JP2018111732A - Olopatadine-containing aqueous composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To improve the safety of olopatadine in an aqueous composition comprising olopatadine and a nonionic surfactant stored in a prescribed container.SOLUTION: The method involves blending (A) at least one selected from the group consisting of olopatadine and a salt thereof, (B) a nonionic surfactant, and (C) menthol thereby obtaining an aqueous composition comprising components (A), (B), and (C). The total concentration of component (A) is 0.1 to 0.11 w/v% based on the total amount of aqueous composition.SELECTED DRAWING: None

Description

  The present invention relates to an aqueous composition.

  Olopatadine has antihistaminic activity as well as antiallergic action, and is used in aqueous compositions as a therapeutic agent for allergic or inflammatory disorders (Patent Document 1).

  On the other hand, olopatadine is known to degrade over time during storage by additives such as excipients, disintegrants, binders and lubricants frequently used in the manufacture of pharmaceutical preparations for oral administration. (Patent Document 2), formulation design in which olopatadine is stabilized is required (Patent Document 3).

  Patent Document 4 reports a method for improving the stability of an olopatadine preparation by not containing crystalline cellulose in a solid preparation containing olopatadine.

Special table 2004-536096 gazette Japanese Patent No. 3828247 JP 2011-105694 A JP 2011-20960 A

  The inventors of the present invention conducted various studies on an aqueous composition containing olopatadine, and obtained an aqueous composition containing olopatadine and a nonionic surfactant from polyethylene terephthalate, polyethylene naphthalate, polypropylene, It has been found that the stability of olopatadine is significantly reduced when filled in any container selected from the group consisting of polyarylate, polybutylene terephthalate, polycarbonate and glass.

  Accordingly, an object of the present invention is to improve the stability of olopatadine in an aqueous composition contained in the container and containing olopatadine and a nonionic surfactant.

  As a result of extensive research, the present inventors have (A) at least one selected from the group consisting of olopatadine and a salt thereof (hereinafter sometimes referred to as “component (A)”), (B) non- At least one terpenoid selected from the group consisting of an ionic surfactant (hereinafter sometimes referred to as “component (B)”) and (C) menthol, camphor, borneol and cineol (hereinafter referred to as “(C)”) The aqueous composition containing the component "sometimes referred to as a component") is found to suppress the decrease in the stability of the component (A) in the aqueous composition even when contained in the container. It came to be completed.

That is, the present invention provides the following [1] to [10].
[1] It is contained in any container selected from the group consisting of polyethylene terephthalate, polyethylene naphthalate, polypropylene, polyarylate, polybutylene terephthalate, polycarbonate, and glass, and (A) olopatadine and its At least one selected from the group consisting of salts, (B) a nonionic surfactant, and (C) at least one terpenoid selected from the group consisting of menthol, camphor, borneol and cineol Aqueous composition.
[2] The aqueous composition according to [1], wherein the component (A) is olopatadine hydrochloride.
[3] The component (B) is selected from the group consisting of polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyethylene glycol monostearate and polyoxyethylene / polyoxypropylene block copolymer The aqueous composition according to [1] or [2], which is at least one nonionic surfactant.
[4] The aqueous composition according to any one of [1] to [3], wherein the component (C) is menthol.
[5] The aqueous composition according to any one of [1] to [4], further comprising (D) at least one selected from the group consisting of glycyrrhizic acid and salts thereof.
[6] The aqueous composition according to [5], wherein the component (D) is dipotassium glycyrrhizinate.
[7] The aqueous composition according to any one of [1] to [6], which is a composition applied to mucosa.
[8] The aqueous composition according to [7], wherein the mucosa-applied composition is an ophthalmic composition.
[9] Housed in any container selected from the group consisting of polyethylene terephthalate, polyethylene naphthalate, polypropylene, polyarylate, polybutylene terephthalate, polycarbonate, and glass, (A) olopatadine and its A method for stabilizing the component (A) in an aqueous composition comprising at least one selected from the group consisting of salts and (B) a nonionic surfactant, the component (A), ( Aqueous composition containing (A) component, (B) component and (C) component by mixing at least one terpenoid selected from the group consisting of B) component and (C) menthol, camphor, borneol and cineol A way to get things.
[10] Component (A), Component (B), Component (C), Component (D) Mixing at least one selected from the group consisting of glycyrrhizic acid and salts thereof, Component (A), Component (B) The method according to [9], wherein an aqueous composition containing the components (C) and (D) is obtained.

  The olopatadine-containing aqueous composition of the present invention contains a nonionic surfactant and is made of a group consisting of polyethylene terephthalate, polyethylene naphthalate, polypropylene, polyarylate, polybutylene terephthalate, polycarbonate, and glass. The stability of olopatadine is improved by further containing at least one terpenoid selected from the group consisting of menthol, camphor, borneol and cineol while being contained in any of the selected containers. Therefore, even when the aqueous composition is stored for a long period of time or exposed to a high temperature environment, the medicinal effect of olopatadine can be exhibited.

  Moreover, the stability of olopatadine is further improved by further containing at least one selected from the group consisting of glycyrrhizic acid and its salt, in the olopatadine-containing aqueous composition of the present invention.

  In this specification, the unit of concentration “%” means “w / v%” and is synonymous with “g / 100 mL”.

  In this specification, unless otherwise specified, the abbreviation “POE” means polyoxyethylene. In this specification, unless otherwise specified, the abbreviation “POP” means polyoxypropylene.

