JP6913792B2 - Topical mucosal application aqueous composition - Google Patents

Description

The present invention relates to topical mucosal applicable aqueous compositions.

Rebamipide [2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionic acid] has a gastric mucosal prostaglandin E2 increasing effect and a gastric mucosal volume increasing effect. It has a gastric mucosal cell neoplastic activity activating effect, etc., and is mainly used by oral administration, and is a drug showing an excellent improving effect on gastric ulcers and gastric mucosal lesions appearing in acute gastritis and chronic gastritis in the acute exacerbation period ( Non-Patent Document 1).

In recent years, rebamipide has also been applied to the eye in the form of eye drops, and has been used as a therapeutic agent for dry eye, that is, dry eye syndrome by exerting an effect of increasing goblet cells and promoting mucin production (Patent Document 1). ).

Japanese Patent Publication No. 2011-524854

"Gastritis / Gastric Ulcer Therapeutic Agent Japanese Pharmacopoeia Rebamipide Tablets Mucosta (Registered Trademark) Tablets 100 mg", Pharmaceutical Interview Form, July 2013 (Revised 11th Edition)

An object of the present invention is to provide a locally mucosally applicable aqueous composition having excellent properties.

The present inventor has found a new problem that a composition containing rebamipide, a rebamipide derivative, and / or a salt thereof makes a sticky feeling when applied locally such as the surface of an eye, and solves the above problem. As a result of repeated diligent studies, it was found that stickiness can be improved by coexisting a specific component in a topical mucosal application aqueous composition containing rebamipide, and the present invention has been completed.

That is, the present invention provides the following [1] to [9].
[1] At least one selected from the group consisting of (A) rebamipide, rebamipide derivatives, and salts thereof, and (B) at least one selected from the group consisting of ethanolamine, tromethamole, and salts thereof. Aqueous composition for topical mucosa containing;
[2] The locally mucosal applicable aqueous composition according to [1], wherein the component (B) is ethanolamine, and the ethanolamine is monoethanolamine;
[3] The locally mucosally applicable aqueous composition according to [1] or [2], wherein the content of the component (A) is 0.0001 to 10 w / v%;
[4] The locally mucosally applicable aqueous composition according to any one of [1] to [3], wherein the content of the component (B) is 0.0001 to 5 w / v%;
[5] The topical mucosal application aqueous composition according to any one of [1] to [4], which further contains a buffer;
[6] The locally applied aqueous composition according to any one of [1] to [5], which further contains a nonionic surfactant;
[7] The locally mucosal applicable aqueous composition according to any one of [1] to [6], which further contains a vinyl polymer;
[8] The locally mucosally applicable aqueous composition according to any one of [1] to [7], which further contains a polyhydric alcohol;
[9] The aqueous composition for topical mucosa comprises at least one selected from the group consisting of (A) rebamipide, rebamipide derivatives, and salts thereof, and (B) ethanolamine, tromethamole, and salts thereof. A method of imparting the effect of preventing stains on the local mucosa at the time of application by coexisting at least one selected from the group.

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a locally mucosally applicable aqueous composition containing rebamipide, a rebamipide derivative, or a salt thereof and having less stickiness.

It is a photograph showing the evaluation result of the white residue after dropping the ocular mucosa application composition of the present invention and the ocular mucosa application composition of the comparative example on a slide glass and letting it stand for 24 hours. It is a photograph showing the evaluation result of the precipitation generation by the stability test of the ocular mucosa application composition of this invention and the ocular mucosa application composition of the comparative example.

In the present specification, the unit of content "w / v%" is synonymous with "g / 100 mL".

The aqueous composition for topical mucosa of the present invention comprises at least one selected from the group consisting of (A) rebamipide, rebamipide derivatives, and salts thereof, and (B) a group consisting of ethanolamine, tromethamole, and salts thereof. Contains at least one more selected.

In the present specification, the component (A) rebamipide is 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinoline-4-yl) propionic acid ((2RS) -2-yl). It is a compound also called (4-Chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propanoic acid (IUPAC)). Rebamipide may be synthesized by a known method or may be obtained as a commercially available product.

Examples of the levamipide derivative include, but are not limited to, an esterified derivative of levamipide, an etherified derivative, an amidated derivative, a sulfonated derivative, a nitrated derivative, a nitrosated derivative, and a halogenated derivative. Preferably, the derivative is an esterified derivative and / or an etherified derivative, more preferably an esterified derivative.

Among the components (A) used in the present invention, the salt of levamipide and the levamipide derivative is not particularly limited as long as it is pharmaceutically, pharmacologically or physiologically acceptable, but specifically. , Organic acid salts, inorganic acid salts, organic bases, or inorganic bases. Examples of the organic acid salt include monocarboxylic acid salts such as acetate, trifluoroacetate, butyrate, palmitate, and stearate; fumarate, maleate, succinate, malonate, and the like. Polyvalent carboxylates; oxycarboxylates such as lactates, tartrates and citrates; organic sulfonates such as methanesulfonates, toluenesulfonates and tosylates are exemplified. Examples of the inorganic acid salt include hydrochloride, sulfate, nitrate, hydrobromide, and phosphate. Examples of the salt with an organic base include salts with organic amines such as methylamine, triethylamine, triethanolamine, diethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picolin and ethylenediamine. Examples of salts with inorganic bases include ammonium salts; alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, and various salts such as salts with metals such as aluminum. These rebamipide salts may be used alone or in any combination of two or more. The "pharmaceutically or physiologically acceptable salt" may include a solvate or hydrate of the salt.

