JP5382972B2 - Composition with reduced viscosity prevention - Google Patents

Description

  The present invention relates to a composition for applying to mucosa in which the viscosity of a composition containing a cellulosic thickener is stably maintained. The present invention also relates to a method for stably maintaining the viscosity of a composition containing a cellulosic thickener. Furthermore, this invention relates to the method of improving the usability | use_condition of the composition containing a cellulosic thickener.

  In a composition applied to mucous membranes applied to ocular mucosa, nasal mucosa, intraoral mucosa, etc., it is necessary to improve the retention of the composition in the mucous membrane in order to enhance bioavailability. Then, the formulation design which mix | blended cellulose type thickeners, such as methylcellulose and a hydroxypropyl methylcellulose, made the composition viscosity was improved, and the retention was improved.

  In eye tissue, a simple treatment to relieve symptoms by administering artificial tears to dry eye, in other words, keratoconjunctival epithelial disorder caused by qualitative or quantitative abnormalities of tears There is a way. By adding a thickening agent such as methylcellulose to the artificial tears-type eye drops used for the treatment of dry eye, it is possible to expect a dry eye treatment effect with improvement in conjunctival sac retention.

  Useful effects such as the effect of improving mucosal retention and the effect of alleviating dry eye symptoms are mainly attributed to the viscosity imparted to the composition by containing the above-mentioned cellulosic thickener. Therefore, in the composition applied to mucosa, it is important to set an appropriate viscosity and to maintain a desired set viscosity stably for a long period of time.

  By the way, in order to increase the stability and solubility of medicinal components and the feeling of use (functionality), a surfactant may be added to the composition applied to mucous membranes such as eye drops and eye wash. It has been found that the viscosity of the composition containing the cellulosic thickener decreases with time in the presence of a nonionic surfactant. The decrease in viscosity affects the feeling in use and may reduce the effect of the thickening agent.

  To date, polymers of bioadhesives or viscosity enhancing agents such as poly (acrylic acids), acrylate copolymers, cross-linked polyacrylic acids, cellulose, cellulose derivatives, dextran, hyaluronic acid Decomposition is facilitated by metal ions in solution or slurry, but free metal ions can be reduced by using phosphonic acid or phosphonic acid ester, a chelating agent that has a greater ability to complex with free ions than EDTA. It has been found that the viscosity of the polymer composition can be reduced to reduce the rate of disintegration, degradation or other inactivation (US Pat.

  Moreover, it has been found that viscosity reduction due to light or heat of thickening agents such as cellulose derivatives and polyvinyl compounds can be suppressed by blending xanthines and nonionic surfactants or chelating agents (Patent Literature). 2). However, none of the literature has known a method for suppressing a decrease in viscosity when a cellulosic thickener and a surfactant are used in combination.

  By the way, when a composition containing a thickening agent is applied to the eyes, depending on the viscosity of the applied composition, it may feel sticky or may feel resistance in blinking. In addition, the sensation of use may be affected, for example, the field of view may be unclear for a while after application. Therefore, it is important not only to suppress the decrease in viscosity but also to improve the feeling of use when applying the composition to the mucosa at a desired viscosity.

Japanese National Patent Publication No. 11-510480 JP 2003-201241 A

  Therefore, there has been a demand for a method for maintaining the viscosity of the composition imparted by the cellulosic thickener for a long time even in the presence of a nonionic surfactant. Moreover, the method of improving the usability | use_condition of the composition containing a cellulose thickener was calculated | required.

  As a result of intensive studies to achieve the above object, the present inventors have found that a) a composition containing a cellulose-based thickener and b) a nonionic surfactant, c) sesame oil, olive oil, soybean The viscosity of the composition applied to mucosa is determined by containing at least one vegetable oil selected from oil or peanut oil, almond oil, wheat germ oil, camellia oil, corn oil, rapeseed oil, sunflower oil, cottonseed oil and coconut oil The present invention has been completed by finding that it can be stably maintained at a viscosity of 5 and that the feeling in use can be improved.

The present invention has been developed based on such knowledge.
That is, the present invention is a composition listed in the following (1) to (7):
(1) i) cellulosic thickener, ii) nonionic surfactant, and iii) sesame oil, olive oil, soybean oil, peanut oil, almond oil, wheat germ oil, camellia oil, corn oil, rapeseed oil A mucosa-applied composition containing at least one vegetable oil selected from sunflower oil, cottonseed oil or coconut oil,
(2) The composition applied to mucosa according to (1), wherein the viscosity at 20 ° C. is 2 mPa · s or more and 100,000 mPa · s or less,
(3) The mucosal application according to (1) or (2), wherein the cellulosic thickener is at least one selected from methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, or a salt thereof. Composition,
(4) The nonionic surfactant is a nonionic surfactant selected from a polyoxyethylene-polyoxypropylene block copolymer, a polyoxyethylene sorbitan fatty acid ester or a polyoxyethylene hydrogenated castor oil (1 ) To (3), the composition for applying to mucosa,
(5) The composition for applying to mucosa according to any one of (1) to (4), which is an eye drop, an eye wash, a contact lens mounting solution, and a nasal drop,
(6) The composition for applying to mucosa according to any one of (1) to (5), wherein the pH is 4.0 to 10.0.
(7) The composition for applying to mucosa according to any one of (1) to (6), further comprising an ethylenediamineacetic acid derivative or a salt thereof,
(8) The composition for applying to mucosa according to any one of (1) to (7), further comprising one or more compounds selected from menthol, camphor or borneol,
Furthermore, the present invention is the method described in the following (9) to (10):
(9) Sesame oil, olive oil, soybean oil, peanut oil, almond oil, wheat germ oil, camellia oil, corn oil, rapeseed oil, sunflower oil, cottonseed oil or with cellulosic thickener and nonionic surfactant A method of stabilizing the viscosity of a composition by blending at least one vegetable oil selected from coconut oil.
(10) Sesame oil, olive oil, soybean oil, peanut oil, almond oil, wheat germ oil, camellia oil, corn oil, rapeseed oil, sunflower oil, cottonseed oil or with cellulosic thickener and nonionic surfactant A method of stabilizing the feeling of use of a composition by blending at least one vegetable oil selected from coconut oil.
In the present specification, unless otherwise specified,% means w / v%. Further, in the present specification, the contact lens is meant to include all types of contact lenses such as hard, oxygen permeable hard, soft, and color.