  The aqueous composition according to this embodiment comprises (A) at least one selected from the group consisting of olopatadine and a salt thereof, (B) a nonionic surfactant, and (C) menthol, camphor, borneol and cineol. Any one selected from the group consisting of polyethylene terephthalate, polyethylene naphthalate, polypropylene, polyarylate, polybutylene terephthalate, polycarbonate and glass, containing at least one terpenoid selected from the group Housed in a container.

Component (A) Olopatadine is a known compound whose chemical name is (Z) -11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo [b, e] -oxepin-2-acetic acid, and is known It may be synthesized by the above method or may be obtained as a commercial product.

  The salt of olopatadine is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such salts include salts with inorganic acids [eg, hydrochlorides, bromates, sulfates, phosphates, sodium-orthophosphates, potassium hydrogensulfates, etc.] and salts with organic acids. [E.g. acetate, glycolate, lactate, pyruvate, malonate, succinate, glutarate, fumarate, malate, tartrate, citrate, ascorbate, maleic acid Salt, hydroxymaleate, benzoate, hydroxybenzoate, phenylacetate, cinnamate, salicylate, 2-phenoxybenzoate, etc.].

  These olopatadines and / or their salts may be used alone or in any combination of two or more. From the viewpoint of the effect of improving the stability of olopatadine in the aqueous composition, the component (A) is preferably olopatadine or a salt thereof with an inorganic acid, and more preferably olopatadine hydrochloride.

  In the aqueous composition according to the present embodiment, the concentration of the component (A) is not particularly limited, the type of the component (A), the types and concentrations of the components (B) and (C) to be used together, the use of the aqueous composition, It is appropriately set according to the formulation form, usage method and the like. As the concentration of the component (A), for example, the total concentration of the component (A) is preferably 0.002 to 1 w / v% based on the total amount of the aqueous composition according to the present embodiment. It is more preferably 005 to 0.5 w / v%, still more preferably 0.01 to 0.22 w / v%, and particularly preferably 0.01 to 0.11 w / v%. The concentration of the component (A) is suitable from the viewpoint of the effect of improving the stability of olopatadine in the aqueous composition.

Component (B) The nonionic surfactant is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such nonionic surfactants include POE (20) sorbitan monolaurate (polysorbate 20), POE (20) sorbitan monooleate (polysorbate 80), and POE sorbitan monostearate (polysorbate 60). ), POE sorbitan fatty acid ester such as POE sorbitan tristearate (polysorbate 65); 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 cured POE hydrogenated castor oil, such as castor oil 60, POE hydrogenated castor oil 100; POE castor oil, such as POE castor oil 3, POE castor oil 10, POE castor oil 35; polyethylene stearate polyethylene glycol such as polyoxyl 40 stearate; POE ( 96) Polyoxyethylene / polyoxypropylene block copolymers such as POP (67) glycol (poloxamer 407, Pluronic F127), POE (200) POP (70) glycol; POE-POP block copolymer adducts of ethylenediamine such as poloxamine; POE (9) POE alkyl ethers such as lauryl ether; POE (20) POP (4) POE / POP alkyl ethers such as cetyl ether; POE (10) POE alkyl phenyl ethers such as nonyl phenyl ether. The numbers in parentheses indicate the number of added moles.

  These nonionic surfactants may be used alone or in any combination of two or more.

  In the aqueous composition according to the present embodiment, POE sorbitan fatty acid ester, POE hydrogenated castor oil, POE castor oil, polyethylene glycol monostearate and polyoxyethylene / polyoxypropylene block copolymer are preferable as component (B), and POE sorbitan More preferred are fatty acid esters, POE hydrogenated castor oil, POE castor oil and polyethylene glycol monostearate, polysorbate 80, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene castor oil 10, polyoxyethylene. Castor oil 35 and polyoxyl stearate 40 are more preferred, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene castor oil 35 and polyoxystearate. 40 is particularly preferred.

  In the aqueous composition according to the present embodiment, the concentration of the component (B) is not particularly limited, the type of the component (B), the types and concentrations of the components (A) and (C) to be used together, the use of the aqueous composition, It is appropriately set according to the formulation form, usage method and the like. As the concentration of the component (B), for example, based on the total amount of the aqueous composition according to the present embodiment, the total concentration of the component (B) is preferably 0.001 to 5.0 w / v%, It is more preferably 0.005 to 3.0 w / v%, still more preferably 0.01 to 2.0 w / v%, and particularly preferably 0.05 to 1.5 w / v%. .

  Moreover, the content ratio of the (B) component with respect to the (A) component in the aqueous composition according to the present embodiment is not particularly limited, and the types of the (A) component and the (B) component, the use of the aqueous composition, and the formulation form It is set as appropriate according to the method of use. As a content ratio of (B) component with respect to (A) component, for example, with respect to 1 mass part of total content of (A) component contained in the aqueous composition which concerns on this embodiment, total content of (B) component The amount is preferably 0.01 to 500 parts by mass, more preferably 0.05 to 200 parts by mass, still more preferably 0.1 to 70 parts by mass, and 0.45 to 30 parts by mass. Part is particularly preferred. The content ratio of the component (B) to the component (A) is preferable from the viewpoint of further improving the stability of olopatadine in the aqueous composition.

Component (C) The terpenoid of component (C) may be any of d-form, l-form and dl-form. However, cineol has no optical isomer. Moreover, you may use the essential oil or plant extract containing the said terpenoid in the aqueous composition which concerns on this embodiment. Examples of such essential oils include eucalyptus oil, peppermint oil, and peppermint oil. Cool mint no. 71212 or the like may be used.

