JP6732441B2 - Aqueous composition for topical mucosa application - Google Patents

Description

The present invention relates to an aqueous composition for topical mucosa application.

Rebamipide [2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionic acid] is a gastric mucosal prostaglandin E2 increasing action, gastric mucus amount increasing action, It is a drug that has a gastric mucosal cell neopotency activating effect, etc., and is mainly used by oral administration and shows an excellent improving effect on gastric ulcer and gastric mucosal lesions that appear during acute gastritis and acute exacerbation of chronic gastritis ( Non-Patent Document 1).

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

Special table 2011-524854 gazette

"Therapeutic agent for gastritis and gastric ulcer Japanese Pharmacopoeia Rebamipide Tablets Mucosta (registered trademark) 100 mg", Pharmaceutical Interview Form, July 2013 (Revision 11th Edition)

An object of the present invention is to provide an aqueous composition for topical mucosa which has excellent properties.

The present inventor has found that rebamipide, a composition containing rebamipide derivative, and/or a salt thereof has a new problem of causing stickiness when applied topically such as the surface of the eye, and solves the above problem. As a result of intensive studies, they have found that stickiness can be improved by coexisting a specific component in an aqueous composition for topical mucosa containing rebamipide, and have completed the present invention.

That is, the present invention provides the following [1] to [9].
[1] At least one selected from the group consisting of (A) rebamipide, a rebamipide derivative, and salts thereof, and (B) at least one selected from the group consisting of ethanolamine, trometamol, and salts thereof. An aqueous composition for application to topical mucosa containing;
[2] The aqueous composition for topical mucosal application according to [1], wherein the component (B) is ethanolamine, and the ethanolamine is monoethanolamine;
[3] The aqueous composition for topical mucosa application according to [1] or [2], wherein the content of the component (A) is 0.0001 to 10 w/v%;
[4] The aqueous composition for topical mucosa application according to any one of [1] to [3], wherein the content of the component (B) is 0.0001 to 5 w/v%.
[5] The aqueous composition for topical mucosal application according to any one of [1] to [4], further containing a buffering agent;
[6] The aqueous composition for topical mucosa application according to any one of [1] to [5], further containing a nonionic surfactant;
[7] The aqueous composition for topical mucosa application according to any one of [1] to [6], which further comprises a vinyl polymer.
[8] The aqueous composition for topical mucosal application according to any one of [1] to [7], which further contains a polyhydric alcohol; and
[9] At least one selected from the group consisting of (A) rebamipide, rebamipide derivative, and salts thereof, and (B) ethanolamine, trometamol, and salts thereof in an aqueous composition for topical mucosa application A method of imparting an effect of preventing stain on local mucosa during application by allowing at least one selected from the group to coexist.

According to the present invention, it is possible to provide an aqueous composition for topical mucosa which contains rebamipide, a rebamipide derivative, or a salt thereof and which has little stickiness.

It is a photograph showing the evaluation result of white residue after the composition for ocular mucosa application of the present invention and the composition for ocular mucosa application of Comparative Example were dropped on a slide glass and left standing for 24 hours. It is a photograph showing the evaluation result of deposit generation by the stability test of the composition for ocular mucosa application of the present invention and the composition for ocular mucosa application of Comparative Example.

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

The aqueous composition for topical mucosa application of the present invention comprises at least one selected from the group consisting of (A) rebamipide, rebamipide derivatives, and salts thereof, and (B) ethanolamine, trometamol, and salts thereof. It contains at least one selected from

In the present specification, rebamipide of the component (A) is 2-(4-chlorobenzoylamino)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionic acid ((2RS)-2- It is also a compound 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 commercial product.

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

Of the component (A) used in the present invention, the salt of rebamipide or a rebamipide derivative is not particularly limited as long as it is a pharmaceutically, pharmacologically or physiologically acceptable salt. , 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. Examples thereof include polyvalent carboxylates; oxycarboxylates such as lactate, tartrate and citrate; and organic sulfonates such as methanesulfonate, toluenesulfonate and tosylate. Examples of the inorganic acid salt include hydrochloride, sulfate, nitrate, hydrobromide, and phosphate. Examples of the salt with an organic base include salts with an organic amine such as methylamine, triethylamine, triethanolamine, diethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline and ethylenediamine. Examples of the salt with an inorganic base include various salts such as an ammonium salt; a salt with an alkali metal such as sodium or potassium; an alkaline earth metal such as calcium or magnesium; or a metal 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 a hydrate of the salt.