In the locally applied aqueous composition of the present invention, the total content of the component (A) with respect to the total amount of the locally applied aqueous composition is appropriately set depending on the balance with other components. The total content of the component (A) is preferably 0.0001 w / v% or more, more preferably 0.001 w / v% or more, and more preferably 0, based on the total amount of the locally applied aqueous composition. It is 0.01 w / v% or more, more preferably 0.05 w / v% or more, even more preferably 0.1 w / v% or more, and particularly preferably 1 w / v%. The total content of the component (A) is preferably 10 w / v% or less, more preferably 5 w / v% or less, still more preferably 3 w / v% or less, based on the total amount of the locally applied aqueous composition. Most preferably, it is 2 w / v% or less. The total content of the component (A) is preferably 0.0001 w / v% to 10 w / v%, more preferably 0.001 w / v% to 5 w / v, based on the total amount of the locally applied aqueous composition. %, More preferably 0.01 w / v% to 3 w / v%, even more preferably 0.05 w / v% to 2 w / v%, 0.1 w / v% to 2 w / v%, most preferably 1 w / v%. It is v% to 2w / v%.

In the present invention, the ethanolamine component (B) includes, for example, monoethanolamine (2-aminoethanol), diethanolamine (2,2'-iminodiethanol), triethanolamine (2,2', 2 "-nitrilotriethanol. ), Etc., as the component (B), at least one selected from the group consisting of monoethanolamine, diethanolamine, triethanolamine, and tromethamole (2-Amino-2-hydroxymethyl-propane-1,3-diol). Species or a combination of two or more thereof can be used as appropriate. These may be synthesized by a known method or may be obtained as a commercially available product.

In the present invention, as the component (B), ethanolamine is preferable, and monoethanolamine is more preferably used from the viewpoint of exerting the effect of the present application more remarkably.

In the locally applied aqueous composition of the present invention, the total content of the component (B) with respect to the total amount of the locally applied aqueous composition is appropriately set depending on the balance with other components. The total content of the component (B) is preferably 0.0001 w / v% or more, more preferably 0.001 w / v% or more, still more preferably 0.01 w, based on the total amount of the locally applied aqueous composition. / V% or more, still more preferably 0.1 w / v% or more, preferably 5 w / v% or less, more preferably 3 w / v% or less, still more preferably 1 w / v% or less, still more preferably. It is 0.5 w / v% or less.

In the locally applied aqueous composition of the present invention, the ratio of the blending amount of the component (B) to the component (A) is the total content of the component (B) to 1 part by weight of the total content of the component (A). Is preferably 0.0001 to 10 parts by weight, more preferably 0.001 to 5 parts by weight, further preferably 0.01 to 3 parts by weight, and particularly preferably 0.05 to 1 part by weight.

The topical mucosa-applied aqueous composition of the present invention preferably further contains a buffer in addition to the components (A) and (B) from the viewpoint that the effect according to the present invention is more prominently exhibited. The buffer that can be blended in the locally applied aqueous composition of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, and is an organic buffer or an organic buffer. Any of the inorganic buffers can be used. Examples of such buffers include borate buffer, phosphate buffer, carbonic acid buffer, citric acid buffer, acetate buffer, aspartic acid, aspartate, epsilon-aminocaproic acid, hydrochloric acid, sodium hydroxide and the like. Be done. These buffers may be used in combination.

Examples of the boric acid buffer include borate, and borates such as an alkali metal boric acid salt and an alkaline earth metal boric acid salt. Examples of the phosphoric acid buffer include phosphates, or phosphates such as alkali metal phosphates and alkaline earth metal phosphates. Examples of the carbonic acid buffer include carbonic acid, or carbonates such as alkali metal carbonate and alkaline earth metal carbonate. Examples of the citric acid buffer include citric acid, an alkali metal citrate salt, and an alkaline earth metal citrate salt. Moreover, you may use the hydrate of each salt as a buffering agent. More specifically, as a borate buffer, boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, boar sand, etc.); as a phosphate buffer, phosphoric acid or its salt. Salts (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); Or its salt (sodium hydrogen carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate, magnesium carbonate, etc.); as a citrate buffer, citric acid or its salt (sodium citrate, potassium citrate, citrus) Calcium acid, sodium dihydrogen citrate, disodium citrate, etc.); As an acetate buffer, acetic acid or a salt thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.); (Magnetic aspartate, potassium aspartate, magnesium aspartate / potassium equal amount mixture, etc.) can be exemplified. These buffers may be used alone or in any combination of two or more. The buffer may be synthesized by a known method or may be obtained as a commercially available product.

Among the above buffers, boric acid buffer, citric acid buffer, phosphate buffer, and epsilon-aminocaproic acid are preferable, and boric acid buffer, citric acid buffer, and epsilon-aminocaproic acid, especially boric acid, are particularly preferable. Buffers and epsilon-aminocaproic acid are suitable. Suitable specific examples of the boric acid buffer include boric acid, a combination of boric acid and a salt thereof (for example, boric acid and borax), preferably a combination of boric acid, boric acid and borax, and more preferably. Boric acid is exemplified. Examples of the citric acid buffer include citric acid and a combination of citric acid and a salt thereof, and citric acid is preferably exemplified.