  These terpenoids may be used alone or in any combination of two or more. From the viewpoint of improving the stability of olopatadine, l-menthol, d-camphor, dl-camphor, d-borneol and cineol are preferable, l-menthol, d-camphor, dl-camphor and cineol are more preferable, l- Menthol is more preferred.

  In the aqueous composition according to the present embodiment, the concentration of the component (C) is not particularly limited, the type of the component (C), the type and concentration of the components (A) and (B) to be used together, the use of the aqueous composition, It is appropriately set according to the formulation form, usage method and the like. As the concentration of the component (C), for example, based on the total amount of the aqueous composition according to the present embodiment, the total concentration of the component (C) is preferably 0.00001 to 1.0 w / v%, 0 More preferably, it is 0.005 to 0.5 w / v%, still more preferably 0.001 to 0.1 w / v%, and particularly preferably 0.004 to 0.1 w / v%. In addition, when using the essential oil containing (C) component, it can set so that (C) component in the essential oil contained in an aqueous composition may satisfy | fill the said density | concentration. The concentration of the component (C) is suitable from the viewpoint of improving the stability of olopatadine.

  In addition, the content ratio of the component (C) to the component (A) in the aqueous composition according to this embodiment is not particularly limited, and the types of the components (A) and (C), the use of the aqueous composition, and the formulation form It is set as appropriate according to the method of use. As the content ratio of the component (C) to the component (A), for example, the total content of the component (C) with respect to 1 part by mass of the total content of the component (A) included in the aqueous composition according to this embodiment. The amount is preferably 0.0005 to 100 parts by weight, more preferably 0.001 to 50 parts by weight, still more preferably 0.005 to 20 parts by weight, and 0.04 to 10 parts by weight. Part is particularly preferred. The content ratio of the component (C) to the component (A) is preferable from the viewpoint of further improving the stability of olopatadine in the aqueous composition.

  The aqueous composition according to this embodiment is made of polyethylene terephthalate (PET), polyethylene naphthalate (PEN), polypropylene (PP), polyarylate (PAR), polybutylene terephthalate (PBT), polycarbonate (PC) The container is accommodated in any container selected from the group consisting of glass and glass. Preferable are PET, PEN, PP, PAR, PC, and glass, and more preferable are PET, PP, and glass.

  In this specification, a container mainly means a container (primary container) that directly stores an olopatadine-containing aqueous composition. In addition, the container may have a lid part and an extraction port part attached to the container body part. The above material mainly means the material of the container main body.

  When the container containing the aqueous composition according to this embodiment is made of a synthetic resin, the container may be formed from only a single synthetic resin, or may be formed by combining a plurality of synthetic resins. Good. When combining a plurality of synthetic resins, the above synthetic resins (PET, PEN, PP, PAR, PBT and PC) may be combined, and in addition to the above synthetic resins, they are usually used to mold a synthetic resin container. A synthetic resin may be combined. As such synthetic resins, polyester resins (polyethylene terephthalate resin, polyethylene naphthalate resin, polybutylene terephthalate, etc.), olefin resins (polyethylene, polypropylene, etc.), polyarylate resins, polyphenylene ether resins, polycarbonate resins, polysulfone resins Examples thereof include resins such as resins, polyamide resins, polyimide resins, hard vinyl chloride resins, styrene resins (polystyrene, acrylonitrile-styrene copolymers, etc.), and cellulose acetates. In addition, when combining a plurality of synthetic resins, the method is not limited, and a copolymer of these synthetic resins may be used, or these synthetic resins may be simply mixed, or a copolymer may be mixed. Good. The copolymer may be any of an alternating copolymer, a random copolymer, a block copolymer, and a graft copolymer.

  When the container for containing the aqueous composition according to the present embodiment is a synthetic resin container, the total weight of PET, PEN, PP, PAR, PBT and PC with respect to the weight of the entire constituent material of the container is not particularly limited, but preferably The total weight of PET, PEN, PP, PAR, PBT and PC is 50 w / w% or more, more preferably 65 w / w% or more, particularly preferably 80 w / w, based on the total weight of the constituent materials of the container. w or more%. In a more preferred embodiment, the weight of the synthetic resin of any one of PET, PEN, PP, PAR, PBT, and PC is 50 w / w% or more, 65 w / w% or more, or the weight of the entire constituent material of the container, It is 80 w / w% or more.

  The container containing the aqueous composition according to the present embodiment may be a container to which an ultraviolet blocking agent is added or coated. For example, a container molded after adding an ultraviolet blocking agent to the resin, or a container formed by coating the ultraviolet blocking agent after processing the resin into a sheet, and then blocking the ultraviolet after molding the resin into the final container shape Examples include containers coated with an agent. In addition, a sheet-like resin to which an ultraviolet blocking agent is added or coated may be subjected to shrinking or label packaging in a molded container.