In the aqueous composition for topical mucosa application of the present invention, the total content of the component (A) with respect to the total amount of the aqueous composition for topical mucosa application 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, more preferably 0 with respect to the total amount of the aqueous composition for topical mucosa application. 0.01 w/v% or more, more preferably 0.05 w/v% or more, even more preferably 0.1 w/v% or more, 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, relative to the total amount of the aqueous composition for topical mucosa application. 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 with respect to the total amount of the aqueous composition for topical mucosa application. %, 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% to 2 w/v%.

In the present invention, the ethanolamine as the 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 trometamol (2-Amino-2-hydroxymethyl-propane-1,3-diol). These may be used alone or in combination of two or more, and they may be synthesized by known methods or may be obtained as commercial products.

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

In the aqueous composition for topical mucosa application of the present invention, the total content of the component (B) with respect to the total amount of the aqueous composition for topical mucosa application 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, and further preferably 0.01 w with respect to the total amount of the aqueous composition for topical mucosa application. /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, even more preferably 1 w/v% or less, even more preferably It is 0.5 w/v% or less.

In the aqueous composition for topical mucosa application of the present invention, 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 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, still more preferably 0.01 to 3 parts by weight, and particularly preferably 0.05 to 1 part by weight.

The aqueous composition for topical mucosa application of the present invention preferably further contains a buffering agent in addition to the components (A) and (B) from the viewpoint that the effect of the present invention is more remarkably exhibited. The buffer that can be added to the aqueous composition for topical mucosa application of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, and an organic buffer or Any of the inorganic buffers can be used. Examples of such buffers include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, aspartic acid, aspartate, epsilon-aminocaproic acid, hydrochloric acid, sodium hydroxide and the like. To be These buffer agents may be used in combination.

Examples of the borate buffer include boric acid or borate salts such as alkali metal borate and alkaline earth metal borate. Examples of the phosphate buffer include phosphoric acid or phosphates such as alkali metal phosphates and alkaline earth metal phosphates. Examples of the carbonate buffer include carbonic acid or carbonates such as alkali metal carbonates and alkaline earth metal carbonates. Examples of the citric acid buffer include citric acid, alkali metal citrate salts, and alkaline earth metal citrate salts. As the buffer, hydrate of each salt may be used. As a more specific example, as a borate buffer, boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.); As a phosphate buffer, phosphoric acid or the Salts (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); Or a salt thereof (sodium hydrogen carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate, magnesium carbonate, etc.); as a citric acid buffer, citric acid or a salt thereof (sodium citrate, potassium citrate, citric acid). Calcium acid, sodium dihydrogen citrate, disodium citrate, etc.; Acetic acid buffer, acetic acid or a salt thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.); Aspartic acid or a salt thereof (sodium aspartate, Examples thereof include magnesium aspartate, potassium aspartate, and an equal mixture of magnesium and potassium aspartate. 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 commercial product.

Of the above buffers, borate buffer, citrate buffer, phosphate buffer, and epsilon-aminocaproic acid are preferred, especially borate buffer, citrate buffer, and epsilon-aminocaproic acid, especially boric acid. Buffers and epsilon-aminocaproic acid are preferred. Specific preferred 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 boric acid, a combination of 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 its salt, and citric acid is preferably exemplified.

When a buffering agent is added to the aqueous composition for topical mucosa application of the present invention, the blending ratio of the buffering agent is, for example, the type of buffering agent used, the type and amount of other compounding ingredients, and the use of the aqueous composition for topical mucosal application. However, the total content of the buffer is preferably 0.01 w/v% or more, more preferably 0.05 w/v, relative to the total amount of the aqueous composition for topical mucosa application. v% or more, more preferably 0.1 w/v% or more, preferably 10 w/v% or less, more preferably 5 w/v% or less, even more preferably 3 w/v% or less, even more preferably 2 w/ v% or less.