When a buffer is added to the locally applied aqueous composition of the present invention, the mixing ratio of the buffer is determined by the type of buffer used, the type and amount of other ingredients, the use of the locally applied aqueous composition, etc. The total content of the buffer is preferably 0.01 w / v% or more, more preferably 0.05 w / /, based on, for example, the total amount of the aqueous composition applied to the topical mucosa. V% or more, more preferably 0.1 w / v% or more, preferably 10 w / v% or less, more preferably 5 w / v% or less, still more preferably 3 w / v% or less, still more preferably 2 w / It is v% or less.

In the locally applied aqueous composition of the present invention, the ratio of the blending amount of the buffer to the component (A) is such that the total content of the buffer is 0.001 with respect to 1 part by weight of the total content of the component (A). ~ 50 parts by weight is preferable, 0.005 to 10 parts by weight is more preferable, 0.01 to 5 parts by weight is more preferable, and 0.05 to 2 parts by weight is particularly preferable.

The locally applied aqueous composition of the present invention preferably contains a nonionic surfactant in addition to the components (A) and (B) from the viewpoint that the effect according to the present invention is more prominently exhibited. The nonionic surfactant that can be blended in the locally applied aqueous composition of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.

Specific examples of the nonionic surfactant that can be blended in the locally applied aqueous composition of the present invention include polyoxyethylene (hereinafter, also referred to as POE) (20) polyoxypropylene (hereinafter, also referred to as POP). ) (20) Glycol (Pluronic® L44), POE (42) POP (67) Glycol (Poloxamer 403, Pluronic® P123), POE (54) POP (39) Glycol (Poloxamer 235, Pluronic (20) Registered Trademarks) P85), POE (120) POP (40) Glycol (Pluronic® F87), POE (160) POP (30) Glycol (Poloxamer 188, Pluronic® F68), POE (196) POP (67) Glycol (Poloxamer 407, Pluronic® F127), POE / POP glycol such as POE (200) POP (70) glycol; POE / POP glycol of ethylenediamine such as poloxamer; POE (20) sorbitan monolaurate POE sorbitan fatty acid esters such as (polysorbate 20), POE sorbitan monostearate (polysorbate 60), POE sorbitan tristearate (polysorbate 65), monooleic acid POE (20) sorbitan (polysorbate 80); POE hardened castor oil 5 , POE hardened sardine oil 10, POE hardened sardine oil 20, POE hardened sardine oil 40, POE hardened sardine oil 50, POE hardened sardine oil 60, POE hardened sardine oil 100, etc. POE poloxamer oil such as oil 10, POE poloxamer oil 35; POE alkyl ethers such as POE (9) lauryl ether; POE (20) POP (4) POE / POP alkyl ethers such as cetyl ether; POE (10) nonyl POE alkyl phenyl ethers such as phenyl ether; polyethylene glycol monostearate such as polyoxyl 40 stearate and the like can be mentioned. The numbers in parentheses indicate the number of additional moles.

In the locally applied aqueous composition of the present invention, these nonionic surfactants may be used alone or in combination of two or more. Further, the surfactant may be synthesized by a known method and can be obtained as a commercially available product.

When a nonionic surfactant is blended in the aqueous composition for topical mucosa application of the present invention, the blending ratio of the nonionic surfactant includes the type of nonionic surfactant, the type and amount of other components, and application to the topical mucosa. It can be appropriately set according to the use of the aqueous composition and the like. As an example of the blending ratio of the nonionic surfactant, the total content of the nonionic surfactant is preferably 0.001 w / v% or more, more preferably 0. It is 005 w / v% or more, more preferably 0.01 w / v% or more, preferably 5 w / v% or less, more preferably 3 w / v% or less, still more preferably 1 w / v% or less.

In the locally applied aqueous composition of the present invention, the ratio of the blending amount of the nonionic surfactant to the component (A) is the total content of the nonionic surfactant to 1 part by weight of the total content of the component (A). The content is preferably 0.0001 to 30 parts by weight, more preferably 0.0005 to 20 parts by weight, further preferably 0.001 to 10 parts by weight, and particularly preferably 0.005 to 1 part by weight.

The locally applied aqueous composition of the present invention preferably further contains a vinyl polymer in addition to the components (A) and (B) from the viewpoint that the effect according to the present invention is more prominently exhibited. Examples of the vinyl polymer that can be blended in the locally applied aqueous composition of the present invention include polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone (K17, K25, K30, K90, etc.), and carboxyvinyl polymer. .. These vinyl-based polymers may be used alone or in combination of two or more. The vinyl polymer may be synthesized by a known method and can be obtained as a commercially available product.

Among these vinyl-based polymers, polyvinylpyrrolidone is preferable, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, and polyvinylpyrrolidone K30 are more preferable, and polyvinylpyrrolidone K25 and polyvinylpyrrolidone K30 are even more preferable.

When a vinyl-based polymer is blended in the locally-applied aqueous composition of the present invention, the blending ratio thereof includes the type of vinyl-based polymer used, the type and amount of other components, and the locally-applied aqueous composition. It depends on the application. Although not particularly limited, for example, the total content of the vinyl polymer is preferably 0.001 w / v% or more, more preferably 0.005 w / v%, based on the total amount of the aqueous composition applicable to the local mucosa. The above is more preferably 0.01 w / v% or more, particularly preferably 0.1 w / v% or more, most preferably 1 w / v% or more, and the total amount of the vinyl polymer is preferably 10 w / v% or more. Below, it is more preferably 7 w / v% or less, still more preferably 5 w / v% or less, and particularly preferably 3 w / v% or less.