  Examples of the ultraviolet blocking agent include zinc oxide, titanium oxide, triazole compound, benzoate compound, substituted acrylonitrile compound, cyanoacrylate compound, triazine compound, oxalate anilide compound, nickel complex compound; methyl diisopropylcinnamate Cinnamates such as cinoxate, diparamethoxycinnamate mono-2-ethylhexanoate glyceryl, paramethoxycinnamate isopropyl diisopropylcinnamate ester mixture, paramethoxycinnamate 2-ethylhexyl, cinnamate benzyl UV absorbers; paraaminobenzoic acid, ethyl paraaminobenzoate, glyceryl paraaminobenzoate, amyl paradimethylaminobenzoate, 2-ethylhexyl paradimethylaminobenzoate, 4- [N, N-di (2-hydroxypro) L) Amino] benzoic acid ester UV absorbers such as ethyl benzoate; salicylic acid UV absorbers such as ethylene glycol salicylate, octyl salicylate, dipropylene glycol salicylate, phenyl salicylate, homomenthyl salicylate, methyl salicylate, guaiazulene, dimethoxybenzylidene di Oxoimidazolidine propionate 2-ethylhexyl, 2,4,6-tris [4- (2-ethylhexyloxycarbonyl) anilino] 1,3,5-triazine, parahydroxyanisole, 2- (2-hydroxy-5-methyl) Phenyl) benzotriazole, 4-tert-butyl-4′-methoxydibenzoylmethane, phenylbenzimidazolesulfonic acid, 2- (4-diethylamino-2-hydroxybenzoyl) -benzoate Acid hexyl, hindered amine, riboflavin, anthraquinone dye (1-amino-4-methylanthraquinone, 1,4-diaminoanthraquinone, anthraquinone yellow, etc.), phthalocyanine dye (phthalocyanine blue (CI Pigment Blue 15); I. 74160; blue 404), phthalocyanine green (C.I. Pigment Green 7) and the like.

  As the ultraviolet blocking agent, preferably zinc oxide, titanium oxide, 2-ethylhexyl paramethoxycinnamate, glyceryl mono-2-ethylhexanoate diparamethoxycinnamate, 2,4,6-tris [4- (2 -Ethylhexyloxycarbonyl) anilino] 1,3,5-triazine, phenylbenzimidazolesulfonic acid, 2- (4-diethylamino-2-hydroxybenzoyl) -benzoic acid hexyl, dimethoxybenzylidene dioxoimidazolidinepropionate 2-ethylhexyl Can be mentioned. Zinc oxide and titanium oxide may be further coated with silica, silicon, zinc silicate or the like.

  The container containing the aqueous composition according to the present embodiment may be a transparent container that can visually recognize the inside of the container, or an opaque container that is difficult to visually recognize the interior of the container. Here, the “transparent container” includes both a colorless transparent container and a colored transparent container.

  The aqueous composition according to this embodiment preferably further contains (D) at least one selected from the group consisting of glycyrrhizic acid and salts thereof.

Component (D) Glycyrrhizic acid is also called 20β-carboxy-11-oxo-30-noroleana-12-en-3β-yl-2-O-β-D-glucopyranuronosyl-α-D-glucopyranoside uronic acid. And can be synthesized by known methods or obtained as a commercial product.

  The salt of glycyrrhizic acid is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. The thing of a form is illustrated. Among these salts, preferred are salts with inorganic bases, more preferred are alkali metal salts and / or ammonium salts, still more preferred are sodium salts, potassium salts and / or ammonium salts, and particularly preferred are potassium salts. These glycyrrhizic acid salts may be used alone or in any combination of two or more.

  Among the glycyrrhizic acid and its salt, glycyrrhizic acid, its alkali metal salt and / or its ammonium salt are preferable from the viewpoint that a higher stability improving effect can be obtained. Disodium glycyrrhizinate, trisodium glycyrrhizinate, diglycyrrhizinate Potassium, tripotassium glycyrrhizinate and / or monoammonium glycyrrhizinate are more preferred, and dipotassium glycyrrhizinate is particularly preferred.

  In the aqueous composition according to this embodiment, the concentration of the component (D) is not particularly limited, and the type of the component (D), the types and concentrations of the components (A), (B), and (C) to be used together, the aqueous composition Is appropriately set according to the use, formulation form, method of use and the like. As the concentration of the component (D), for example, the total concentration of the component (D) is preferably 0.001 to 2 w / v% based on the total amount of the aqueous composition according to the present embodiment. It is more preferably 005 to 1 w / v%, further preferably 0.01 to 0.5 w / v%, and particularly preferably 0.01 to 0.25 w / v%. The concentration of the component (D) is suitable from the viewpoint of improving the stability of olopatadine.

  Further, the content ratio of the component (D) to the component (A) in the aqueous composition according to the present embodiment is not particularly limited, and the types of the component (A) and the component (D), the use of the aqueous composition, and the formulation form It is set as appropriate according to the method of use. As a content ratio of (D) component with respect to (A) component, for example, with respect to 1 mass part of total content of (A) component contained in the aqueous composition which concerns on this embodiment, total content of (D) component The amount is preferably 0.005 to 100 parts by mass, more preferably 0.01 to 50 parts by mass, still more preferably 0.05 to 25 parts by mass, and 0.5 to 25 parts by mass. Part is particularly preferred. The content ratio of the component (D) to the component (A) is preferable from the viewpoint of further improving the stability of olopatadine in the aqueous composition.

