqueous thickener, and the composition of Comparative Example 4 containing an aqueous thickener to the nasal mucosa.

The present invention relates to a composition for application to mucosal epithelium that contains an oil-based thickener, an oil and an active ingredient, and is substantially free of water.

In the present invention, "mucosal epithelium" refers to epithelium forming a mucosa, and epithelium refers to a cell layer on the surface of the body, or a cell layer facing a lumen or body cavity. Examples of "mucosal epithelium" include epithelial cell layers forming mucosa in the eyes, ears (middle ear cavity), nose (nasal cavity), mouth (oral cavity), respiratory system (pharynx, bronchi, lungs, etc.), digestive tract (esophagus, stomach, small intestine, large intestine, rectum, anus, etc.), urinary system (ureter, bladder, urethra, etc.), reproductive system (uterus, vagina, seminal vesicles, etc.), etc.

In the present invention, "application to mucosal epithelium" means the use or method of using the composition of the present invention on the mucosal epithelium. When the composition of the present invention is used, it adheres to and remains on the mucosal epithelium, and the effect of the active ingredient contained therein can be expressed in the mucosal epithelium.

In the present invention, the term "oil-based thickener" refers to a substance that can thicken, solidify, and/or sol-gel a liquid oil or fat by being added to and dissolved in the liquid oil or fat. As such an oil-based thickener, a polyglycerin fatty acid ester, which contains fatty acids and polyglycerin as constituents, can be suitably used.

With regard to the fatty acids constituting the polyglycerol fatty acid ester (hereinafter referred to as "constituent fatty acids"), high gel strength can be obtained when linear fatty acids having 16 to 18 carbon atoms account for 45% or more of the total number of molecules of the constituent fatty acids. This ratio indicates the ratio of the number of moles of linear fatty acids having 16 to 18 carbon atoms to the number of moles of all constituent fatty acids.

The constituent fatty acids preferably include any of straight-chain fatty acids having 8 to 14 carbon atoms, branched fatty acids having 18 to 22 carbon atoms, and unsaturated fatty acids having 18 to 22 carbon atoms.

The constituent fatty acids include (a) at least one type of linear saturated fatty acid having 16 to 22 carbon atoms, and (b) at least one type selected from the group consisting of linear saturated fatty acids having 8 to 14 carbon atoms, branched fatty acids having 18 to 22 carbon atoms, and unsaturated fatty acids having 18 to 22 carbon atoms. When the molar ratio of fatty acid (a) to fatty acid (b) in the constituent fatty acids is 0.91:0.09 to 0.99:0.01, the gel strength is high even with a low addition amount, and separation of oils and fats can be suppressed for a long period of time.

Fatty acids (a) include, but are not limited to, palmitic acid, stearic acid, arachidic acid, behenic acid, etc. Fatty acids (b) include, but are not limited to, caprylic acid, capric acid, lauric acid, myristic acid, oleic acid, erucic acid, isostearic acid, etc.

It is preferable to use polyglycerin that constitutes the polyglycerin fatty acid ester, which has an average degree of polymerization based on the hydroxyl value of 10 or more. If polyglycerin with an average degree of polymerization of less than 10 is used, sufficient gel strength cannot be obtained, and separation of oils and fats may not be suppressed for a long period of time. More preferably, the average degree of polymerization of polyglycerin is 20 or more, even more preferably 30 or more, and even more preferably 40 or more. The higher the average degree of polymerization, the higher the gel strength, and solidification can be achieved with a small amount added.

The average degree of polymerization of polyglycerol based on the hydroxyl value can be calculated according to the terminal group analysis method and the hydroxyl value according to the 1996 edition of the Standard Methods for Analysis of Fats, Oils and Related Materials (I) Established by the Japan Oil Chemists' Society, edited by the Japan Oil Chemists' Society.