In the locally applied aqueous composition of the present invention, the ratio of the blending amount of the vinyl polymer to the component (A) is the total content of the vinyl polymer with respect to 1 part by weight of the total content of the component (A). Is preferably 0.001 to 500 parts by weight, more preferably 0.01 to 100 parts by weight, even more preferably 0.05 to 50 parts by weight, and particularly preferably 0.1 to 10 parts by weight.

The locally applied aqueous composition of the present invention preferably contains a polyhydric alcohol in addition to the components (A) and (B) from the viewpoint that the effect according to the present invention is more prominently exhibited. The polyhydric alcohol that can be blended in the locally applied aqueous composition of the present invention may be a component having an action of assisting the dissolution of levamipide and / or a salt thereof, which are sparingly soluble in water, in an aqueous solution, for example. Glycerin, propylene glycol, polyethylene glycol (400, 4000, 6000, etc.) and the like can be mentioned. These polyhydric alcohols may be used alone or in any combination of two or more. The polyhydric alcohol may be synthesized by a known method or may be obtained as a commercially available product.

Among these polyhydric alcohols, glycerin, propylene glycol and polyethylene glycol are more preferable, glycerin and propylene glycol are further preferable, and glycerin is particularly preferable.

When a polyhydric alcohol is blended in the locally mucosa-applied aqueous composition of the present invention, the blending ratio thereof includes the type of polyhydric alcohol used, the type and amount of other components, the use of the locally mucosa-applied aqueous composition, etc. Depends on. Although not particularly limited, for example, the total content of the polyhydric alcohol is preferably 0.001 w / v% or more, more preferably 0.005 w / v% or more, based on the total amount of the locally applied aqueous composition. , More preferably 0.01 w / v% or more, particularly preferably 0.05 w / v% or more, and the total amount of polyhydric alcohol is preferably 10 w / v% or less, more preferably 5 w / v% or less. More preferably, it is 3 w / v% or less, and particularly preferably 1 w / v% or less.

In the locally applied aqueous composition of the present invention, the ratio of the compounding amount of the polyvalent alcohol to the component (A) is such that the total content of the polyvalent alcohol is 0 with respect to 1 part by weight of the total content of the component (A). .001 to 10 parts by weight is preferable, 0.005 to 5 parts by weight is more preferable, 0.01 to 2 parts by weight is more preferable, and 0.05 to 1 part by weight is particularly preferable.

The pH of the locally applied aqueous composition of the present invention is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable range, but as an example, The pH is 4.0 to 9.5, preferably 5.0 to 9.0, more preferably 6.0 to 8.8, still more preferably 6.0 to 8.6, and particularly preferably 6.5 to. The range of 8.5 can be mentioned.

The locally applied aqueous composition of the present invention can be further adjusted to an osmotic pressure ratio within a range acceptable to the living body, if necessary. The appropriate osmotic pressure ratio varies depending on the application site, dosage form, etc., but is usually in the range of 0.5 to 5.0, more preferably 0.6 to 3.0, and further preferably 0.7 to 2.0. Be done. The osmotic pressure can be adjusted by a method known in the art using an inorganic salt, a polyhydric alcohol, or the like. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to the osmotic pressure of 286 mOsm (0.9 w / v% sodium chloride aqueous solution) based on the 16th revised Japanese Pharmacopoeia. Measure according to the freezing point descent method). The standard solution for measuring the osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution) is prepared by drying sodium chloride (standard reagent of the Japanese Pharmacopoeia) at 500 to 650 ° C. for 40 to 50 minutes and then in a desiccator (silica). Allow to cool, weigh accurately 0.900 g, dissolve in purified water to prepare exactly 100 mL, or use a commercially available standard solution for measuring osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution).

The viscosity of the locally mucosa-applicable aqueous composition of the present invention is within the physiologically or pharmaceutically acceptable range, the type and content of the compounding ingredients, the use, the formulation form, and the use of the locally mucosa-applicable aqueous composition. It is appropriately set according to the method and the like. The viscosity at 20 ° C. measured with a rotational viscometer (RE550 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor; 1 ° 34'x R24) is preferably 0.01 to 10000 mPa · s, preferably 0.05 to 8000 mPa. -S is more preferable, 0.5 to 1000 mPa · s is further preferable, and 1 to 1000 mPa · s is even more preferable.

The locally mucosa-applied aqueous composition of the present invention may contain various pharmacologically active ingredients and physiologically active ingredients in combination in an appropriate amount in addition to the above-mentioned components as long as the effects of the present invention are not impaired. Examples of such pharmacologically active ingredients and physiologically active ingredients include active ingredients in various pharmaceutical products described in the 2012 edition of the OTC drug manufacturing and marketing approval standard (supervised by the Regulatory Science Society). Specifically, the following components can be mentioned.