  The aqueous composition according to the present embodiment can further contain a buffer. Thereby, pH of aqueous composition can be adjusted. The buffer is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such buffers include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, tris buffer, aspartic acid, aspartate, epsilon-aminocaproic acid, and the like. It is done. These buffering agents may be used alone or in any combination of two or more. Examples of the boric acid buffer include boric acid or boric acid 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 carbonates or carbonates such as alkali metal carbonates and alkaline earth metal carbonates. Examples of the citrate buffer include citric acid, alkali metal citrate, and alkaline earth metal citrate. Moreover, you may use the borate or the hydrate of a phosphate as a borate buffer or a phosphate buffer. As a more specific example, boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.); as a phosphate buffer, phosphoric acid or a salt thereof Salt (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 bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, magnesium carbonate, etc.); citric acid or a salt thereof (sodium citrate, potassium citrate, citric acid, etc.) Acid calcium, sodium dihydrogen citrate, disodium citrate, etc.); acetic acid Agents as, acetic acid or a salt thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.); aspartic acid or a salt thereof (sodium aspartate, magnesium aspartate, potassium aspartate, etc.) and the like. Among these buffering agents, boric acid buffering agents (for example, a combination of boric acid and borax) and phosphoric acid buffering agents (for example, a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate) are preferable. An acid buffer is more preferred.

  When the aqueous composition according to the present embodiment contains a buffering agent, the concentration is appropriately determined according to the type of buffering agent, the type and concentration of other components, the use of the aqueous composition, the formulation form, the method of use, etc. Is set. As the concentration of the buffer, for example, the total concentration of the buffer is preferably 0.01 to 15 w / v%, based on the total amount of the aqueous composition of the present invention, and 0.05 to 10 w / v%. It is more preferable that it is 0.1-7.5 w / v%, and it is especially preferable that it is 0.5-5 w / v%.

  The aqueous composition according to the present embodiment can further contain a thickener. Thereby, the viscosity of the aqueous composition which concerns on this embodiment can be adjusted. Examples of the thickener include polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone (K25, K30, K90, etc.), carboxyvinyl polymer, cellulose derivatives [methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose. (2208, 2906, 2910, etc.), carboxymethylcellulose, carboxyethylcellulose, nitrocellulose or their salts], polyethylene glycol (Macrogol 300, Macrogol 400, Macrogol 1500, Macrogol 4000, Macrogol 6000, etc.), chondroitin Sodium sulfate, sodium hyaluronate, gum arabic, tragacanth, dextran (40, 70, etc.), Examples thereof include sucrose and sorbitol, preferably polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone (K25, K30, K90), carboxyvinyl polymer, cellulose derivative (methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose) (2208, 2906, 2910), carboxymethylcellulose or a salt thereof), polyethylene glycol (macrogol 300, macrogol 400, macrogol 4000, macrogol 6000, etc.), dextran (70), and more preferably polyvinyl alcohol ( Completely or partially saponified), polyvinylpyrrolidone (K25, K30, K90), carboxyvinyl polymer, methylcellulose, hydride Carboxymethyl cellulose, hydroxypropyl methylcellulose (2208, 2906, 2910), carboxymethyl cellulose or a salt thereof, polyethylene glycol (Macrogol 300, Macrogol 400, Macrogol 4000, Macrogol 6000), dextran (70). These thickening agents may be used alone or in any combination of two or more.

  When the aqueous composition according to the present embodiment contains a thickener, the concentration depends on the type of the thickener, the type and concentration of other components, the use of the aqueous composition, the formulation form, the method of use, etc. Is set as appropriate. As the concentration of the thickener, for example, based on the total amount of the aqueous composition of the present invention, the total concentration of the thickener is preferably 0.0001 to 5 w / v%, and is preferably 0.0005 to 3 w / v. It is more preferably v%, further preferably 0.001 to 1 w / v%, and particularly preferably 0.01 to 0.2 w / v%.

  Moreover, the aqueous composition which concerns on this embodiment can contain a tonicity agent further. The isotonic agent is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such isotonic agents include, for example, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen sulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride Potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, glycerin, propylene glycol, polyethylene glycol, glucose, mannitol, sorbitol and the like. Among these isotonic agents, glycerin, propylene glycol, glucose, sodium chloride, potassium chloride, calcium chloride, or magnesium chloride is preferable, sodium chloride or glycerin is more preferable, and sodium chloride is still more preferable. These isotonic agents may be used alone or in any combination of two or more.

  When the aqueous composition according to this embodiment contains a tonicity agent, the concentration is the type of tonicity agent, the type and concentration of other components, the use of the aqueous composition, the formulation form, the method of use, etc. It is set appropriately according to As the concentration of the tonicity agent, for example, the total concentration of the tonicity agent is preferably 0.01 to 10 w / v% based on the total amount of the aqueous composition according to the present embodiment. It is more preferable that it is 05-5 w / v%, and it is still more preferable that it is 0.1-3 w / v%.

  About pH of the aqueous composition which concerns on this embodiment, if it exists in the range accept | permitted pharmaceutically, pharmacologically (pharmaceutical) or physiologically, it will not specifically limit. As pH of an aqueous composition, it is preferable that it is 4.0-9.5, for example, it is more preferable that it is 5.0-9.0, and it is still more preferable that it is 5.5-8.5. .

  Moreover, about the osmotic pressure of the aqueous composition which concerns on this embodiment, if it is in the range accept | permitted by a biological body, it will not restrict | limit in particular. The osmotic pressure ratio of the aqueous composition is, for example, preferably 0.5 to 5.0, more preferably 0.6 to 3.0, and further preferably 0.7 to 2.0. Preferably, it is 0.9-1.55. The osmotic pressure can be adjusted by a method known in the art using an inorganic salt, a polyhydric alcohol, a sugar alcohol, a sugar, or the like. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (0.9 w / v% sodium chloride aqueous solution) based on the 16th revised Japanese Pharmacopoeia. Measure with reference to (freezing point depression method). In addition, about the standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution), after drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500-650 degreeC for 40-50 minutes, it is in a desiccator (silica gel). It is allowed to cool, and 0.900 g is accurately weighed and dissolved in purified water to prepare exactly 100 mL, or a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution) can be used. .