  In this invention, the fall of the viscosity of a composition can be prevented by containing a specific vegetable oil in the composition containing a cellulose thickening agent and a nonionic surfactant. The mucosa-applied composition of the present invention having such effects includes eye drops, eye washes, eye ointments, contact lens mounting liquids, contact lens preparations (cleaning liquids, storage liquids, bactericidal liquids, multipurpose solutions, etc.) It is useful as an ophthalmic composition such as an ophthalmic composition and a nasal drop.

  The cellulose thickening agent in the present invention is a cellulose derivative obtained by replacing the hydroxyl group of cellulose with a polar group or a nonpolar group, and is a compound capable of imparting viscosity to an aqueous composition. Examples of the functional group that substitutes the hydroxyl group of cellulose include a methoxyl group, an ethoxyl group, a hydroxyethoxyl group, and a hydroxypropoxyl group. Examples of cellulose derivatives include methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, carboxyethyl cellulose, and pharmacologically acceptable salts thereof. Among these, at least one selected from methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, or a salt thereof is preferable. Here, examples of the pharmacologically acceptable salt include alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, and salts with metals such as aluminum.

  In addition, the cellulose thickening agent used in the present invention is not limited in the degree of substitution of the substituent or the molecular weight, but for example, the weight average molecular weight is 50,000 to 1,000,000, preferably 10,000 to 500,000, and more preferably. Can be about 10,000 to 100,000. Moreover, a commercially available thing can be used for these cellulose type thickening agents, You may use these compounds combining 1 type (s) or 2 or more types.

  The amount of cellulosic thickener used for the composition applied to mucosa can be set as appropriate according to the desired viscosity to be applied to the composition, and varies depending on the molecular weight and type, but cannot generally be specified. The concentration of the thickening agent in the composition is 0.001 to 10%, preferably 0.005 to 5%, more preferably 0.01 to 2%, and particularly preferably about 0.1 to 2%. be able to.

  The nonionic surfactant in the present invention decreases the viscosity of the composition applied to mucosa by blending with a cellulosic thickener, but suppresses the decrease in viscosity of the composition applied to mucosa by blending with a specific vegetable oil. it can. As such a nonionic surfactant, those which can be usually used by those skilled in the art for a composition applied to mucosa can be used. For example, polyoxyethylene (hereinafter also referred to as POE) which is a nonionic surfactant. A polyoxypropylene (hereinafter also referred to as POP) block copolymer (for example, poloxamer 407, poloxamer 235, poloxamer 188, etc.); a POE-POP block copolymer adduct of ethylenediamine such as poloxamine; POE (20) sorbitan monolaurate ( POE sorbitan fatty acid esters such as polysorbate 20), monooleic acid POE (20) sorbitan (polysorbate 80), POE sorbitan monostearate (polysorbate 60), POE sorbitan tristearate (polysorbate 65); POE hydrogenated castor oil 5, POE cured chick POE hardened castor oils such as Pear oil 10, POE hardened castor oil 20, POE hardened castor oil 50, POE hardened castor oil 50, POE hardened castor oil 60, POE hardened castor oil 100; POE such as POE (9) lauryl ether POE (20) POP (4) POE / POP alkyl ethers such as cetyl ether; POE alkyl phenyl ethers such as POE (10) nonyl phenyl ether. The numbers in parentheses indicate the number of added moles.

  Among them, nonionic surfactants selected from polyoxyethylene-polyoxypropylene block copolymers, POE sorbitan fatty acid esters or POE hydrogenated castor oils are preferable, and polyoxyethylene-polyoxypropylene blocks are particularly preferable. Copolymer, polysorbate 80, polyoxyethylene hydrogenated castor oil 60.

  The amount of the nonionic surfactant used in the ophthalmic composition varies depending on the type of the surfactant and the like, and thus cannot be specified unconditionally, but is usually 0.0001 to 5%, preferably 0.001 to 1%. More preferably, it is used at about 0.001 to 0.8%, particularly preferably about 0.005 to 0.5%. The ratio of the nonionic surfactant and the specific vegetable oil of the present invention varies depending on the type of vegetable oil and cannot be defined unconditionally. Usually, however, the total amount of nonionic surfactant is 1 part by weight of the total amount of vegetable oil. Is preferably 0.5 to 100 parts by weight, more preferably 1 to 50 parts by weight, still more preferably 1 to 10 parts by weight, and particularly preferably about 2 to 8 parts by weight.

  In the composition of the present invention, a specific vegetable oil is selected from sesame oil, olive oil, soybean oil or peanut oil, almond oil, wheat germ oil, camellia oil, corn oil, rapeseed oil, sunflower oil, cottonseed oil or coconut oil Contains at least one vegetable oil as an essential component.

  Sesame oil refers to a vegetable oil obtained from the seeds of a plant belonging to the genus Sesame, such as Sesamum indicum Linne (Pedaliaceae). It can be obtained from seeds using known exploitation methods and known purification methods. For example, sesame oil listed in the Japanese Pharmacopoeia (see 14th revision Japanese Pharmacopoeia Description D-389-390) It can be obtained by refining the collected oil without frying.

  Olive oil refers to a vegetable oil obtained from the fruit of a plant belonging to the genus Oleaceae (Olea europaea Linne (Oleaceae), etc.). It can be obtained from fruits using known exploitation methods and known purification methods. For example, olive oil listed in the Japanese Pharmacopoeia (see 14th revised Japanese Pharmacopoeia D-174-177) is a mature fruit The oil can be immediately extracted by a cold pressure (squeezing without heating) method, then processed by physical filtration or centrifugation, and subjected to a normal purification step.

  Soybean oil refers to a vegetable oil obtained from the seed of a plant of the leguminous soybean genus (Glycine max Merrill (Leguminosae, etc.)). It can be obtained from seeds using known exploitation methods and known purification methods. For example, soybean oil listed in the Japanese Pharmacopoeia (see 14th revised Japanese Pharmacopoeia D-700-701) After crushing and crushing (essential oil can be obtained by cold pressure or hot pressure), oil can be collected by extraction with a solvent (hexane).