Anti-allergic or antihistamine agents: for example, diphenhydramine hydrochloride, iproheptin, chlorpheniramine maleate, acitazanolast, anlexanox, ibudilast, tranilast, levocabastine hydrochloride, sodium cromoglycate, ketotifen fumarate, pemirolast potassium, olopatadine hydrochloride and the like.
Decongestant: for example, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride and the like.
Eye muscle regulators: For example, cholinesterase inhibitors having an active center similar to acetylcholine, specifically neostigmine methylsulfate, tropicamide, helenien, atropine sulfate and the like.
Disinfectants: for example, acrinol, cetylpyridinium, chlorhexidine hydrochloride, chlorhexidine gluconate, polyhexanide hydrochloride and the like.
Vitamins: For example, flavin adenine dinucleotide sodium, cyanocobalamin, retinyl acetate, retinol palmitate, pyridoxine hydrochloride, panthenol, calcium pantothenate, sodium pantothenate, tocopherol acetate and the like. Amino acids: For example, aminoethyl sulfonic acid and the like.
Anti-inflammatory agents: for example, dipotassium glycyrrhizinate, allantin, berberine chloride, berberine sulfate, lysozyme chloride, sodium azulene sulfonate, indomethacin, pranoprofen, ibuprofen and the like.
Astringent: For example, zinc oxide, zinc lactate, zinc sulfate, etc.
Others: Sulfamethoxazole, sodium sulfamethoxazole, sulfisoxazole, sodium sulfisomidin, etc.

Further, in the locally applied aqueous composition of the present invention, a carrier, a thickener, a sugar alcohol, a sugar, an amino sugar, an isotonic agent, a pH adjuster, a stabilizer, a chelating agent, a preservative, and a cooling agent. Additives such as agents, oils, and anionic surfactants may be selected, and at least one of them may be used in combination to contain an appropriate amount. Examples of these additives include various additives described in the Pharmaceutical Additives Dictionary 2007 (edited by the Japan Pharmaceutical Additives Association). The following additives can be mentioned as typical components.

Carrier: For example, an aqueous carrier such as water or hydrous ethanol.
Thickener: For example, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, gellan gum, alginic acid and the like.
Sugar alcohols: For example, xylitol, sorbitol, mannitol and the like. These may be d-form, l-form or dl-form.
Sugars: For example, glucose and the like. Amino sugar: For example, meglumine and the like.
Isotonic agents: for example, sodium hydrogen sulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride and the like.
pH adjuster: For example, hydrochloric acid, dilute hydrochloric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide and the like.
Stabilizers: For example, dibutylhydroxytoluene, butylhydroxyanisole, sodium formaldehyde sulfoxylate (longalit), tocopherol, sodium metabisulfite, aluminum monostearate, glycerin monostearate, cyclodextrin, diisopropanolamine and the like.
Chelating agent: For example, ascorbic acid, tetrasodium edetate, sodium edetate and the like.
Preservatives: For example, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, zinc chloride, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl paraoxybenzoate , Ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biganide compounds (specifically, polyhexanide hydrochloride (polyhexamethylene biganide), etc.), Gloquil (manufactured by Rhodia) Product name) etc.
Cooling agents: for example, menthol, menthol, camphor, borneol, geraniol, cineole, citronellol, carboxylic, anator, eugenol, limonene, linalool, linaryl acetate, timol, simene, terpineol, pinene, camphor, isobornol, fenchen, nerol. , Milsen, Milsenol, Linalool acetate, Lavangelol, Eucalyptus oil, Bergamot oil, Peppermint oil, Cool mint oil, Spare mint oil, Peppermint oil, Wikyo oil, Keihi oil, Rose oil, Camphor oil, etc.
Oils: For example, vegetable oils such as sesame oil, castor oil, soybean oil and olive oil, animal oils such as squalane and refined lanolin, and mineral oils such as liquid paraffin and petrolatum. Anionic surfactants: for example, polyoxyethylene alkyl ether phosphate, polyoxyethylene alkyl ether sulfate, alkylbenzene sulfonate, alkyl sulfate, N-acyl taurine salt and the like.
Others: Caffeine, etc.

The aqueous composition for topical mucosa of the present invention is prepared by adding a desired amount of the above-mentioned components (A) and (B) and, if necessary, other compounding components to the carrier so as to have a desired content. .. Specifically, for example, it can be prepared by dissolving or suspending the above components in purified water, adjusting the pH and osmotic pressure to a predetermined value, and sterilizing by filtration sterilization or the like.

In the topical mucosal application aqueous composition of the present specification, water is added to 1 w / v% or more, preferably 5 w / v% or more, more preferably 20 w / v% or more, still more preferably 50 w / v of the whole composition. % Or more, more preferably 70 w / v% or more, and most preferably 90 w / v% or more. The water contained in the locally applied aqueous composition of the present invention may be pharmaceutically, pharmacologically or physiologically acceptable. For example, distilled water, normal water, purified water, sterilized purified water, water for injection, distilled water for injection and the like can be used. These definitions are based on the 16th revised Japanese Pharmacopoeia.

The topical mucosal application aqueous composition of the present invention can take various pharmaceutical forms depending on the intended purpose. For example, a liquid preparation, a semi-solid preparation (ointment, etc.) and the like can be mentioned as a pharmaceutical form of the locally applied aqueous composition of the present invention. It is preferably a liquid agent.

The locally applied aqueous composition of the present invention is an aqueous composition directly applied to local mucosa such as ocular mucosa, nasal mucosa, oral mucosa, and pharyngeal mucosa.

Therefore, the locally applied aqueous composition of the present invention can be used as a pharmaceutical product, a non-pharmaceutical product, or the like. It can be used for various purposes such as things.