The esterification rate of the polyglycerol fatty acid ester is preferably 70% or more. If the esterification rate is less than 70%, sufficient gel strength cannot be obtained, and separation of oils and fats may not be suppressed for a long period of time. More preferably, the esterification rate of the polyglycerol fatty acid ester is 80% or more, and even more preferably 90% or more. The higher the esterification rate, the higher the gel strength, and solidification can be achieved with a small amount added.

The esterification rate can be calculated according to a conventional method (JP Patent Publication No. 2018-42550).

In the present invention, the polyglycerol fatty acid ester may be one produced according to a conventional method, and more specifically, one produced by charging the above-mentioned components in a composition that satisfies the above-mentioned conditions, adding a catalyst such as sodium hydroxide, and subjecting the mixture to an esterification reaction under normal pressure or reduced pressure may be used. In addition, the polyglycerol fatty acid ester may be a commercially available product, and for example, TAISET AD (Taiyo Kagaku Co., Ltd.), TAISET 50 (Taiyo Kagaku Co., Ltd.), Ryoto Polyglycerol B-100D (Mitsubishi Chemical Foods Co., Ltd.), etc. may be suitably used.

The composition for application to mucosal epithelium of the present invention may contain an oil-based thickener in any amount, and the content of the oil-based thickener may be an amount that can impart the desired properties described below to the composition for application to mucosal epithelium of the present invention together with other components. For example, the composition for application to mucosal epithelium of the present invention may contain an oil-based thickener in an amount appropriately selected from the range of 0.01% by mass to 20% by mass, preferably 0.1% by mass to 10% by mass, and more preferably 0.5% by mass to 5% by mass. If the oil-based thickener is less than 0.01% by mass, the gelation of the oil may be insufficient, and if it is more than 20% by mass, the gel strength of the oil may be too high, resulting in insufficient adhesion of the composition for application to mucosal epithelium of the present invention to the applied mucosal epithelium, in which case the composition may not remain for a long time, or the active ingredient may not be released sufficiently.