  The viscosity of the aqueous composition according to the present embodiment is not particularly limited as long as it is within a range acceptable for a living body. The viscosity at 25 ° C. measured with a rotational viscometer (RE550 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1 ° 34 ′ × R24) is preferably 0.01 to 1000 mPa · s, for example, 0.05 It is more preferably ˜100 mPa · s, and further preferably 0.1 to 10 mPa · s.

In addition, the aqueous composition according to the present embodiment may contain an appropriate amount of various pharmacologically active ingredients and physiologically active ingredients in addition to the above ingredients, as long as the effects of the present invention are not hindered. Such an ingredient is not particularly limited, and examples thereof include active ingredients in various pharmaceuticals described in the over-the-counter drug manufacturing (import) approval standard 2000 edition (supervised by the Pharmaceutical Affairs Research Committee). Specifically, the following components are listed as components used in ophthalmic drugs.
Antihistamine or antiallergic agent: for example, ketotifen fumarate, iproheptin, diphenhydramine hydrochloride, chlorpheniramine maleate, pemirolast potassium, sodium cromoglycate and the like.
Decongestant: Tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, naphazoline hydrochloride, naphazoline nitrate, epinephrine, epinephrine hydrochloride, ephedrine, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, and the like.
Eye muscle modulating agent: for example, cholinesterase inhibitor having an active center similar to acetylcholine, specifically, neostigmine methyl sulfate, tropicamide, atropine sulfate helenien.
Bactericides: for example, acrinol, cetylpyridinium, benzalkonium chloride, benzethonium chloride, chlorhexidine, polyhexamethylene biguanide, alkyldiaminoethylglycine hydrochloride, etc.
Vitamins: flavin adenine dinucleotide sodium, cyanocobalamin, retinol acetate, retinol palmitate, pyridoxine hydrochloride, panthenol, calcium pantothenate, sodium pantothenate, tocopherol acetate, etc.
Amino acids: potassium aspartate, magnesium aspartate, magnesium and potassium aspartate (a mixture of equal amounts), aminoethylsulfonic acid, and the like.
Anti-inflammatory agents: for example, allantoin, berberine chloride, berberine sulfate, zinc sulfate, zinc lactate, glycyrrhetinic acid, methyl salicylate, glycol salicylate, sodium azulenesulfonate, tranexamic acid, epsilon-aminocaproic acid, lysozyme, licorice, pranoprofen and the like.
Other: for example, sodium hyaluronate, sulfamethoxazole, sodium sulfamethoxazole, indomethacin, ibuprofen, ibuprofen piconol, bufexamac, flufenamic acid butyl, bendazac, piroxicam, ketoprofen, felbinac, purple root, tochinoki, and These salts etc.

In addition, in the aqueous composition according to the present embodiment, various additives are appropriately selected according to a conventional method depending on the use and the formulation form, as long as the effects of the invention are not impaired. The above may be used in combination to contain an appropriate amount. Examples of these additives include various additives described in Pharmaceutical Additives Encyclopedia 2007 (edited by Japan Pharmaceutical Additives Association). Typical additives include the following additives.
Carrier: An aqueous carrier such as water or hydrous ethanol.
Sugars: for example, glucose, cyclodextrin and the like.
Sugar alcohols: For example, xylitol, sorbitol, mannitol and the like. These may be any of D-form, L-form and DL-form.
Preservatives, bactericides or antibacterial agents: for example, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, paraoxy Methyl benzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide, etc.), Glowyl (manufactured by Rhodia) Name) etc.
Stabilizers: trometamol, sodium formaldehyde sulfoxylate (Longalite), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, glyceryl monostearate, etc.
Fragrance: Mentone, geraniol, citronellol, carvone, anethole, eugenol, limonene, linalool, linalyl acetate, bergamot oil, spearmint oil, fennel oil, cinnamon oil, rose oil, camphor oil, etc.

  In the aqueous composition according to the present embodiment, the component (A), the component (B) and the component (C), and the component (D) and other components as necessary are used as a carrier so as to have a desired concentration. It is prepared by adding. For example, in the case of an ophthalmic composition, it can be prepared by dissolving or suspending the above components with purified water, adjusting to a predetermined pH and osmotic pressure, and sterilizing by filtration sterilization or the like. Regarding the dissolution of the above component (C) and other highly hydrophobic components, after stirring together with a component having a solubilizing action such as a surfactant (including the component (B)), purified water is further added. May be added to dissolve or suspend.

  In the present embodiment, the aqueous composition means a composition having a water concentration of 85 w / v% or more based on the total amount of the aqueous composition. The concentration of water in the aqueous composition is preferably 90 w / v% or more, more preferably 92 w / v% or more, still more preferably 94 w / v% or more, and 96 w / v% or more. It is particularly preferred. As water used in the aqueous composition according to the present embodiment, water that is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable may be used, and as such water, specifically, Examples thereof include distilled water, normal water, purified water, sterilized purified water, water for injection, and distilled water for injection. In addition, the dosage form of the aqueous composition in the present embodiment is not particularly limited, and examples thereof include a liquid agent and a semisolid agent (such as an ointment), and are preferably liquid. These definitions are based on the 16th revision Japanese Pharmacopoeia.