Ophthalmic mucosa-applied compositions include eye drops (including eye drops that can be used while wearing contact lenses), artificial tears (including artificial tears that can also be used while wearing contact lenses), Eye drops, eye ointments, contact lens mounting solutions, contact lens care agents (contact lens disinfectants, contact lens preservatives, contact lens cleaning agents, contact lens cleaning preservatives, contact lens disinfecting / cleaning / preserving agents Etc.) etc. are included. Here, the contact lens includes all contact lenses currently on the market or commercially available in the future (soft contact lenses, hard contact lenses, and oxygen permeable hard contact lenses), and soft contacts. Lenses include both ionic and non-ionic, both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses, and also include color contact lenses of all materials). Can be done.

The nasal mucosa application composition includes a nasal drop, a nasal ointment, a nasal wash, and the like. Oral mucosal application compositions include oropharyngeal creams, oropharyngeal gels, oropharyngeal ointments, oropharyngeal sprays, mouthwashes, inhalants and the like. The ear mucosa application composition includes ear drops and ear ointments.

Among the above-mentioned uses, the composition for ocular mucosa is preferable from the viewpoint of more remarkably exerting the stickiness suppressing effect, the visibility improving effect, and the stain suppressing effect of the present invention.
Among the ophthalmic compositions, eye drops are preferable from the viewpoint of remarkably exerting the stickiness suppressing effect and the stain suppressing effect of the present invention because they are used many times per day.

The topical mucosal application aqueous composition of the present invention is provided in an arbitrary container. The container for accommodating the locally applied aqueous composition of the present invention is not particularly limited, and may be made of glass or resin, for example. The container for accommodating the locally applied aqueous composition of the present invention may be a resin container in which a resin is further reinforced by containing a reinforcing agent such as glass fiber.

Specifically, in the locally applied aqueous composition of the present invention, at least a part of the container is made of polyethylene terephthalate (PET), polyethylene naphthalate (PEN), polypropylene (PP), or polyarylate (PAR). , Polybutylene terephthalate (PBT), Polycarbonate (PC), Polyethylene (PE). Preferably, it is made of PET, PEN, PP, PAR, PBT, PC, PE, more preferably PET, PBT, PP, PE, and even more preferably PET, PP, It is made of PE, particularly preferably made of PET or PP, and most preferably made of PET.

As used herein, the term "container" mainly means a container (primary container) that directly contains a rebamipide-containing topical mucosa-applied aqueous composition. Further, the container may have a lid portion or an extraction port portion attached to the container body portion. The above material mainly means the material of the container body.

When the container containing the locally applied aqueous composition according to the present embodiment is made of resin, the container may be molded from only a single resin, or may be molded by combining a plurality of synthetic resins. May be good. When combining a plurality of synthetic resins, the above synthetic resins (PET, PEN, PP, PAR, PBT, PC and PE) may be combined, and in addition to the above synthetic resins, usually for molding a synthetic resin container. The synthetic resin used may be combined.

The container containing the locally mucosal-applied aqueous composition of the present invention may be a transparent container in which the inside of the container can be visually recognized, or an opaque container in which the inside of the container is difficult to see. Here, the "transparent container" includes both a colorless transparent container and a colored transparent container.

In the present invention, the shape of the container and the capacity that can be accommodated inside are not particularly limited. For example, in the case of a container used for topical mucosal application such as eye drops and nasal drops, the content is 0.1 mL or more and 500 mL or less, 1 mL or more and 100 mL or less, preferably 2 mL or more and 50 mL or less, more preferably. Can be a container that can accommodate 3 mL or more and 25 mL or less.

When the topical mucosal application aqueous composition of the present invention is an eye drop, it is particularly preferable that it is a multi-dose eye drop.

The topical mucosa-applied aqueous composition of the present invention is provided in a resin container alone or in the form of a kit.

The locally applied aqueous composition according to the embodiment of the present invention is preferably used as an ocular mucosa applied composition having a therapeutic or preventive effect on dry eye disease based on the medicinal effect of the component (A).

Furthermore, the locally applied aqueous composition of the present invention is suitably used as an ocular mucosal composition such as an eye drop for improving eye discomfort (particularly when wearing contact lenses).

When the topical mucosa-applied aqueous composition of the present invention is an ocular mucosa-applied composition, particularly an eye drop, the dosage and administration thereof is not particularly limited as long as it is effective and has few side effects. For example, a method of instilling 1 to 3 drops at a time and 3 to 6 times a day (for example, morning, noon, evening and before bedtime) is preferable. The number of drops is 1 to 2 at a time, particularly 1 drop, and the number of instillations is more preferably 4 times a day.

According to the locally applied aqueous composition of the present invention, although it is a locally applied aqueous composition containing rebamipide, a rebamipide derivative, and / or a salt thereof, it is sticky especially when applied locally to the eyes and the like. It is improved, itching at the time of instillation is suppressed, deterioration of visibility after instillation is suppressed, and white residue at the time of drying is suppressed.

Furthermore, crystal precipitation is suppressed even when stored at a low temperature for a long period of time, and a clear, pharmaceuticalally stable, locally-applied aqueous composition for a long period of time can be obtained. The locally applied aqueous composition of the present invention is suitably used as a composition for ocular mucosa such as an eye drop.

In the present invention, further, at least one selected from the group consisting of (A) rebamipide, rebamipide derivatives, and salts thereof, and (B) ethanolamine, tromethamole, and / Alternatively, the coexistence of these salts provides a method for suppressing stains (unpleasant irritation) on the local mucous membrane at the time of application, particularly on suppressing stains in the eye portion at the time of instillation. This method of imparting action can be performed by preparing a topical mucosal application aqueous composition.