In the aqueous composition for application to topical mucosa of the present invention, the ratio of the compounding amount of the buffering agent to the component (A) is such that the total content of the buffering agent is 0.001 with respect to 1 part by weight of the total content of the component (A). ˜50 parts by weight is preferred, 0.005 to 10 parts by weight is more preferred, 0.01 to 5 parts by weight is even more preferred, and 0.05 to 2 parts by weight is particularly preferred.

The aqueous composition for application to topical mucosa of the present invention preferably contains a nonionic surfactant in addition to the components (A) and (B) from the viewpoint that the effect of the present invention is more remarkably exhibited. The nonionic surfactant that can be incorporated into the aqueous composition for topical mucosa application 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 incorporated in the aqueous composition for topical mucosa application 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 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 (200) POP (70) POE/POP glycol such as glycol; POE•POP glycol of ethylenediamine such as poloxamine; POE(20) sorbitan monolaurate (polysorbate 20), POE sorbitan monostearate (polysorbate 60), POE sorbitan tristearate (polysorbate 65) POE sorbitan fatty acid esters such as POE (20) sorbitan monooleate (polysorbate 80); POE hydrogenated castor oil 5, POE hydrogenated castor oil 10, POE hydrogenated castor oil 20, POE hydrogenated castor oil 40, POE hydrogenated castor oil 50 POE hydrogenated castor oil such as POE hydrogenated castor oil 60 and POE hydrogenated castor oil 100; POE castor oil such as POE castor oil 3, POE castor oil 10 and POE castor oil 35; POE (9) POE alkyl ether such as lauryl ether POE (20) POP (4) POE/POP alkyl ether such as cetyl ether; POE (10) POE alkyl phenyl ether such as nonyl phenyl ether; polyethylene glycol monostearate such as polyoxyl 40 stearate To be The numbers in parentheses indicate the number of added moles.

In the aqueous composition for topical mucosa application 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 or may be obtained as a commercial product.

When a nonionic surfactant is added to the aqueous composition for topical mucosa application of the present invention, the mixing ratio of the nonionic surfactant is such that the type of nonionic surfactant, the type and amount of other components, and the application of topical mucosa It can be appropriately set depending on the application of the aqueous composition. 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 aqueous composition for application to topical mucosa of the present invention, the ratio of the blending amount of the nonionic surfactant to the component (A) is such that the total amount of the nonionic surfactant is 1 part by weight relative to 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, even more preferably 0.001 to 10 parts by weight, and particularly preferably 0.005 to 1 part by weight.

The aqueous composition for topical mucosa application of the present invention preferably further contains a vinyl polymer in addition to the components (A) and (B) from the viewpoint that the effect of the present invention is more remarkably exhibited. Examples of vinyl polymers that can be incorporated into the aqueous composition for topical mucosa application of the present invention include polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone (K17, K25, K30, K90, etc.), carboxyvinyl polymer, and the like. .. These vinyl-based polymers may be used alone or in any combination of two or more. The vinyl polymer can be synthesized by a known method or can be obtained as a commercial product.

Among these vinyl 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 the vinyl-based polymer is blended in the aqueous composition for topical mucosa application of the present invention, the blending ratio is the type of vinyl-based polymer to be used, the type and blending amount of other components, and the aqueous composition for topical mucosa application. 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% with respect to the total amount of the aqueous composition for topical mucosa application. Or more, 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 vinyl polymer is preferably 10 w/v%. Or less, more preferably 7 w/v% or less, further preferably 5 w/v% or less, particularly preferably 3 w/v% or less.

In the aqueous composition for application to topical mucosa of the present invention, the ratio of the blending amount of the vinyl polymer to the component (A) is such that the total content of the vinyl polymer is 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 aqueous composition for application to topical mucosa of the present invention preferably further contains a polyhydric alcohol in addition to the components (A) and (B) from the viewpoint that the effect of the present invention is more remarkably exhibited. The polyhydric alcohol that can be incorporated into the topical mucosa-applied aqueous composition of the present invention may be a component having a function of helping rebamipide and/or its salt, which is poorly soluble in water, to be dissolved in an aqueous solution, for example, Examples thereof include glycerin, propylene glycol, polyethylene glycol (400, 4000, 6000, etc.). 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 commercially available.