  Moreover, since the aqueous composition which concerns on this embodiment can express the pharmacological action based on (A) component, and since the aqueous composition also contains the (D) component, since the pharmacological action can also be expressed. It is effective for applications such as anti-inflammatory and anti-allergy, and in particular, inflammatory diseases of the external eye and anterior eye (blinditis, conjunctivitis, keratitis, scleritis, episclerosis, anterior eye uvea) It can be used as a pharmaceutical or quasi-drug formulation in applications such as symptomatic treatment of inflammation and postoperative inflammation) and treatment of allergic conjunctivitis and spring catarrh.

  The aqueous composition according to the present embodiment can be used as a pharmaceutical preparation, a quasi-drug, and the like. It can be used in various applications such as a composition, a composition for subcutaneous administration, and a composition for external use on the skin.

  The aqueous composition according to this embodiment is useful as a mucosa-applied composition applied to ocular mucosa such as cornea and conjunctiva, oral mucosa, nasal mucosa, and pharyngeal mucosa.

  Specifically, the composition applied to mucosa according to this embodiment includes eye drops (also referred to as eye drops or eye drops. Eye drops include eye drops that can be applied while wearing contact lenses), artificial tears Ophthalmic compositions such as liquids, eyewashes (also referred to as eyewashes or eyewashes. Eyewashes include eyewashes that can be washed while wearing contact lenses), eye ointments, etc .; contact lens compositions [contact Lens mounting solution, contact lens care composition (contact lens disinfectant, contact lens preservative, contact lens cleaning agent, contact lens cleaning preservative, etc.)]; nasal composition such as nasal drops, nasal wash Oral compositions such as oropharyngeal drugs and gargles (gargle preparations); can be used as ear drops and the like. In view of the pharmacological action of the components (A) and (D), the aqueous composition according to this embodiment is preferably an ophthalmic composition, and more preferably an eye drop.

  In addition, the said composition for contact lenses is applicable to all contact lenses including a hard contact lens and a soft contact lens. Soft contact lenses include both ionic and non-ionic, and include silicone hydrogel contact lenses (hereinafter abbreviated as SHCL) and non-silicone hydrogel contact lenses (silicone hydrogel lenses). Including both soft contact lenses).

From another viewpoint, this embodiment is accommodated in any container selected from the group consisting of polyethylene terephthalate, polyethylene naphthalate, polypropylene, polyarylate, polybutylene terephthalate, polycarbonate, and glass. , A method of stabilizing the component (A) in the aqueous composition containing the component (A) and the component (B), wherein the component (A), the component (B) and the component (C) are mixed, The present invention provides a method for obtaining an aqueous composition containing the component (A), the component (B) and the component (C). The component (A), the component (B) and the component (C) may be mixed in any order, and the finally obtained aqueous composition has the component (A), the component (B) and the component (C). As long as it is, the component (A) is stabilized. In the said method, Preferably (D) component is also mixed and the aqueous composition containing (A) component, (B) component, (C) component, and (D) component is obtained. The component (A), the component (B), the component (C) and the component (D) may be mixed in any order, and the aqueous composition finally obtained is the component (A), the component (B), (C As long as it has component ()) and component (D), component (A) is stabilized.
Moreover, this embodiment contains (A) component, (B) component, and (C) component in an aqueous composition from another viewpoint, and this aqueous composition is made of polyethylene terephthalate, made of polyethylene naphthalate, A method for producing an aqueous composition in which component (A) is stabilized by being housed in any container selected from the group consisting of polypropylene, polyarylate, polybutylene terephthalate, polycarbonate, and glass. It is to provide.

  Hereinafter, the present invention will be described in detail with reference to Examples and Test Examples, but the present invention is not limited to these Examples and the like. When the test was performed using a plastic container, the weight of the sample was measured before and after storage to determine the transpiration rate, and the concentration change due to transpiration was corrected.

[Test Example 1 Test for Stability (1)]
An aqueous composition was prepared according to Table 1 below, and the stability of olopatadine or a salt thereof was evaluated.

First, each aqueous composition shown in Table 1 was prepared by a conventional method. Next, 5 mL of the prepared aqueous composition was put into a polyethylene terephthalate container (PET; capacity 15 mL), a polypropylene container (PP; capacity 15 mL), a polyethylene container (PE; capacity 10 mL), and a polystyrene container (PS; capacity 15 mL). Each was filled and sealed, and stored in a thermostatic chamber at 50 ° C., protected from light. 14 days after the start of storage, each test solution was taken out, and the content of olopatadine hydrochloride in the aqueous composition was quantified using high performance liquid chromatography (HPLC), and the residual ratio of olopatadine hydrochloride was calculated according to the following formula (I). did.
Formula (I)
Residual rate (%) = (Olopatadine hydrochloride content after storage) / (Olopatadine hydrochloride content before storage) × 100

  As shown in Table 1, when the aqueous composition containing olopatadine hydrochloride was stored in a container made of polyethylene terephthalate, if the aqueous composition contained polysorbate 80, which is a nonionic surfactant, the remaining olopatadine hydrochloride It was observed that the rate decreased and the stability of olopatadine hydrochloride decreased (Reference Example 1-1 and Comparative Example 1-1). However, when the aqueous composition further contained l-menthol, which is a terpenoid, the residual ratio of olopatadine hydrochloride was increased, and the stability of olopatadine hydrochloride was improved (Example 1-1). The same phenomenon was observed even when the aqueous composition containing olopatadine hydrochloride was stored in a polypropylene container (Reference Example 1-2, Comparative Example 1-2, and Example 1-2).