In the present invention, the term "oils and fats" refers to those that are commonly used in the fields of medicines, food and beverages, and cosmetics, such as canola oil, olive oil, rapeseed oil, coconut oil, sesame oil, soybean oil, corn oil, tea oil, palm oil, cottonseed oil, coconut oil, rice oil, avocado oil, linseed oil, argan oil, almond oil, perilla oil, orange roughy oil, cocoa butter, carrot oil, cucumber oil, beef tallow, grapeseed oil, wheat germ oil, rice bran oil, camellia oil, safflower oil, shea butter, turtle oil, clove oil, evening primrose oil, camellia oil, lard, pearl barley oil, palm kernel oil, peanut oil, castor oil, sunflower oil, hazelnut oil, macadamia nut oil, mink oil, melon oil, thyme ... Doughfoam oil, rosehip oil, milk fat, pearl barley oil, jojoba oil, lavender oil, egg yolk oil, lanolin, rosemary oil, etc., fatty acids (e.g., oleic acid, palmitic acid, capric acid, caprylic acid, stearic acid, behenic acid, myristic acid, arachidonic acid, isostearic acid, undecylenic acid, erucic acid, sebacic acid, palm kernel fatty acid, hydroxystearic acid, coconut oil fatty acid, lanolin fatty acid, linoleic acid, linolenic acid, etc.), higher alcohols (e.g., oleyl alcohol, octyldodecanol, isostearyl alcohol, octyl alcohol, stearyl alcohol, cetanol, chimyl alcohol, cetostearyl alcohol, decyl alcohol, batyl alcohol, etc.), Cholesteric acid, hexyldecanol, hexyldecanol, behenyl alcohol, myristyl alcohol, lauryl alcohol, lanolin alcohol, etc.), hydrocarbon oils (for example, paraffin, squalane, isododecane, ceresin, pristane, liquid paraffin, liquid isoparaffin petrolatum, etc.), ester oils (for example, dioctyl adipate, diisopropyl adipate, diisobutyl adipate, di-2-hexyldecyl adipate, diheptylundecyl adipate, avocado oil fatty acid ethyl, alkyl benzoate, isostearyl glyceryl, hexyldecyl isostearate, isopropyl isostearate, octyldodecyl isostearate, isostearic acid Socetyl, isostearyl isostearate, glyceryl isostearate, cholesteryl isostearate, isotridecyl isononanoate, isononyl isononanoate, isodecyl isononanoate, tridecyl isononanoate, octyl isopalmitate, octyl isopelargonate, cetyl ethylhexanoate, octyldodecyl erucate, cetostearyl ethylhexanoate, ethylene glycol fatty acid ester, octyldodecyl erucate, alkyl octanoate (C14, C16, C18), isocetyl octanoate, cetearyl octanoate, stearyl octanoate, cetyl octanoate, isostearyl octanoate, ethyl oleate, oleyl oleate, octyl oleate Ludodecyl, Decyl Oleate, Phytosteryl Oleate, Cetyl Caprate, Cetyl Caprylate, Dioctyl Succinate, Polypropylene Glycol Succinate Oligoester, Lanolin Acetate, Glyceryl Diisostearate, Neopentyl Glycol Diisostearate, Propylene Glycol Dicaprylate, Neopentyl Glycol Dicaprate, Neopentyl Glycol Dioctanoate, Ethylene Glycol Dioctanoate, Ethylene Glycol Dioleate, Propylene Glycol Dicaprate, Hexyldecyl Dimethyloctanoate, Octyldodecyl Dimethyloctanoate, Propylene Glycol Dipelargonate, Hexyldecyl Stearate, Dialkyl Carbonate, De Decaglyceryl isostearate, pentaerythrityl tetraoctanoate, diglyceryl tetraisostearate, glyceryl triisostearate, diglyceryl triisostearate, polyglyceryl triisostearate, trimethylolpropane triisostearate, glyceryl trioleate, glyceryl tricaprylate, trioctanoin, trimethylolpropane trioctanoate, caprylic/capric triglyceride, lauryl lactate, octyldodecyl lactate, hexyldecyl neodecanoate, decaglyceryl nonaisostearate, isostearyl palmitate, isopropyl palmitate, octyl palmitate, isocetyl palmitate, hyaluronic acid octyl droxystearate, isotridecyl myristate, isocetyl myristate, isostearyl myristate, isopropyl myristate, octyldodecyl myristate, isostearyl laurate, isopropyl lanolate, hexyl laurate, octyldodecyl ricinoleate, tocopherol linoleate, octyldodecyl ricinoleate, diisostearyl malate, etc.), silicone oils (e.g., dimethicone, trisiloxane, cyclopentasiloxane, diphenyl dimethicone, methylphenyl polysiloxane, etc.), silicones (e.g., (dimethicone/vinyl dimethicone) crosspolymer, (stearoxymethicone/dimethicone) copolymer, -, (dimethylsiloxane/methylcetyloxysiloxane) copolymer, stearyl dimethicone, cetyl dimethicone silicone, methyl hydrogen polysiloxane, alkoxy modified polysiloxane, phenyl trimethicone, aminopropyl dimethicone, alkyl methicone, polyether modified organopolysiloxane, polyoxyalkylene alkylmethyl polysiloxane-methyl polysiloxane copolymer, etc.), waxes (e.g., carnauba wax, candelilla wax, whale wax, beeswax, montan wax, rice wax, lanolin wax, etc.), essential oils (e.g., those derived from plant stems, flowers, buds, leaves, roots, fruit skins, bark, resins, etc., but are not limited to these). Particularly preferably, the "oils and fats" in the present invention are animal and vegetable oils and fats used for food (sometimes called edible oils).

In the present invention, any oil or fat may be used alone or in combination with different oils or fats.