  Peanut oil refers to a vegetable oil obtained from seeds of a plant belonging to the genus Arachis hypogaea Linne (Leguminosae). It can be obtained from seeds using known exploitation methods and known purification methods. For example, peanut oil listed in the Japanese Pharmacopoeia (see 14th revised Japanese Pharmacopoeia Description D-1194-1196), seed Can be obtained by crushing with a roll, heating, pressing, and filtering and purifying the oil obtained.

  Almond oil refers to a vegetable oil obtained from the nuclear seeds of the Rosaceae family, such as Prunus amygdalus Batsch (Rosaceae). It can be obtained from nuclei using a known exploitation method or a known purification method (see Pharmaceutical Additive Standard 1998, P97, etc.).

  Wheat germ oil refers to vegetable oil obtained from the germ of plants of the genus Wheat (Triticum aestivum Linne (Gramdneae), etc.). It can be obtained from the embryo using a known exploitation method or a known purification method (see Pharmaceutical Additive Standard 1998 P318 etc.).

  Camellia oil refers to a vegetable oil obtained from the seeds of plants belonging to the genus Camellia japonica Linne (Theaceae). It can be obtained from seeds using known exploitation methods and known purification methods. For example, camellia oil listed in the Japanese Pharmacopoeia (see 14th revised Japanese Pharmacopoeia Description D-778-779) It is obtained by pulverizing, steaming and pressing seeds that have been sun-dried or artificially dried and then seeded, and then purified by filtration.

  Corn oil refers to a vegetable oil obtained from the germ of a genus Gramineae (Zea mays Linne (Gramineae), etc.). It can be obtained from embryos using known exploitation methods and known purification methods. For example, corn oil listed in the Japanese Pharmacopoeia (see 14th revised Japanese Pharmacopoeia D-816-817) Can be separated from the grain, pressed after rapid drying, extracted with hexane and oiled.

  Rapeseed oil refers to a vegetable oil obtained from the seeds of plants of the Brassicaceae genus Brassica (Brassica campestris Linne subsp. Napus Hooker fil. Et Anderson var. Nippo-oleifera Makino (Cruciferae), etc.). It can be obtained from seeds using known exploitation methods or known purification methods. For example, rapeseed oil listed in the Japanese Pharmacopoeia (see 14th revised Japanese Pharmacopoeia D-839) heats the seeds. After squeezing, the residue is generally solvent extracted and combined with the squeezed oil to obtain crude oil. The crude oil obtained is refined and used.

  Sunflower oil is a vegetable oil obtained from the seeds of plants of the genus Helianthus annuus Linne (Compositae), which can be obtained from seeds using known extraction methods and known purification methods (standards for pharmaceutical additives) 1998 P518 etc.).

  Cottonseed oil refers to a vegetable oil obtained from the seeds of a plant of the family Mallow (Gossypium hirsutum Linne (Gossypium) or its genus plant (Malvaceae), etc.). It can be obtained from seeds using a known extraction method or a known purification method. For example, it can be obtained by purifying non-volatile fatty oil obtained from a seed by a pressing method or extraction method (standard for pharmaceutical additives) 1998 P719 or 14th revision Japanese Pharmacopoeia Manual B-936 etc.).

  Palm oil refers to a vegetable oil obtained from the seeds of a plant of the genus Cocos nucifera Linne (Palmae). It can be obtained from seeds using known exploitation methods or known purification methods. For example, palm oil listed in the Japanese Pharmacopoeia (see 14th revised Japanese Pharmacopoeia Description D-1160 to 1161), Copra It is obtained by crushing, steaming and squeezing, removing the suspended solids and purifying.

  These specific oils can be used alone or in combination of two or more. Of these, sesame oil, olive oil, soybean oil, and peanut oil are preferable, and sesame oil is particularly preferable. In addition, as these specific vegetable oils, those that can be used for a composition applied to mucosa by those skilled in the art can be used, and commercially available ones can also be used.

  The amount of the specific vegetable oil of the present invention used in the composition applied to mucosa varies depending on the type of vegetable oil and the like, but cannot be specified unconditionally, but is usually 0.00001 to 60%, preferably 0.0001 to 30%, more preferably. Is 0.0001 to 10%, particularly preferably about 0.001 to 1%. In the case of an ophthalmic composition, about 0.00001 to 0.5% is more preferable. Furthermore, specifically in the case of sesame oil, it is usually 0.00001 to 20%, preferably 0.0001 to 10%, more preferably 0.0001 to 5%, particularly preferably about 0.0005 to 0.3%. is there.

  The viscosity reduction inhibitory effect of the specific vegetable oil of the present invention becomes more prominent when an ethylenediamineacetic acid derivative or a salt thereof is blended in the mucosa-applied composition. In the present invention, a cellulosic thickener and a nonionic surfactant are contained, but the viscosity is stably maintained by containing a specific vegetable oil, and further, an ethylenediamineacetic acid derivative or a salt thereof is added. By containing, a mucosa-applied composition with further improved viscosity stability can be obtained.

  Examples of such ethylenediamineacetic acid derivatives or salts thereof include edetic acid (ethylenediaminetetraacetic acid, EDTA), ethylenediaminediacetic acid (EDDA), diethylenetriaminepentaacetic acid (DTPA), and N- (2-hydroxyethyl) ethylenediaminetriacetic acid (HEDTA). Etc. can be exemplified. These may be used alone or in combination, and may be used as a pharmacologically or physiologically acceptable salt (for example, sodium ethylenediaminetetraacetate). Among them, ethylenediaminetetraacetic acid or a salt thereof is preferable, for example, ethylenediaminetetraacetic acid disodium, ethylenediaminetetraacetic acid disodium dihydrate (hereinafter also referred to as sodium edetate).

  The content of the ethylenediamineacetic acid derivative or a salt thereof in the composition for applying to mucosa of the present invention varies depending on the molecular weight, type, etc., and thus cannot be defined unconditionally, but is preferably 0.0001 to 1%, more preferably 0.0005 to 0.00. 5%, particularly preferably about 0.001 to 0.3%.

  When one or more compounds selected from menthol, camphor or borneol are further added to the composition for applying to mucosa of the present invention, the effect of improving the feeling of use becomes more remarkable. These compounds may be d-form, l-form or dl-form. Moreover, you may use essential oils, such as peppermint oil and eucalyptus oil.