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 with the aqueous composition for topical mucosa application of the present invention, the blending ratio is, for example, the type of polyhydric alcohol to be used, the types and blending amounts of other components, and the use of the aqueous composition for topical mucosa application. 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 with respect to the total amount of the aqueous composition for topical mucosa application. , 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 3 w/v% or less, and particularly preferably 1 w/v% or less.

In the aqueous composition for topical mucosa application of the present invention, the ratio of the polyhydric alcohol to the component (A) is such that the total content of the polyhydric alcohol is 0 relative to 1 part by weight of the total content of the component (A). 0.001 to 10 parts by weight is preferred, 0.005 to 5 parts by weight is more preferred, 0.01 to 2 parts by weight is even more preferred, and 0.05 to 1 part by weight is particularly preferred.

The pH of the topical mucosa-applied aqueous composition of the present invention is not particularly limited as long as it is in a pharmaceutical, pharmacologically (pharmaceutical) 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. The range is 8.5.

The aqueous composition for topical mucosa application of the present invention can be adjusted to an osmotic pressure ratio within a range that is acceptable to the living body, if necessary. The appropriate osmotic pressure ratio varies depending on the application site, dosage form, etc., but is usually 0.5 to 5.0, more preferably 0.6 to 3.0, and further preferably 0.7 to 2.0. To be 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, and the osmotic pressure is the osmotic pressure measurement method described in the Japanese Pharmacopoeia ( Freezing point depression method). In addition, the standard solution for osmotic pressure ratio measurement (0.9 w/v% sodium chloride aqueous solution) was dried in sodium chloride (Japanese Pharmacopoeia standard reagent) at 500 to 650° C. for 40 to 50 minutes, and then in a desiccator (silica gel). Allow to cool, measure exactly 0.900 g, dissolve in purified water to prepare exactly 100 mL, or use a commercially available standard solution for osmotic pressure ratio measurement (0.9 w/v% sodium chloride aqueous solution).

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

The aqueous composition for application to topical mucosa of the present invention may contain an appropriate amount of various pharmacologically active ingredients or physiologically active ingredients in combination with 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 medicines described in the OTC drug manufacturing and marketing approval standard 2012 version (supervised by the Regulatory Science Society of Japan). Specifically, the following components are included.

Antiallergic or antihistamine agents: For example, diphenhydramine hydrochloride, iproheptin, chlorpheniramine maleate, acitazanolast, amlexanox, ibudilast, tranilast, levocabastine hydrochloride, sodium cromoglycate, ketotifen fumarate, pemirolast potassium, olopatadine hydrochloride and the like.
Decongestants: For example, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, etc.
Ocular muscle regulators: For example, cholinesterase inhibitors having an active center similar to acetylcholine, specifically neostigmine methylsulfate, tropicamide, heleniene, atropine sulfate and the like.
Bactericide: For example, acrinol, cetylpyridinium, chlorhexidine hydrochloride, chlorhexidine gluconate, polyhexanide hydrochloride and the like.
Vitamins: For example, flavin adenine dinucleotide sodium, cyanocobalamin, retinol 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 agent: For example, dipotassium glycyrrhizinate, allantoin, berberine chloride, berberine sulfate, lysozyme chloride, sodium azulene sulfonate, indomethacin, pranoprofen, ibuprofen and the like.
Astringent: for example, zinc white, zinc lactate, zinc sulfate and the like.
Others: sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, sulfisomidine sodium, etc.

Furthermore, in the aqueous composition for topical mucosa application of the present invention, a carrier, a thickener, sugar alcohols, sugars, amino sugars, isotonic agents, pH adjusting agents, stabilizers, chelating agents, preservatives, and cooling agents. Additives such as agents, oils and anionic surfactants may be selected, and at least one kind may be used in combination and contained in an appropriate amount. Examples of such additives include various additives described in Encyclopedia of Pharmaceutical Additives 2007 (edited by Japan Pharmaceutical Additives Association). The following additives are listed as typical components.