The composition for application to mucosal epithelium of the present invention may contain any amount of oil, and the content of the oil, together with other components, may be an amount capable of imparting the composition for application to mucosal epithelium of the present invention with the desired properties described below. For example, the composition for application to mucosal epithelium of the present invention may contain oil in an amount appropriately selected from the range of 80.0% to 99.5% by mass, preferably 85.0% to 99.0% by mass, and more preferably 90.0% to 98.0% by mass. If the oil is less than 80.0% by mass or more than 99.5% by mass, the composition for application to mucosal epithelium of the present invention may not adhere sufficiently to the applied mucosal epithelium and may not remain there for a long time, or the active ingredient may not be released sufficiently.

In the present invention, the term "active ingredient" refers to any ingredient that is delivered to the mucosal epithelium by the composition for application to mucosal epithelium of the present invention and exhibits a specific activity, such as physiological activity. The active ingredient is not particularly limited, but a fat-soluble active ingredient is preferred. The "fat-soluble active ingredient" is preferably one that can be dissolved in the above-mentioned oils and fats, and examples of the "fat-soluble active ingredient" include, but are not limited to, menthol, vitamin E, vitamin A, vitamin K, vitamin D, gingerol, and sanshool. The composition for application to mucosal epithelium of the present invention can contain one or more active ingredients.

The composition for application to mucosal epithelium of the present invention may contain any amount of active ingredient, and the content may vary depending on factors such as the type and activity of the active ingredient, the form and method of use of the composition for application to mucosal epithelium, the age and weight of the subject, and the target symptom or condition, but may contain an amount that is effective for the target symptom or condition, and/or an amount that, together with other components, can impart the desired properties described below to the composition for application to mucosal epithelium of the present invention. For example, the composition for application to mucosal epithelium of the present invention may contain the active ingredient in an amount appropriately selected from the range of 0.001% to 20% by mass, preferably 0.01% to 10% by mass, and more preferably 0.1% to 5% by mass.

The composition for application to mucosal epithelium of the present invention is characterized by being substantially free of water. In the present invention, "substantially free of water" does not mean that the composition for application to mucosal epithelium of the present invention is completely free of water, and may contain water to the extent that the desired properties of the composition described below are not hindered. For example, the composition for application to mucosal epithelium of the present invention may contain water in an amount of 1% by mass or less. For example, the composition for application to mucosal epithelium of the present invention may contain water in an amount of about 0-1% by mass, 0-0.9% by mass, 0-0.8% by mass, 0-0.7% by mass, 0-0.6% by mass, or 0-0.5% by mass. This water includes water that is mixed into one or more raw materials constituting the composition for application to mucosal epithelium of the present invention during the preparation process of the raw materials. When the water content is more than 1% by mass, the composition for application to mucosal epithelium of the present invention may not adhere sufficiently to the applied mucosal epithelium or separation of oils and fats may not be suppressed, and the composition may not remain on the applied mucosal epithelium for a long time.

The composition for application to mucosal epithelium of the present invention may be in any form suitable for application to the mucosal epithelium. Preferably, the composition for application to mucosal epithelium of the present invention has the form of a sol, gel, paste, or cream. In particular, the composition for application to mucosal epithelium of the present invention preferably has a viscosity of 100 mPa·s to 20,000 mPa·s at 25°C and a shear rate of 10 (1/s), more preferably a viscosity of 200 mPa·s to 15,000 mPa·s under the same conditions, and even more preferably a viscosity of 200 mPa·s to 5,000 mPa·s.

The viscosity can be measured by removing particles of 1 mm or more from a sample using a rotational viscoelasticity measuring device (e.g., RheoStress 6000 manufactured by HAAKE Corporation) with a 35 mm diameter parallel plate at 25° C. and at shear rates ranging from 0.1 ^s to 300 ^s , starting from the low shear rate side.