  The use amount of one or more compounds selected from menthol, camphor or borneol in the composition for applying to mucosa of the present invention is preferably 0.0001 to 5%, and preferably 0.001 to 2% as the total amount of the compounds. Is more preferable, 0.005 to 1% is more preferable, and 0.007 to 0.8% is particularly preferable.

  In the present invention, the composition for applying to mucosa containing a cellulosic thickener can be initially set to an appropriate viscosity to obtain a desired effect, and the set viscosity can be stably maintained over a long period of time. The viscosity of the ophthalmic composition has a great effect on the comfort (use feeling), drug retention, and treatment of diseases such as dry eye when applied to the ocular mucosa. It is important that the designed viscosity is kept stable over the long term. In the case of setting an appropriate viscosity, it is usually designed to be 1.2 mPa · s or higher, for example, an ophthalmic composition with a viscosity at 20 ° C. of 2 mPa · s or higher, usually 2 to 300 mPa · s, Preferably, it can be designed to be 2 to 200 mPa · s, particularly preferably 5 to 100 mPa · s, and more preferably about 10 to 80 mPa · s. If the viscosity is 2 mPa · s or less, the useful effect of the cellulosic thickener cannot be sufficiently exerted, and if it is 300 mPa · s or more, the stickiness is large and management of the production process tends to be difficult. The nasal composition is preferably designed with a viscosity at 20 ° C. of 2 to 100,000 mPa · s or more, usually 2 to 100,000 mPa · s, preferably 50 to 10,000 mPa · s, particularly Preferably, it can design to about 100-5000 mPa * s.

  The use application of the mucosa of the present invention is not specified as long as it uses the effects of the invention, and can be used in various fields such as pharmaceuticals, quasi drugs, and miscellaneous goods. For example, eye drops (including eye drops that can be used while wearing hard or soft contact lenses, also referred to as eye drops), eye wash (hard or soft contact lenses should also be used while wearing Eye ointment, contact lens mounting solution, contact lens preparation (cleaning solution, preservative solution, bactericidal solution, multi-purpose solution, etc.), nasal drops and the like. Among these, it is useful for eye drops, eye wash, contact lens mounting liquid, and nasal drops.

The mucosa-applied composition of the present invention may contain various components (including pharmacologically active components and physiologically active components) in combination as long as the effects of the present invention are not hindered. The type of such components is not particularly limited, and examples thereof include, for example, a decongestant component, an eye regulator component, an anti-inflammatory component or an astringent component, an antihistamine component or an antiallergic component, vitamins, amino acids, and antibacterial agents. Examples include components, bactericidal components, saccharides, polysaccharides or derivatives thereof, cellulose or derivatives or salts thereof, water-soluble polymers other than those described above, local anesthetic components, steroid components, and glaucoma therapeutic agents. Examples of suitable components in the present invention include the following components.
Decongestant: For example, α-adrenergic agonists, specifically epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, epinephrine hydrogen tartrate, naphazoline nitrate. These may be d-form, l-form or dl-form.
Eye muscle modulator component: For example, cholinesterase inhibitor having an active center similar to acetylcholine, specifically, neostigmine methyl sulfate, tropicamide, atropine sulfate helenien, and the like.
Anti-inflammatory component or astringent component: for example, zinc sulfate, zinc lactate, allantoin, epsilon-aminocaproic acid, indomethacin, lysozyme chloride, silver nitrate, pranoprofen, sodium azulenesulfonate, dipotassium glycyrrhizinate, diclofenac sodium, bromfena Sodium chloride, berberine chloride, berberine sulfate, etc.
Antihistamine component or antiallergic agent component: for example, acitazanolast, amlexanox, ibudilast, tranilast, diphenhydramine hydrochloride, levocabastine hydrochloride, ketotifen fumarate, sodium cromoglycate, pemirolast potassium, chlorpheniramine maleate, and the like.
Vitamins: for example, retinol acetate, retinol palmitate, pyridoxine hydrochloride, flavin adenine dinucleotide sodium, pyridoxal phosphate, cyanocobalamin, panthenol, calcium pantothenate, sodium pantothenate, ascorbic acid, tocopherol acetate and the like.
Amino acids: For example, aminoethylsulfonic acid (taurine), glutamic acid, creatinine, potassium aspartate, magnesium aspartate, magnesium / aspartate mixture, sodium glutamate, sodium chondroitin sulfate and the like. These may be d-form, l-form or dl-form.
Antibacterial component or bactericidal component: For example, alkylpolyaminoethylglycine, sulfamethoxazole, sulfisoxazole, sulfamethoxazole sodium, sulfisomidine sodium, berberine sulfate, berberine chloride, boro Acid, etc.
Sugars: for example, monosaccharides, disaccharides, specifically glucose, trehalose and the like.
Polysaccharides or derivatives thereof: for example, sodium hyaluronate, sodium chondroitin sulfate, etc.
Cellulose or a derivative thereof or a salt thereof: for example, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose and the like.
Water-soluble polymers other than those described above: polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone, and the like.
Local anesthetic components: for example, oxybuprocaine hydrochloride, cocaine hydrochloride, cornecaine hydrochloride, dibucaine hydrochloride, tetracaine hydrochloride, diethylaminoethyl parabutylaminobenzoate, piperocaine hydrochloride, procaine hydrochloride, proparacaine hydrochloride, hexothiocaine hydrochloride, lidocaine hydrochloride.
Steroid component: for example, dexamethasone, hydrocortisone, fluorometholone, prednisolone, methylprednisolone, hydroxymesterone, hydrocortisone caproate, prednisolone caproate, cortisone acetate, hydrocortisone acetate, prednisolone acetate, sodium dexamethasone metasulfobenzoate, sodium dexamethasone sulfate Dexamethasone sodium phosphate, triamcinolone acetonide, betamethasone sodium phosphate, dexamethasone sodium metasulfobenzoate, methylprednisolone and the like.

  The compounding amounts of these components in the mucosa-applied composition are appropriately selected according to the type of preparation, the type of active ingredient, and the like, and the compounding amounts of various components are known in the art. For example, it can be selected from the range of about 0.0001 to 30%, preferably about 0.001 to 10% with respect to the whole preparation. More specifically, the content of each component is, for example, as follows for the ophthalmic composition.