Next, the present invention will be specifically described with reference to Examples, but the present invention is not limited to the following Examples.
The unit of each component amount in the table is w / v%.

Test Example 1: Usability test 1
An aqueous composition (eye drops) applicable to the ocular mucosa having the composition shown in Table 1 was prepared according to a conventional method. Specifically, each component was weighed in a 100 mL capacity beaker, and a required amount of distilled water was added. The mixture was stirred while warming, and the final pH was adjusted at room temperature to obtain a uniform formulation. Here, as rebamipide, rebamipide conforming to the Japanese Pharmacopoeia was used.

Next, the obtained ocular mucosa application composition was filtered through a membrane filter (thermofisher scientific bottle top filter) having a pore size of 0.2 μm, and then 13 mL was placed in a polyethylene terephthalate eye drop container having an internal volume of 14.2 mL. Filled. Each composition was clear and colorless. After filling, a polyethylene nozzle was attached to the eye drop container. Three subjects were instilled with each eye drop into the left and right eyes, and immediately after the instillation, the feeling of execution after instillation regarding the symptoms shown in Table 1 was evaluated based on the following evaluation criterion 1. All subjects were naked eyes.

<Evaluation Criteria 1>
0 points: I hardly feel it.
1 point: I feel weak.
2 points: I feel.
3 points: I feel strongly.
4 points: I feel unbearably strong.

The average value of the scores of the three persons was calculated, and the improvement rate (%) with respect to Comparative Example 1-1 was calculated according to the following formula 1.
[Equation 1] Symptomatology improvement rate (%) =
[(Average value of scores of Comparative Example 1-1-Average value of scores of each example) / Average value of scores of Comparative Example 1-1] × 100

The results are also shown in Table 1.

From the results in Table 1, when the components (A) and (B) are used in combination, the indicators of stickiness and itchiness of the eyes tend to be significantly improved as compared with the eye drops containing only the component (A). Was confirmed.

Test example 2 Usability test 2
Each ocular mucosa-applicable aqueous composition (eye drop) was prepared in the same manner as in Test Example 1 according to the formulation shown in Table 2, and filtered with a membrane filter (thermofisher scientific bottle top filter) having a pore size of 0.2 μm. After that, 13 mL was filled in a polyethylene terephthalate eye drop container having an internal volume of 14.2 mL. After filling, a polyethylene nozzle was attached to the eye drop container. Three subjects were instilled with each eye drop into the left and right eyes, and 5 minutes after the instillation, the feeling of execution of the symptoms shown in Table 2 was evaluated based on the following evaluation criterion 2. All subjects were naked eyes.
The average value of the scores of the three persons was calculated, and the improvement rate (%) with respect to Comparative Example 2-1 was calculated according to the following formula 1.

Visibility improvement rate (%) =
[(Average value of scores of each example-Average value of scores of Comparative Example 2-1) / Average value of scores of Comparative Example 2-1] × 100

<Evaluation Criteria 2>
0 points: Very hard to see.
1 point: It's a little hard to see.
2 points: No change before and after instillation.
3 points: A little easier to see.
4 points: Very easy to see.

From the results in Table 2, it was confirmed that when the component (A) and the component (B) were used in combination, the visibility score was improved as compared with the eye drops containing only the component (A). Further, in Comparative Example 2-1 all selected "0 points: very difficult to see" or "1 point: slightly difficult to see", but in Examples 1-2 and 2-2, all selected 2 points or more. Therefore, it was confirmed that the eye drops of Comparative Example 2-1 tended to be less visible (problem), and that the problem was solved by containing both monoethanolamine and tromethamole.

Test Example 3: Usability test 3
Each ocular mucosa-applicable aqueous composition (eye drop) was prepared in the same manner as in Test Example 1 according to the formulation shown in Table 3, and filtered with a membrane filter (thermofisher scientific bottle top filter) having a pore size of 0.2 μm. After that, 13 mL was filled in a polyethylene terephthalate eye drop container having an internal volume of 14.2 mL. After filling, a polyethylene nozzle was attached to the eye drop container. Each of the eye drops was applied to the left and right eyes of three subjects, and the number of people corresponding to the symptoms shown in Table 4 was calculated.

From the results in Table 4, it was confirmed that when the components (A) and (B) were used in combination, the stains at the time of instillation tended to be reduced as compared with the eye drops containing only the component (B). rice field.

Test Example 4: White residue test Each ocular mucosa-applicable aqueous composition (eye drop) was prepared in the same manner as in Test Example 1 according to the formulation shown in Table 5. After filtering each ocular mucosa-applicable aqueous composition with a membrane filter (thermofisher scientific bottle top filter) having a pore size of 0.2 μm, 100 μL of each is dropped onto a slide glass and allowed to stand for 24 hours under shading at 20 ° C. did. The state of each test solution on the slide glass after 24 hours was observed, and the degree of white residue was evaluated according to the following evaluation criteria for white residue. The results are shown in Table 5 below. Further, FIG. 1 shows an image taken by a digital camera.