And/or, the composition for application to mucosal epithelium of the present invention preferably has a gel strength at 25° C. of 800 N/m ² to 51,000 N/m ² , more preferably a gel strength under the same conditions of 650 N/m ² to 30,000 N/m ² , and even more preferably 500 N/m ² to 10,000 N/m ^2. By virtue of having such properties, the composition for application to mucosal epithelium of the present invention is likely to adhere to the mucosal epithelium to which it is applied, and can remain there for a long period of time.

The gel strength can be measured by filling a sample into a container with a diameter of 40 mm and a height of 15 mm, and measuring it at room temperature (20 to 25°C) using a rheometer (YAMADEN RE2-33005B) with a cylindrical plunger with a diameter of 20 mm at a compression speed of 10 mm/sec and a clearance of 5 mm.

The composition for application to mucosal epithelium of the present invention may further contain, in addition to the above-mentioned components, additives such as excipients, lubricants, binders, disintegrants, etc. that are commonly used in the manufacture of pharmaceuticals, foods, beverages, and cosmetics, as necessary, and may be manufactured and provided as pharmaceuticals, foods, beverages, and cosmetics having a dosage form or shape suitable for the intended administration route, ingestion method, and method of use.

Examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, glucose, corn starch, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminometasilicate, etc.

Examples of lubricants include sugar esters such as sucrose fatty acid esters and glycerin fatty acid esters, calcium stearate, magnesium stearate, stearic acid, stearyl alcohol, hydrogenated oils such as powdered vegetable oils and fats, waxes such as white beeswax, talc, silicic acid, silicon, etc.

Binders include, for example, pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, etc.

Examples of disintegrants include lactose, sucrose, starch, carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethylstarch, light anhydrous silicic acid, and low-substituted hydroxypropylcellulose.

In addition, the composition for application to mucosal epithelium of the present invention may further contain, as necessary, herbal medicines (e.g., royal jelly, ginseng, etc.), amino acids (e.g., glutamine, cysteine, leucine, arginine, etc.), polyhydric alcohols (e.g., ethylene glycol, polyethylene glycol, propylene glycol, glycerin, sugar alcohols, etc.), natural polymers (e.g., lecithin, starch, dextrin, etc.), vitamins (e.g., vitamin C, B vitamins, etc.), minerals (e.g., calcium, magnesium, zinc, iron, etc.), dietary fiber (e.g., mannan, pectin, hemicellulose, etc.), surfactants (e.g., glycerin fatty acid esters, sorbitan fatty acid esters, etc.), diluents, stabilizers, isotonicity agents, pH adjusters, buffers, wetting agents, solubilizers, suspending agents, colorants, flavorings, odorants, fragrances, antioxidants, sweeteners, taste-providing components, acidulants, etc. that are commonly used in the manufacture of pharmaceuticals, foods, beverages, and cosmetics, and may be manufactured and provided as pharmaceuticals, foods, beverages, and cosmetics having a dosage form or shape suitable for the intended administration route, ingestion method, and usage method.

The composition for application to mucosal epithelium of the present invention can be in any dosage form or shape, such as tablets, gums, sublingual tablets, troches, drops, buccal tablets, adhesive tablets, chewable tablets, powders, powders, granules, inhalants, suppositories, creams, ointments, gels, lotions, liniments, tics, aerosols, sprays, and patches. Preferably, the composition for application to mucosal epithelium of the present invention can be an oral composition, which may be encapsulated (e.g., hard capsules, soft capsules, sustained-release capsules, enteric-coated capsules, etc.) or coated (e.g., sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, etc.) as necessary, or may be in a dosage form with controlled release, such as sustained-release formulations, delayed-release formulations, or immediate-release formulations, using known techniques.

The composition for application to mucosal epithelium of the present invention can be used in mammals (e.g., humans, monkeys, chimpanzees, cows, horses, pigs, sheep, dogs, cats, mice, rats, etc.), preferably humans. The composition for application to mucosal epithelium of the present invention can remain on the mucosal epithelium to which it is applied for a long period of time, and can provide the active ingredient for a long period of time.