Decongestant component (vasoconstrictor or sympathomimetic drug): For example, 0.0001 to 0.5%, preferably 0.0005 to 0.3%, more preferably 0.001 to 0.1%.
Eye muscle modulator component: For example, 0.0001 to 0.5%, preferably 0.0005 to 0.1%, more preferably 0.0005 to 0.01%.
Anti-inflammatory component or astringent component: for example, 0.0001-10%, preferably 0.0001-5%.
Antihistamine component or antiallergic agent component: for example, 0.0001 to 10%, preferably 0.001 to 5%.
Vitamins: For example, 0.0001 to 1%, preferably 0.0001 to 0.5%.
Amino acids: For example, 0.0001 to 10%, preferably 0.001 to 3%.
Antibacterial component or bactericidal component: For example, 0.00001 to 10%, preferably 0.0001 to 10%.
Saccharides: For example, 0.0001 to 5%, preferably 0.001 to 5%, more preferably 0.01 to 2%.
Polysaccharide or derivative thereof: for example, 0.0001 to 2%, preferably 0.01 to 2%, more preferably 0.01 to 1%.
Cellulose or a derivative thereof or a salt thereof: For example, 0.001 to 5%, preferably 0.01 to 1%.
Water-soluble polymers other than those described above: For example, 0.001 to 10%, preferably 0.001 to 5%, more preferably 0.01 to 3%.
Local anesthetic component: For example, 0.001-1%, preferably 0.01-1%.
Steroid component: For example, 0.001 to 1%, preferably 0.01 to 1%.

  Further, in the composition for applying to mucosa of the present invention, various components and additives are appropriately selected according to conventional methods according to the use and form as long as the effects of the invention are not impaired. May be used in combination. As those components or additives, for example, carriers (water, aqueous solvents, aqueous or oily bases, etc.) commonly used in the preparation of semi-solids and liquids, thickeners, sugars, surfactants, Various additives such as preservatives, bactericides or antibacterial agents, pH regulators, tonicity agents, fragrances or refreshing agents, and buffering agents can be mentioned.

Although the typical component used for the mucosa application composition of this invention is illustrated below, it is not limited to these.
Thickeners: for example, dextran, carboxyvinyl polymer, alginic acid or a salt thereof, polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone, macrogol, chondroitin sodium sulfate and the like.
Sugars: for example, glucose, cyclodextrin and the like.
Sugar alcohols: For example, xylitol, sorbitol, mannitol and the like.
These may be d-form, l-form or dl-form.
Surfactant: For example, glycine-type amphoteric surfactant such as alkyldiaminoethylglycine; alkyl quaternary ammonium salt (specifically, cationic surfactant such as benzalkonium chloride, benzethonium chloride, etc.) The number indicates the number of moles added.
Preservatives, bactericides or antibacterial agents: for example, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, paraoxy Methyl benzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide, etc.), Glow Kill (manufactured by Rhodia) Name) etc.
pH adjuster: For example, hydrochloric acid, boric acid, aminoethylsulfonic acid, epsilon-aminocaproic acid, acetic acid, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, borax, triethanolamine, monoethanolamine and the like.
Isotonizing agents: for example, sodium bisulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, dihydrogen phosphate Sodium, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glycerin, propylene glycol and the like.
Fragrance or cooling agent: For example, geraniol, menthone, linalyl acetate, citral other than those described above. These may be d-form, l-form or dl-form.
Buffer: aminoethyl sulfonic acid, epsilon-aminocaproic acid, citrate buffer, acetate buffer, carbonate buffer, borate buffer, phosphate buffer, etc. Specifically, citric acid, sodium citrate, acetic acid, potassium acetate, sodium acetate, sodium hydrogen carbonate, sodium carbonate, boric acid, borax, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate Such.
Stabilizer: Dibutylhydroxytoluene, trometamol, sodium formaldehyde sulfoxylate (Longalite), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, etc.
Solubilizer, base: octyldodecanol, titanium oxide, potassium bromide, paraffin, castor oil, plastibase, lanolin, petrolatum, etc.

Thickener: 0.0005 to 50%, for example, preferably 0.001 to 10%
Saccharides: for example 0.001 to 10%, preferably 0.01 to 5%
Surfactant: For example, 0.0001 to 10%, preferably 0.005 to 5%
Preservative, bactericidal agent or antibacterial agent: for example, 0.00001-5%, preferably 0.0001-2%
pH regulator: for example, 0.00001-5%, preferably 0.0001-2%
Isotonizing agent: for example 0.001 to 10%, preferably 0.01 to 5%
Perfume or refreshing agent: for example, 0.00001-5%, preferably 0.0001-2%
Buffer: for example 0.001-10%, preferably 0.01-5%

  The mucosa-applied composition of the present invention is used after adjusting to an osmotic pressure within a range acceptable for a living body, if necessary. The osmotic pressure is about 100 to 1200 mOsm, preferably about 100 to 600 mOsm, particularly preferably about 150 to 400 mOsm, and the osmotic pressure ratio with respect to physiological saline is usually 0.3 to 4.1, preferably 0.3 to 2. 1, particularly preferably about 0.5 to 1.4.

The mucosa-applied composition of the present invention is used after adjusting to an osmotic pressure within a range applicable to a living body, if necessary. The pH is usually pH 4.0 to 10.0, preferably 4.5 to 9.5, particularly preferably 5.0 to 9.0. The pH can be adjusted using a buffer, the pH adjuster, or the like.
Here, examples of the buffer include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, and acetate buffer. Preferred buffering agents are borate buffer, phosphate buffer, carbonate buffer and citrate buffer. Particularly preferred buffering agents are borate buffers or phosphate buffers. Examples of the boric acid buffer include borates such as boric acid, alkali metal borates, and alkaline earth metal borates, and combinations of boric acid and borates. Examples of the phosphate buffer include phosphates such as phosphoric acid, alkali metal phosphates, and alkaline earth metal phosphates, and combinations of phosphoric acid and phosphates. Moreover, you may use the borate or the hydrate of a phosphate as a borate buffer or a phosphate buffer. More specifically, boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, etc.), phosphoric acid or a salt thereof (sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, etc.) , Carbonic acid or a salt thereof (sodium bicarbonate, sodium carbonate, etc.), citric acid or a salt thereof (sodium citrate, potassium citrate, etc.). When a borate buffer or a phosphate buffer is used as the buffer, the concentration of these buffers in the ophthalmic composition of the present invention is, for example, about 0.0001 to 10.0%.