Carrier: For example, an aqueous carrier such as water or hydrous ethanol.
Thickening agents: 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.
Sugar: For example, glucose.
Amino sugar: For example, meglumine and the like.
Isotonicity agents: for example, sodium bisulfite, 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.
Stabilizer: For example, dibutylhydroxytoluene, butylhydroxyanisole, sodium formaldehyde sulfoxylate (Rongalit), tocopherol, sodium pyrosulfite, aluminum monostearate, glyceryl monostearate, cyclodextrin, diisopropanolamine and the like.
Chelating agents: 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, biguanide compounds (specifically, polyhexanide hydrochloride (polyhexamethylene biguanide), etc.), glowkill (manufactured by Rhodia) Product name) etc.
Cooling agents: For example, menthol, menthone, camphor, borneol, geraniol, cineol, citronellol, carvone, anethole, eugenol, limonene, linalool, linalyl acetate, thymol, cymene, terpineol, pinene, camphene, isoborneol, fenchen, nerol. , Myrcen, myrcenol, linalool acetate, lavangulol, eucalyptus oil, bergamot oil, peppermint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon 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, mineral oils such as liquid paraffin and vaseline.
Anionic surfactant: 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 application to topical mucosa of the present invention is prepared by adding desired amounts of the above-mentioned components (A) and (B) and, if necessary, other compounding ingredients to a carrier so as to have a desired content. .. Specifically, for example, it can be prepared by dissolving or suspending the above components with purified water, adjusting the pH and osmotic pressure to predetermined levels, and sterilizing by filtration sterilization or the like.

In the aqueous composition for topical mucosa application in the present specification, water is contained in an amount of 1 w/v% or more, preferably 5 w/v% or more, more preferably 20 w/v% or more, further preferably 50 w/v. % Or more, more preferably 70 w/v% or more, and most preferably 90 w/v% or more. The water contained in the aqueous composition for topical mucosa application of the present invention may be pharmaceutically, pharmacologically or physiologically acceptable. For example, distilled water, ordinary 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 aqueous composition for application to topical mucosa of the present invention can take various formulation forms depending on the purpose. Examples of the formulation form of the aqueous composition for topical mucosa application of the present invention include liquid preparations, semisolid preparations (ointments, etc.) and the like. A liquid agent is preferable.

The aqueous composition for application to topical mucosa of the present invention is an aqueous composition which is directly applied to topical mucosa such as ocular mucosa, nasal mucosa, oral mucosa and pharyngeal mucosa.

Therefore, the aqueous composition for topical mucosa application of the present invention can be used as a drug product or a quasi drug, for example, a composition for ocular mucosa, a composition for nasal mucosa, a composition for oral mucosa, a composition for ear mucosa. It can be used for various purposes such as objects.

The composition for application to the ocular mucosa, eye drops (including eye drops that can also be used during contact lens wearing), artificial tears (including artificial tears that can also be used during contact lens wearing), Eye wash, eye ointment, contact lens mounting solution, contact lens care agent (contact lens disinfectant, contact lens preservative, contact lens cleaning agent, contact lens cleaning preservative, contact lens disinfecting/washing/preservative agent) Etc.) etc. are included. Here, the contact lens includes all contact lenses that are commercially available now or will be commercially available in the future (including soft contact lenses, hard contact lenses, and oxygen-permeable hard contact lenses. The lens includes both ionic and nonionic, includes both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses, and further includes color contact lenses of all materials.) You can

The composition for application to nasal mucosa includes nasal drops, nasal ointment, nasal wash, and the like. The composition for application to the oral mucosa includes an oropharyngeal cream, an oropharyngeal gel, an oropharyngeal ointment, an oropharyngeal spray, a mouthwash, an inhalant and the like. The ear mucosa application composition includes ear drops and ear ointment.

Among the above-mentioned applications, the composition for ocular mucosa is preferable from the viewpoint of more remarkably exhibiting 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 because they have a large number of times of use per day, and thus the stickiness suppressing effect and the stain suppressing effect of the present invention are remarkably exhibited.

The aqueous composition for topical mucosa application of the present invention is provided by being contained in any container. The container containing the aqueous composition for topical mucosa application of the present invention is not particularly limited, and may be, for example, glass or resin. The container containing the aqueous composition for topical mucosa application 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 aqueous composition for topical mucosa application of the present invention, at least a part of the container is made of polyethylene terephthalate (PET), polyethylene naphthalate (PEN), polypropylene (PP), 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, even more preferably PET, PP, It is made of PE, particularly preferably PET or PP, and most preferably PET.

In the present specification, the container mainly means a container (primary container) that directly contains the rebamipide-containing aqueous composition for topical mucosa application. In addition, a container may have a lid part and an extraction port part attached to the container body part. The above-mentioned materials mainly mean the materials of the container body.