<Evaluation criteria for white residue>
Very intense white residue: +++
White residue is intense: ++
There is white residue: +
There is a small amount of white residue: ±
No white residue is seen:-

In FIG. 1, from the left, Comparative Example 4-1 and Example 4-1 and Comparative Example 4-2 are shown. As is clear from Table 5 and FIG. 1, in the aqueous composition applicable to the ocular mucosa containing only the component (A), it was observed that a white solid substance remained after being dropped on the slide glass (Comparative Example 4-). 1). On the other hand, in the aqueous composition applicable to the ocular mucosa containing monoethanolamine together with the component (A), the white residue was remarkably suppressed (Example 4-1). Therefore, it has been clarified that by adding monoethanolamine to the aqueous composition applicable to the ocular mucosa, white residue during dropping and drying is remarkably suppressed, and an aqueous composition applicable to the ocular mucosa having excellent quality can be obtained. .. On the other hand, when the aqueous composition applicable to the ocular mucosa contained meglumine instead of monoethanolamine (Comparative Example 4-2), almost no effect of suppressing white residue was observed.

Test Example 5: Stability Test Each ocular mucosa-applicable aqueous composition (eye drop) was prepared in the same manner as in Test Example 1 according to the formulations shown in Tables 6 to 8. This solution was filtered through a membrane filter (thermofisher scientific bottle top filter) having a pore size of 0.2 μm, and then 5 mL of each ocular mucosa-applicable aqueous composition was filled in a glass headspace vial having a capacity of 10 mL. After storing at 20 ° C. under shading for 7 days, it was melted at 4 ° C. under shading for 1 day. The presence or absence of precipitates in each aqueous composition applicable to the ocular mucosa was evaluated according to the following evaluation criteria for the amount of precipitates.
<Evaluation criteria for precipitation amount>
20 or more crystals can be confirmed by observing from a distance of 50 cm.
Observing from a distance of 50 cm, 10 to 20 crystals can be confirmed.
Observe from a distance of 50 cm, and 1 to 10 crystals can be confirmed.
Crystals cannot be confirmed when observing from a distance of 50 cm ◎

It was confirmed that by containing the component (A) and the component (B), precipitation is less likely to occur even when stored at a low temperature, and a highly stable preparation can be prepared. In particular, Examples 5-2, 5-3, and 5-4 are particularly excellent in stability, as no increase in crystal precipitation was confirmed even when the crystals were stored in an environment of 4 ° C. for 7 days after the above observation was completed. It was confirmed that there was. Further, it was confirmed that Examples 5-2, 5-3, and 5-4 were kept stable for 2 weeks without increasing precipitation even in another low temperature environment (4 ° C.).

Test Example 6: Stability test Each ocular mucosa-applicable aqueous composition (eye drop) was prepared according to the formulation shown in Table 9. Each ocular mucosa-applicable aqueous composition is filtered through a membrane filter (Thermo Fisher Scientific bottle top filter) having a pore size of 0.2 μm, and then 5 mL each is filled in a glass headspace vial having a capacity of 10 mL and protected from light at 4 ° C. The cells were stored for 14 days and evaluated according to the same evaluation criteria as in Test Example 5. (Evaluation 1) Further, the sample stored at 20 ° C. under shading for about 6 weeks was evaluated according to the same criteria (evaluation 2), and the state was photographed with a digital camera (FIG. 2).

Separately, the similarly filled sample was stored at −20 ° C. under shading for 7 days and then melted at 4 ° C. under shading for 1 day. Then, it was stored again in the shade of −20 ° C. for 7 days, melted in the shade of 4 ° C. for 1 day, and evaluated according to the same criteria. (Evaluation 3)

In FIG. 2, the left side shows Example 6-1 and the right side shows Comparative Example 6-1. As is clear from FIGS. 2 and 9, it was confirmed that the ocular mucosa-applied composition (eye drops) of the present invention is stable even at low temperatures.

Reference test example 1
The locally mucosa-applied aqueous composition of the present invention could be produced, for example, by the following method.

About 50 mL of distilled water was placed in a 100 mL beaker, and the mixture was stirred while warming to 70 ° C. After adding each component into it, about 40 mL of purified water was further added. After stirring at 70 ° C. for 30 minutes or more, the pH was adjusted by returning to room temperature to obtain a uniform formulation.

This pharmaceutical product was filtered through a membrane filter having a pore size of 0.2 μm, filled in an eye drop container, and after filling, a nozzle for an eye drop container was attached.

(Example of formulation)
Eye drops (formulation examples 1-42) are prepared according to the formulations shown in Tables 10 to 13 below. In the preparation examples of Tables 10 to 13, hydrochloric acid and sodium hydroxide are used for pH adjustment, and the locally mucosally applicable aqueous composition is added so as to have the pH shown in Tables 10 to 13. Purified water is added so that the total volume of each solution is 100 mL. The unit of each component amount in the table below is w / v%.

Claims (4)

(A) rebamipide, and at least one selected from the group consisting of salts, and (B) ethanolamine, containing at least one selected from及beauty group consisting of salts, topical mucosal application aqueous It ’s a composition,
The ratio of the blending amount of the component (B) to the component (A) is such that the total content of the component (B) is 0.0001 to 10 parts by weight with respect to the total content of the component (A) of 1 part by weight. Topically mucosally applicable aqueous composition. Before disappeared ethanolamine is monoethanolamine, claim 1 topical mucosal application aqueous composition. The locally mucosally applicable aqueous composition according to claim 1 or 2, wherein the content of the component (A) is 0.0001 to 10 w / v%. The locally mucosally applicable aqueous composition according to any one of claims 1 to 3, wherein the content of the component (B) is 0.0001 to 5 w / v%.

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