  The composition applied to mucosa of the present invention can be produced by a known method. Semi-solid and liquid preparations can be prepared by mixing the base and each component. Furthermore, if necessary, a filtration sterilization treatment process, a container filling process, and the like can be added.

The present invention also includes a cellulosic thickener, a nonionic surfactant, and sesame oil, olive oil, soybean oil, peanut oil, almond oil, wheat germ oil, camellia oil, corn oil, rapeseed oil, sunflower oil And a method of stabilizing the viscosity of the composition by blending at least one vegetable oil selected from cottonseed oil or coconut oil.
Furthermore, the present invention provides a cellulosic thickening agent, a nonionic surfactant, and sesame oil, olive oil, soybean oil, peanut oil, almond oil, wheat germ oil, camellia oil, corn oil, rapeseed oil, sunflower oil And a method of improving the feeling of use of the composition by blending at least one vegetable oil selected from cottonseed oil or coconut oil. In addition, the kind of cellulose thickener to contain, the kind of nonionic surfactant, specific vegetable oil, these usage-amounts, etc. can be performed according to the above-mentioned description regarding the composition of this invention.

Hereinafter, the present invention will be described in detail based on test examples and examples, but the present invention is not limited to these examples.
Viscosity measurement method Viscosity measurement method is a method using a cone-and-plate rotational viscometer (general test method, 45. Viscosity measurement method, second method rotational viscometer method described in the 14th revised Japanese pharmacy method, "( 3) The method described in the section “Cone-plate rotational viscometer” was followed. Specifically, the measurement was performed using a commercially available cone-plate type rotational viscometer and an appropriately selected rotor.
In measuring the viscosity, commercially available viscometers such as E-type viscometers (manufactured by TOKIMEC, sold by Toki Sangyo (Japan)), Synchroelectric PC type (Brookfield, USA), Ferran Tishari (Feranti, UK), Rot Visco R (Haake, Germany), IGK Hischer Rheometer (Ishida Giken, Japan), Shimadzu Rheometer R (Shimadzu, Japan), Weissenberg Greogoniometer (Sangamo, UK), Mechanical spectrometers (Rheometrics, US) can be used. Then, by appropriately selecting these commercially available viscometers and rotors, by appropriately adjusting the petroleum-based hydrocarbon oil (Newtonian fluid) defined by JIS Z8809 for each test sample measurement as a calibration standard solution, The viscosity at 20 ° C. can be measured.

Specifically, as shown in FIG. 1, a sample is put into a gap having an angle α between the cone 1 and the flat disk 2, and the cone 1 or the flat disk 2 is rotated at a constant angular velocity ω or torque T. The torque or angular velocity received by the flat disc 2 or the cone 1 when reaching a steady state was measured, and the viscosity was measured by calculating the viscosity η of the sample by the following equation.
η = 100 × (3α / 2πR ³ ) · (T / ω)
η: Viscosity of sample (mPa · s) (Pa · s = 10 ³ mPa · s)
α: Angle formed by flat disk 2 and cone 1 (rad)
π: Circumference ratio R: Radius of cone 1 (cm)
T: Torque (10 ⁻⁷ N · m) acting on the flat disk 2 or the conical surface
ω: Angular velocity (rad / s)

The viscosity of each comparative example and each example in this test is a TVE-20L type viscometer cone plate type (manufactured by TOKIMEC, Toki Sangyo (Japan)), which is a type of E-type viscometer. Measurement was performed under the following measurement conditions.
Measurement condition:
Standard scale cone rotor (equivalent to cone 1 in Fig. 1) (α = 1 ° 34 ', radius (R) = 24mm) attached to TVE-20L type viscometer cone plate type, full scale torque 6.737 × 10 ^-7 Nm Rotate with a motor through the spring. During measurement, the viscometer is installed so that the rotation axis is perpendicular to the horizontal plane.
1 ml of the test sample is placed on a predetermined position of the cone rotor (a plate, which corresponds to the flat disk 2 in FIG. 1), and is left until the temperature reaches 20.0 ° C. Next, the apparatus is rotated at a rotational speed corresponding to the viscosity of the test sample, and the displayed viscosity is read. In order to obtain highly accurate measurement results, before measurement of the test sample, petroleum-based hydrocarbon oil (Newtonian fluid) specified by JIS Z 8809 is used as the calibration standard solution, and the measured value is the viscosity of the standard solution. Adjust to match. The same result can be obtained by using a commercially available model other than the TVE-20L viscometer cone plate type, selecting a cone rotor in the same manner as described above, and performing calibration appropriately.
Rotor used: Standard rotor (1 ° 34 ', R = 24mm)
Rotation speed: 50rpm
Sample volume: 1ml
Measurement temperature: 20 ° C
Time: Viscosity after 3 minutes was taken as a measured value.

Test Example 1 The preparation of each Example and Test Example used in the viscosity stability test was performed according to the formulation shown in Table 1. Specifically, the preparation method of Example 1 is shown. 0.6 g of hydroxyethyl cellulose (trade name “Fuji Chemi HEC” CF-V, manufactured by Sumitomo Seika) was stirred and dissolved in 100 ml of purified water, and after dissolving hydroxyethyl cellulose (HEC in the table), 3.6 g boric acid, 0.7 g borax was added and dissolved (conditioning liquid A). Add 1.0 ml of polysorbate 80 (trade name “Nikkor TO-10M” manufactured by Nippon Surfactant) and 0.01 g of sesame oil (trade name “Nippon Sesame Oil” manufactured by Kadoya Oil Co., Ltd.) to 50 ml of purified water while stirring and dissolving. The mixture was dissolved with stirring (conditioning liquid B). Adjustment liquid B was added to adjustment liquid A, and purified water was further added to make a total of 200 ml (pH = 7.2). After measuring the viscosity, each glass bottle was filled with 100 ml. Further, according to Example 1, other examples and comparative examples were also prepared.

The viscosity of each Example and each Comparative Example prepared with the formulation shown in Table 1 was measured. Then, 10 mL was filled in a transparent glass bottle, sealed, and stored for 7 days in a thermostatic bath at 50 ° C. (CH20-11M manufactured by Nagano Kagaku Kikai Seisakusho). The viscosity was measured again after storage for 7 days. From the viscosity measured values before and after the heat treatment, the residual viscosity ratio (%) = viscosity after storage at 50 ° C. for 7 days ÷ viscosity before storage at 50 ° C. × 100 was calculated.
The results are shown in Table 1.