When the container for containing the topical mucosa-applied aqueous composition according to the present embodiment is made of resin, the container may be formed of only a single resin, or may be formed by combining a plurality of synthetic resins. Good. When a plurality of synthetic resins are combined, the above synthetic resins (PET, PEN, PP, PAR, PBT, PC and PE) may be combined, and in addition to the above synthetic resins, a synthetic resin container is usually molded. You may combine the synthetic resin used.

The container containing the aqueous composition for application to topical mucosa 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 be visually recognized. 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 application to a topical mucous membrane such as eye drops and nasal drops, the internal volume 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, and further preferably May be a container capable of containing 3 mL or more and 25 mL or less.

When the aqueous composition for topical mucosa application of the present invention is an eye drop, it is particularly preferably a multi-dose eye drop.

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

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

Furthermore, the aqueous composition for topical mucosa application of the present invention is preferably used as an ocular mucosal composition such as an eye drop for improving discomfort to the eye (especially when wearing contact lenses).

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

According to the topical mucosa-applied aqueous composition of the present invention, rebamipide, a rebamipide derivative, and/or a topical mucosa-applied aqueous composition containing a salt thereof, but particularly when applied topically to the eye, etc. It is also improved, and itching and the like at the time of instillation are suppressed, deterioration of legibility after instillation is suppressed, and white residue at the time of drying is suppressed.

Furthermore, even when stored at low temperature for a long period of time, crystal precipitation is suppressed, and a clear, formulationally stable aqueous composition for topical mucosa can be obtained over a long period of time. The aqueous composition for topical mucosa application of the present invention is suitably used as a composition for ocular mucosa such as eye drops.

In the present invention, further, at least one selected from the group consisting of (A) rebamipide, rebamipide derivative, and salts thereof, and (B) ethanolamine, trometamol, and/or Alternatively, the coexistence of a salt thereof provides a method for imparting an effect of suppressing stains (unpleasant sensation) on the local mucosa during application, particularly, suppressing effect of stains on the eye part during instillation. This action imparting method can be performed by preparing an aqueous composition for topical mucosa application.

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 for ocular mucosa (eye drops) having the composition shown in Table 1 was prepared according to a conventional method. Specifically, each component was weighed into a 100 mL beaker, and a required amount of distilled water was added. The mixture was stirred while heating and the final pH was adjusted at room temperature to obtain a uniform preparation. Here, as the rebamipide, rebamipide compatible with the Japanese Pharmacopoeia was used.

Next, the obtained composition for ocular mucosa was filtered with a membrane filter having a pore size of 0.2 μm (a bottle top filter manufactured by Thermo Fisher Scientific Co., Ltd.), and then 13 mL was added to a polyethylene terephthalate eyedrop container having an inner volume of 14.2 mL. Filled. All the compositions were colorless and clear. After filling, a polyethylene nozzle was attached to the eye drop container. Right and left eyes were instilled with each of the three test subjects, and immediately after instillation, the feeling of execution after instillation regarding the symptoms shown in Table 1 was evaluated based on the following evaluation criteria 1. All subjects were naked eyes.

<Evaluation criteria 1>
0 point: Almost no feeling.
1 point: I feel weak.
2 points: I feel.
3 points: I feel strongly.
4 points: Feels too strong to endure.

The average value of the scores of 3 persons was obtained, and the improvement rate (%) with respect to Comparative Example 1-1 was calculated according to the following formula 1.
[Formula 1]
Symptom improvement rate (%) =
[(Average score of Comparative Example 1-1-Average score of each Example)/Average score of Comparative Example 1-1]×100

The results are also shown in Table 1.

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

Test Example 2 Usability test 2
According to the formulation shown in Table 2, each aqueous composition for ocular mucosa (eye drops) was prepared in the same manner as in Test Example 1 and filtered through a membrane filter having a pore size of 0.2 μm (bottle top filter manufactured by Thermo Fisher Scientific Co., Ltd.). After that, 13 mL of a polyethylene terephthalate eyedrop container having an inner volume of 14.2 mL was filled. After filling, a polyethylene nozzle was attached to the eye drop container. Three test subjects were instilled with each eye drop on the left and right eyes, and after 5 minutes from the instillation, the feeling of execution regarding the symptoms shown in Table 2 was evaluated based on the following evaluation criteria 2. All subjects were naked eyes.
The average value of the scores of 3 persons was obtained, and the improvement rate (%) with respect to Comparative Example 2-1 was calculated according to the following formula 1.