The dose of the composition for application to mucosal epithelium of the present invention may vary depending on factors such as the type and activity of the active ingredient, the form and method of use of the composition for application to mucosal epithelium, the age and weight of the subject, and the target symptoms and conditions, and any dose may be adopted. For example, if the composition for application to mucosal epithelium of the present invention is an oral composition, an amount of the active ingredient selected from 0.00001 mg/kg to 500 mg/kg per day may be administered or ingested once or multiple times (e.g., 2 to 5 times, preferably 2 to 3 times).

The composition for application to mucosal epithelium of the present invention can be effective in a small amount and for a short period of time, but can be used for a long period of time. For example, the composition for application to mucosal epithelium of the present invention can be used continuously for a period of one week or more, two weeks or more, one month or more, two months or more, six months or more, one year or more, or longer, according to the above-mentioned dosage and administration method.

The present invention will now be described in more detail with reference to examples.
<1. Oral mucosa >
1. Preparation of Compositions According to the compositions in Table 1 below, a composition of Example 1 containing an oil-based thickener (polyglycerol fatty acid ester (product name: TAISET AD (Taiyo Kagaku Co., Ltd.))), a composition of Comparative Example 1 containing neither an oil-based thickener nor a water-based thickener, and a composition of Comparative Example 2 containing a water-based thickener (xanthan gum) were prepared. The amount of each component in the table is shown by mass ratio.

An oil-based or water-based thickener was added to a given oil or fat according to the composition, and the mixture was heated to 90°C to dissolve, after which a sweetener was added and stirred at 20,000 rpm for 4 minutes with a stirrer. It was then allowed to cool to below 65°C, and a fat-soluble active ingredient (menthol) was added, stirred, and dissolved. The resulting composition was allowed to cool to 25°C and used in the following experiments.

2. Measurement of Viscosity and Gel Strength The viscosity at 25° C. and a shear rate of 10 (1/s) was measured to be 750 mPa·s. The gel strength at 25° C. was measured to be 2500 N/m ² .

3. Sensory Experiment After oral ingestion of each of the compositions of Example 1, Comparative Example 1, and Comparative Example 2, five panelists scored the cooling sensation felt in the oral cavity due to the active ingredient on a 10-point scale from "0: not felt" to "10: felt", and evaluated the sensation over time from 0 to 35 minutes after ingestion.

When taking the composition, the oral cavity was first reset by rinsing with water, and 1 g of the composition was measured out with a teaspoon, placed in the oral cavity, and then swallowed. An interval of at least 30 minutes was allowed before taking the next composition, and the oral cavity was then reset by rinsing with water before taking the next composition.

3. Results The results of the sensory test for each composition are shown in Figure 1. The results are shown as the average scores of five panelists.
The composition of Example 1 containing an oil-based thickener provided a stronger cooling sensation immediately after ingestion than the composition of Comparative Example 1 not containing a gelling agent. Also, the composition of Example 1 containing an oil-based thickener provided a longer cooling sensation than the composition of Comparative Example 1 not containing either an oil-based or water-based thickener, and the composition of Comparative Example 2 containing a water-based thickener.

On the other hand, the composition of Comparative Example 2, which contains an aqueous thickener, gave a stronger cooling sensation immediately after ingestion than the composition of Example 1, but the effect was extremely short-lived, and the effect was less than that of the composition of Example 1 when evaluated just 5 minutes after ingestion. After that, the effect was about the same as that of the composition of Comparative Example 1, which did not contain a gelling agent.

Furthermore, the composition of Example 1, which contained an oil-based thickener, gave a cool sensation in the mouth, throat, and stomach, whereas the composition of Comparative Example 1, which did not contain a gelling agent, and the composition of Comparative Example 2, which contained a water-based thickener, gave a cool sensation that was only felt in the mouth.