  As a result of the test, it was confirmed that the viscosity reduction of the cellulosic thickener was promoted by the presence of the nonionic surfactant, but the viscosity reduction could be suppressed depending on the concentration of vegetable oil by containing sesame oil. . Furthermore, in the Example which contained EDTA with sesame oil, it was shown that the fall inhibitory effect of a viscosity is reinforced. In the composition of the present invention, the desired viscosity set in the formulation design was stably maintained over a long period of time, and it was confirmed that the composition was more excellent as a mucosa-applied composition.

Test Example 2 The preparation of each Example and Test Example used in the viscosity stability test was performed according to the formulations shown in Tables 2 and 3. Specifically, the preparation method of Example 6 is shown. 0.6 g of hydroxyethylcellulose (trade name “Fuji Chemi HEC” CF-V manufactured by Sumitomo Seika) was stirred and dissolved in 100 ml of purified water (conditioning solution A). Add 1.0 ml of polysorbate 80 (trade name “Nikkor TO-10M” manufactured by Nippon Surfactant) and 0.1 g of sesame oil (trade name “Nippon Sesame Oil” manufactured by Kadoya Oil Co., Ltd.) to 50 ml of purified water while stirring and dissolving. The mixture was dissolved with stirring (conditioning liquid B). The adjustment liquid B was added to the adjustment liquid A, and further purified water was added to make the whole 200 ml. After measuring the viscosity, each glass bottle was filled with 100 ml. Furthermore, other examples and comparative examples were also prepared according to Example 6. In addition, the hydroxypropyl methylcellulose (HPMC in a table | surface) used for the test is a brand name "Metrouse 65SH-4000" by Shin-Etsu Chemical Co., Ltd. The olive oil is (trade name “Olive Oil” manufactured by Kominato Pharmaceutical), and the soybean oil is (trade name “soybean oil” manufactured by Kominato Pharmaceutical). Peanut oil is (trade name “Peanut oil” manufactured by Kominato Pharmaceutical).

Each of the Examples and Comparative Examples adjusted according to the formulation shown in the table was filled in 10 mL of a transparent glass bottle and sealed, and the viscosity was measured. These glass bottle filling products were stored for 2 weeks in a 50 ° C. thermostat (CH20-11M manufactured by Nagano Kagaku Kikai Seisakusho). The viscosity was measured again after storage for 2 weeks. From the viscosity measured values before and after the heat treatment, the residual viscosity ratio (%) = viscosity after storage at 50 ° C. for 7 days ÷ viscosity before storage at 50 ° C. × 100 was calculated.
The results are shown in Tables 2 and 3.

  As a result of the test, it was confirmed that the viscosity reduction of the cellulosic thickener can be suppressed by containing a specific vegetable oil. In the composition of the present invention, the desired viscosity set in the formulation design was stably maintained over a long period of time, and it was confirmed that the composition was more excellent as a mucosa-applied composition.

  The formulation components shown in Tables 4 to 8 below are dissolved in purified water to make a total volume of 100 ml, sterilized and filtered for eye drops (or eye drops), eye wash (or eye wash), contact lenses (CL) A solution was prepared.

Test Example 3 Preparation of the test preparation used in the usability test was performed according to the formulation shown in Table 10.
Specifically, the preparation method of the test formulation 2 is shown. Sodium chloride, potassium chloride, potassium sorbate, sodium edetate, polysorbate 80 (TO-10M), polysumer 407, l-menthol, sesame oil (trade name “Nippon Sesame Oil” manufactured by Kadoya Oil Co., Ltd.), borax and boric acid Is stirred and dissolved in 50 ml of purified water, and sodium carboxymethylcellulose (in the table, CMC, trade name “AG Gum M”, Daiichi Kogyo Seiyaku Co., Ltd.) is added and dissolved by stirring to dissolve borax. After addition, purified water and hydrochloric acid / sodium hydroxide were added in appropriate amounts to adjust to pH = 7.5 to make a total of 100 ml.
Other test preparations are hydroxyethyl cellulose (trade name “Fuji Chemi HEC” CF-V Sumitomo Seika Co., Ltd.), hydroxypropyl cellulose (trade name “Metroze 65SH-4000”, Shin-Etsu Chemical Co., Ltd.) instead of sodium carboxymethylcellulose. Was similarly adjusted using.

  The prepared test preparation is filtered and filled into an eye drop container to produce eye drops for use in the test, and each eye drop is used for 20 dedicated monitors (10 naked eyes, 5 oxygen-permeable hard contact lens wearers, soft contact) 5 lens wearers) were instilled to evaluate the feeling of use. After instilling one drop of eye drops containing no sesame oil (Test preparations 1, 3, and 5) into both eyes, and after 30 minutes, applying eye drops containing sesame oil (Test preparations 2, 4, and 6) to both eyes, The feeling of use was compared between the eye drops containing no sesame oil and the eye drops containing sesame oil, and the feeling of use was evaluated according to the following evaluation criteria. The average values of the evaluation points of the naked eye monitor not wearing the contact lens and the contact lens wear monitor are shown in the table.

Evaluation criteria <br/> Presence or absence of stickiness:
Sesame oil-containing eye drops are free of stickiness and more free 3-point sesame oil-containing eye drops and eye drops that do not contain sesame oil are the same degree 2-point sesame oil-containing eye drops are more viscous 1-point visual field Bleeding degree:
The sesame oil-containing eye drops quickly eliminated blurring and clouding in the visual field. The three-point sesame oil-containing eye drops and the eye drops containing no sesame oil have the same degree. The two-point sesame oil-containing eye drops are more blurred. One point that cloudiness is hard to cancel

  As a result of the test, in the eye drops containing a cellulosic thickener and a nonionic surfactant, when sesame oil is added, the sticky feeling is eliminated, the blink is light and smooth, and blurring of the visual field is obtained. It was shown to resolve quickly. Furthermore, similar results were obtained with olive oil and soybean oil.