Improvement rate of visibility (%) =
[(Average score of each example-average score of Comparative Example 2-1)/average score of Comparative Example 2-1] x 100

<Evaluation criteria 2>
0 point: Very hard to see.
1 point: A little hard to see.
2 points: No change before and after instillation.
3 points: Easy to see.
4 points: Very easy to see.

From the results of Table 2, it was confirmed that when the components (A) and (B) were used in combination, the score of legibility was improved as compared with the eye drop containing only the component (A). Further, in Comparative Example 2-1, all chose "0 point: Very difficult to see" or "1 point: A little difficult to see", but in Examples 1-2 and 2-2, everyone selected 2 points or more. From this, it was confirmed that the eye drops of Comparative Example 2-1 tended to reduce the visibility (problem) and that the problem could be solved by containing both monoethanolamine or trometamol.

Test Example 3: Usability test 3
According to the formulation shown in Table 3, each aqueous composition for ocular mucosa (ophthalmic solution) was prepared in the same manner as in Test Example 1, and filtered with a membrane filter having a pore size of 0.2 μm (bottle top filter manufactured by Thermo Fisher Scientific Co.). After that, 13 mL of a polyethylene terephthalate eyedrop container having an inner volume of 14.2 mL was filled. After filling, a polyethylene nozzle was attached to the eye drop container. Three test subjects were instilled with each eye drop on the left and right eyes, and the number of persons corresponding to the symptoms described 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 on instillation were reduced as compared with the eye drops containing only the component (B). It was

Test Example 4: White Residue Test According to the formulation shown in Table 5, each aqueous composition for ocular mucosa (eye drops) was prepared in the same manner as in Test Example 1. After filtering each aqueous composition applied to the ocular mucosa with a membrane filter having a pore size of 0.2 μm (bottle top filter manufactured by Thermo Fisher Scientific Co., Ltd.), 100 μL of each was dropped on a slide glass and allowed to stand still at 20° C. in the dark for 24 hours. did. The state of each test liquid on the slide glass after 24 hours was observed, and the degree of white residue was evaluated according to the following white residue evaluation criteria. The results are shown in Table 5 below. Further, FIG. 1 shows an image taken by a digital camera.

<Evaluation criteria for remaining white>
White residue is very intense: +++
White residue is intense: ++
There is white residue: +
There is a slight white residue: ±
No white residue at all: −

In FIG. 1, from the left, Comparative Example 4-1, Example 4-1, and Comparative Example 4-2 are shown. As is clear from Table 5 and FIG. 1, in the ophthalmic mucosa-applied aqueous composition containing only the component (A), it was observed that a white solid remained after dropping on the slide glass (Comparative Example 4- 1). On the other hand, in the aqueous composition for application to the ocular mucosa containing the component (A) and monoethanolamine, white residue was significantly suppressed (Example 4-1). Therefore, it was clarified that by adding monoethanolamine to the ocular mucosa-applied aqueous composition, white residue at the time of dropping and drying was significantly suppressed, and an ocular mucosa-applied aqueous composition having excellent quality could be obtained. .. On the other hand, when the aqueous composition for ocular mucosa contained meglumine instead of monoethanolamine (Comparative Example 4-2), almost no white residue suppressing effect was observed.

Test Example 5: Stability Test In accordance with the formulations shown in Tables 6 to 8, each aqueous composition for ocular mucosa (eye drops) was prepared in the same manner as in Test Example 1. This liquid was filtered through a membrane filter having a pore size of 0.2 μm (bottle top filter manufactured by Thermo Fisher Scientific Co., Ltd.), and then 5 mL of each aqueous composition for ocular mucosa was filled in a glass head space vial having a volume of 10 mL. After storing at 20° C. in the dark for 7 days, the mixture was thawed at 4° C. in the dark for 1 day.
The presence or absence of precipitates in each aqueous composition applied to the ocular mucosa was evaluated according to the following evaluation criteria for the amount of precipitation.
<Evaluation criteria for precipitation amount>
20 or more crystals can be confirmed by observing from a place 50 cm away ×
10 to 20 crystals can be confirmed by observing from 50 cm away.
1 to 10 crystals can be confirmed by observing from 50 cm away.
Observed from a distance of 50 cm, crystals cannot be confirmed.