<2. Nasal mucosa >
1. Preparation of Compositions According to the compositions in Table 2 below, the composition of Example 2 containing an oil-based thickener (polyglycerin fatty acid ester (product name: TAISET AD (Taiyo Kagaku Co., Ltd.))), the composition of Example 2 containing an oil-based thickener (polyglycerin fatty acid ester (product name: TAISET AD (Taiyo Kagaku Co., Ltd.))), A composition of Comparative Example 3 that did not contain any thickener or aqueous thickener, and a composition of Comparative Example 4 that contained an aqueous thickener (xanthan gum) were prepared. The amount of each component in the table is the mass ratio. As shown in the figure.

The composition was prepared in the same manner as the composition described above in <1. Oral mucosa>, and the resulting composition was allowed to cool to 25°C before being used in the following experiments.

2. Sensory Experiment For each of the compositions of Example 2, Comparative Example 3, and Comparative Example 4, five panelists were asked to rate the cooling sensation due to the active ingredient felt after application to the nasal mucosa on a 10-point scale from "0: not felt" to "10: felt," and evaluated over time from 0 to 50 minutes after application.

When applying the composition, 0.1 g of the composition was soaked into a cotton swab and applied to the mucous membranes of both nostrils. Before applying the next composition, an interval of at least 1 hour was allowed to reset the inside of the nose.

3. Results The results of the sensory test for each composition are shown in Figure 2. The results are shown as the average scores of five panelists.

The composition of Comparative Example 4, which contains a water-based thickener, caused a strong, stinging cooling sensation immediately after application, a strong cooling sensation different from that of the composition of Example 2. However, the effect was extremely short-lived, and when evaluated just 5 minutes after application, there was no difference in effect from the composition of Example 2, and thereafter the effect decreased to the same level as that of the composition of Comparative Example 3.

On the other hand, the composition of Example 2, which contains an oil-based thickener, provided a gradual cooling sensation for a long period of time compared to the composition of Comparative Example 3, which does not contain either an oil-based or water-based thickener, and the composition of Comparative Example 4, which contains a water-based thickener.

From the above results, it was revealed that by including oils and active ingredients together with an oil-based thickener, the effects can be immediately exerted on the mucosal epithelium and can remain for a longer period of time compared to when no thickener is included or when a water-based thickener is included, thereby enabling the effects brought about by the active ingredient to be maintained for a longer period of time.

Claims (7)

A composition for application to mucosal epithelium , which comprises an oil-based thickener, a liquid oil, and a fat-soluble active ingredient, and is substantially free of water and is in the form of a sol, paste, or cream,
The oil-based thickener is a polyglycerol fatty acid ester,
Contains liquid oils and fats in an amount appropriately selected from the range of 80.0% by mass to 99.5% by mass,
A composition in which an oil-based thickener gels a liquid oil or fat, and the viscosity at 25°C and a shear rate of 10 (1/s) is 100 mPa·s to 20,000 mPa·s, or the gel strength at 25°C is 800 N/m 2 ^to 51,000 N/m ² . 2. The composition of claim 1 , having a viscosity of 750 mPa· s at 25° C. and a shear rate of 10 (1/s) or a gel strength of 2500 N/ ^m2 at 25° C. 3. The composition according to claim 1 or 2 , wherein the fat-soluble active ingredient is menthol, vitamin E, vitamin A, vitamin K, vitamin D, shogaol, or sanshool. The composition according to any one of claims 1 to 3 , having a moisture content of 1% by mass or less. The composition according to any one of claims 1 to 4 , wherein the mucosal epithelium is at least one mucosal epithelium selected from the group consisting of the mucosal epithelium of the eye, ear, nose, mouth, respiratory tract, digestive tract, urinary tract, and reproductive organs. The composition according to any one of claims 1 to 5 , which is an oral composition. The composition according to claim 6 , which is in an encapsulated or coated form.