Test Example 4 A polyhydroxy 2-hydroxyethyl methacrylate (hereinafter, pHEMA) gel having a water content of 38% was prepared for use in a friction test, and a 2 cm × 5 cm rectangular block was cut out and immersed in physiological saline for 2 days. The soaked pHEMA gel was taken out of the physiological saline and gently wiped off the water, and then placed on a petri dish fixed on the sample table, and the MIU value was measured quickly 5 times to obtain an average value (this is a basic value). . Next, the pHEMA gel soaked in the same manner was taken out and lightly wiped off, and 1 mL of a test sample was dropped and the MIU value was measured 5 times continuously. The reduction rate was calculated as (MIU basic value of pHEMA gel−MIU value of pHEMA gel dropped for each test sample) ÷ MIU basic value of pHEMA gel, and measurement was performed 5 times with 3 PHEMA gels for each test sample. The average MIU reduction rate was calculated. It shows that the pHEMA gel surface became slippery as the MIU value decreased.
For measurement of the MIU value, a friction tester KES-SE (Kato Tech Co., Ltd.) was used. Each time the PHEMA gel was replaced, the friction element was cleaned with ethanol under the measurement conditions of the friction tester, sensitivity H (20 g / v), load 50 (gf), SPEED 10 mm / sec.

The test samples were as follows. The same HPMC and sesame oil as those used in Test Example 3 were used.
Test sample 1: Purified water test sample 2: Aqueous solution of HPMC (0.6%) and TO-10M (0.01%) Test sample 3: Aqueous solution of HPMC (0.6%), TO-10M (0.01%) and sesame oil (0.002%) Test sample 4: aqueous solution of HPMC (0.6%) and sesame oil (0.002%)

As a result of the test, the MIU value reduction rate (%) in test sample 1 was 0.04, test sample 2 was 0.159, test sample 3 was 0.240, and test sample 4 was 0.120. Surprisingly, when sesame oil was added to the cellulosic thickener, the MIU value decreased slightly, but sesame oil was added in the presence of the cellulosic thickener and a nonionic surfactant. In this case, the MIU value was significantly reduced.
Therefore, in the composition of this invention, it was confirmed that there exists an effect which reduces the friction on pHEMA gel. pHEMA gel is a material commonly used for contact lenses, and friction reduction on such a gel is achieved by the present invention between the contact lens and the eyelid conjunctiva, between the contact lens and the cornea surface, or between the eyelid conjunctiva and the cornea surface. By reducing the friction generated in the eye, it is suggested that the effect of lightening the feeling of blinking or reducing the risk of irritation given to the eye by a contact lens and improving the feeling of use. In addition, when used when a contact lens is mounted, it is possible to significantly reduce discomfort such as a foreign object feeling when the contact lens is mounted.
Although the results are not shown, similar results were obtained with hydroxyethyl cellulose and sodium carboxymethyl cellulose used in Test Example 3.

Test Example 5 Sustained moisturizing test Preparation of eye drops for test (adjusted to pH = 7.5) having the formulation shown in Table 11 and evaluation of moisturizing effect after instillation of each eye drop for test. Went. 10 subjects (including 5 naked eyes, 2 oxygen permeable hard contact lens wearers, 2 soft contact lens wearers) after instilling one drop into both eyes, measuring time every 30 seconds or less The average of evaluation of each subject was obtained by evaluation based on the evaluation criteria shown in FIG. The results are shown in FIG. The eye drop interval for each test eye drop was 1 hour.

Moisture evaluation criteria:
8 Very moistened 7 Well moistened 6 Slightly moistened 5 Slightly moistened 4 Slightly moistened 3 Slightly moistened 2 Rather moistened 2 Feeling neither moist nor dry 1 Slightly There is a dry feeling 0 There is a dry feeling

As a result of the test, in the test eye drop 2 containing sesame oil, there was no difference in the moist feeling compared with the test eye drop used as a control. In the test eye drops having a viscosity of 40 mPa · s, no difference was observed in the persistence of moist feeling between the test eye drops 4 and the test eye drops 6, but in the test eye drops having a viscosity of 3.5 mPa · s, In contrast between the eye drop 3 for the test and the eye drop 5 for the test, a moist feeling lasting effect was observed. In eye drops having a relatively low viscosity, the effect of maintaining a moist feeling was noticeable by the addition of sesame oil.

It is a figure which shows the method of the measurement by the conical one plate type rotational viscometer used in the test example. It is a figure which shows the moisture duration curve shown in the test example.

Claims (13)

a) Cellulosic thickener,
b) a nonionic surfactant, and c) transmucosal compositions containing sesame oil. The composition for mucous membrane application according to claim 1, wherein the viscosity at 20 ° C is 2 mPa · s or more and 100,000 mPa · s or less. The composition for applying to mucosa according to any one of claims 1 and 2, wherein the cellulosic thickener is at least one selected from methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, and salts thereof. . Nonionic surfactants, polyoxyethylene - polyoxypropylene block copolymers, according to claim polyoxyethylene sorbitan fatty acid ester luma others are non-ionic surfactants selected et or polyoxyethylene hydrogenated castor oil 1 4. The composition for applying to mucosa according to any one of items 1 to 3. The composition for applying to mucosa according to any one of claims 1 to 4, which is an eye drop, an eye wash, a contact lens mounting liquid, and a nasal drop. The mucosa-applied composition according to any one of claims 1 to 5, which has a pH of 4.0 to 10.0. Furthermore, the composition applied to mucosa according to any one of claims 1 to 6, further comprising one or more compounds selected from menthol, camphor, and borneol. The mucosa according to any one of claims 1 to 7, further comprising at least one selected from edetic acid, ethylenediaminediacetic acid, diethylenetriaminepentaacetic acid, N- (2-hydroxyethyl) ethylenediaminetriacetic acid, or a salt thereof. Application composition. With cellulosic thickeners and nonionic surfactants, a method for stabilizing the viscosity of mucosal application composition by blending the sesame oil. With cellulosic thickeners and nonionic surfactants, a method of the transmucosal composition by blending sesame oil improves sticky feeling when applied to the mucosa. A method for improving blurring of visual field when a composition for applying mucosa is applied to mucous membranes by adding sesame oil together with a cellulosic thickener and a nonionic surfactant. A method for improving the feeling of friction when applying a composition for applying mucosa to mucous membranes by adding sesame oil together with a cellulose-based thickening agent and a nonionic surfactant. A method for improving a moisturizing feeling when a mucosa-applied composition is applied to mucous membranes by blending sesame oil with a cellulosic thickener and a nonionic surfactant.

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