It was confirmed that, by containing the component (A) and the component (B), precipitation is less likely to occur even when stored at low temperature, and a highly stable preparation can be prepared. In particular, in Examples 5-2, 5-3, and 5-4, no increase in crystal precipitation was observed even after storage for 7 days in a 4° C. environment after completion of the above observation, and stability was particularly excellent. Was confirmed. Further, it was confirmed that in Examples 5-2, 5-3, and 5-4, precipitation was not increased for 2 weeks even under another low temperature environment (4° C.), and was stably maintained.

Test Example 6: Stability Test According to the formulation shown in Table 9, each aqueous composition for ocular mucosa (eye drops) was prepared. After filtering each aqueous composition for application to the ocular mucosa with a membrane filter having a pore size of 0.2 μm (bottle top filter manufactured by Thermo Fisher Scientific Co., Ltd.), 5 mL each was filled in a glass head space vial having a volume of 10 mL and protected from light at 4° C. Was stored for 14 days and evaluated according to the same evaluation criteria as in Test Example 5. (Evaluation 1) Further, the sample was stored at 20° C. under shading for about 6 weeks and evaluated according to the same criteria (evaluation 2), and the state was photographed with a digital camera (FIG. 2).

Separately, similarly filled samples were stored at -20°C and protected from light for 7 days, and then melted at 4°C and protected from light for 1 day. After that, it was stored again at -20°C in the dark for 7 days, melted at 4°C in the dark 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 FIG. 2 and Table 9, it was confirmed that the composition for ocular mucosa application (eye drops) of the present invention was stable even at low temperatures.

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

About 50 mL of distilled water was put into a 100 mL beaker and stirred while heating to 70°C. After adding each component therein, about 40 mL of purified water was further added. After stirring at 70° C. for 30 minutes or more, the temperature was returned to room temperature and the pH was adjusted to obtain a uniform preparation.

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

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

Claims (7)

(A) at least one selected from the group consisting of rebamipide and salts thereof, and (B) at least one selected from the group consisting of ethanolamine, trometamol, and salts thereof;
Buffer;
Polyoxyethylene polyoxypropylene glycol, ethylenediamine polyoxyethylene polyoxypropylene glycol, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene alkyl ethers, polyoxyethylene poly One or more nonionic surfactants of oxypropylene alkyl ethers, polyoxyethylene alkylphenyl ethers, or polyethylene glycol monostearate; and
An aqueous composition for topical mucosa containing a vinyl polymer, which is one or more of polyvinyl alcohol, polyvinylpyrrolidone, or carboxyvinyl polymer . The aqueous composition for topical mucosa application according to claim 1, wherein the component (B) is ethanolamine, and the ethanolamine is monoethanolamine. The topical viscous aqueous composition according to claim 1 or 2 , wherein the buffering agent is boric acid. The aqueous composition for topical mucosa application according to claim 1, wherein the content of the component (A) is 0.0001 to 10 w/v%. The content of the component (B) is an 0.0001~5w / v%, any one topical mucosal application aqueous composition according to claim 1-4. Additionally, glycerine, propylene glycol, or a polyethylene glycol one or more, containing polyhydric alcohol, topical mucosal application aqueous composition according to any one of claims 1-5. In an aqueous composition for topical mucosa application,
(A) at least one selected from the group consisting of rebamipide and salts thereof ;
(B) at least one selected from the group consisting of ethanolamine, trometamol, and salts thereof ;
Buffer;
Polyoxyethylene polyoxypropylene glycol, ethylenediamine polyoxyethylene polyoxypropylene glycol, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene alkyl ethers, polyoxyethylene poly One or more nonionic surfactants of oxypropylene alkyl ethers, polyoxyethylene alkylphenyl ethers, or polyethylene glycol monostearate; and
A method for imparting an effect of preventing stains on a local mucosa during application by coexisting a vinyl polymer, which is one or more of polyvinyl alcohol, polyvinylpyrrolidone, or carboxyvinyl polymer .