  On the other hand, when the aqueous composition containing olopatadine hydrochloride is stored in a polyethylene container, even if the aqueous composition contains polysorbate 80, the residual ratio of olopatadine hydrochloride is hardly decreased, and the stability of olopatadine hydrochloride is stable. The property hardly decreased (Reference Examples 1-3 to 1-5). The same phenomenon was observed even when the aqueous composition containing olopatadine hydrochloride was stored in a polystyrene container.

[Test Example 2 Test for Stability (2)]
An aqueous composition was prepared according to Table 2 below, and the stability of olopatadine or a salt thereof was evaluated. The residual ratio of olopatadine hydrochloride was determined in the same manner as in Test Example 1 except that the aqueous composition was filled in a glass headspace vial (capacity 10 mL).

  As shown in Table 2, when the aqueous composition containing olopatadine hydrochloride was stored in a glass container, if the aqueous composition contained polysorbate 80, the residual ratio of olopatadine hydrochloride was lowered, and the stability of olopatadine hydrochloride was reduced. It was recognized that the property decreased (Reference Example 2 and Comparative Example 2). Moreover, when the aqueous composition further contained l-menthol, the residual ratio of olopatadine hydrochloride increased, and the stability of olopatadine hydrochloride was improved (Example 2).

[Test Example 3 Test for Stability (3)]
An aqueous composition was prepared according to Table 3 below, and the stability of olopatadine or a salt thereof was evaluated. The residual ratio of olopatadine hydrochloride was determined in the same manner as in Test Example 1 except that the storage temperature was changed from 50 ° C. to 70 ° C. and the aqueous composition was filled in a glass headspace vial (capacity 10 mL). It was. Note that storage for 14 days at 70 ° C. corresponds to storage for about 3 years at room temperature.

As shown in Table 3, even when the aqueous composition containing olopatadine hydrochloride was stored at 70 ° C., if the aqueous composition contained polysorbate 80, the residual ratio of olopatadine hydrochloride was lowered, and the stability of olopatadine hydrochloride was reduced. (Reference Example 3 and Comparative Example 3-1). Moreover, when the aqueous composition further contained l-menthol, the residual ratio of olopatadine hydrochloride increased, and the stability of olopatadine hydrochloride was improved (Example 3-1-1). When the aqueous composition contained dipotassium glycyrrhizinate in addition to l-menthol, the stability was further improved as compared with the case where the aqueous composition contained l-menthol (Example 3-1-2). ).
Similarly, when the polyoxyl 40 stearate is contained as a nonionic surfactant, the residual rate of olopatadine hydrochloride decreases, and when 1-menthol is further contained, the residual rate of olopatadine hydrochloride increases. The stability was improved (Comparative Example 3-2, Example 3-2).

[Test Example 4 Test on stability (4)]
An aqueous composition was prepared according to Table 4 below, and the stability of olopatadine or a salt thereof was evaluated. Test Example 1 above, except that the storage temperature was changed from 50 ° C. to 60 ° C., the storage period was changed from 14 days to 7 days, and the aqueous composition was filled into a glass headspace vial (capacity 10 mL). In the same manner as above, the residual ratio of olopatadine hydrochloride was determined.

  When the aqueous composition containing olopatadine hydrochloride contains d-borneol or cineole, which is a terpenoid, it contains a nonionic surfactant as in the case of containing l-menthol. As a result, the stability of olopatadine hydrochloride decreased (Comparative Example 4, Example 4-1, and Example 4-3). In addition, when the aqueous composition contains d-borneol, which is a terpenoid, and further contains dipotassium glycyrrhizinate, the stability of olopatadine hydrochloride is further improved (Examples 4-1 and Examples). 4-2).

[Test Example 5: Stability test (5)]
An aqueous composition was prepared according to Table 5 below, and the stability of olopatadine or a salt thereof was evaluated. The residual ratio of olopatadine hydrochloride was determined in the same manner as in Test Example 1 except that the storage temperature was changed from 50 ° C. to 70 ° C. and the aqueous composition was filled in a polyethylene terephthalate container (capacity 15 mL).

  As shown in Table 5, when the aqueous composition containing olopatadine hydrochloride contains polyoxyethylene hydrogenated castor oil 60 and polyoxyethylene castor oil 35 as nonionic surfactants, Test Examples 1 to 4 Similarly, when terpenoid was contained, the stability of olopatadine hydrochloride, which was lowered by containing a nonionic surfactant, was improved.

[Test Example 6: Test on stability (6)]
An aqueous composition was prepared according to Table 6 below, and the stability of olopatadine or a salt thereof was evaluated. The residual ratio of olopatadine hydrochloride was determined in the same manner as in Test Example 1 except that the aqueous composition was filled in a glass headspace vial (capacity 10 mL).

  As shown in Table 6, when the aqueous composition containing olopatadine hydrochloride contains d-borneol or cineol, which is a terpenoid, as in the case of containing l-menthol, the nonionic surfactant is used. The stability of olopatadine hydrochloride, which was reduced by containing the agent, was improved (Comparative Example 6-1, Example 6-1, Example 6-2).

[Test Example 7: Test on stability (7)]
An aqueous composition was prepared according to Table 7 below, and the stability of olopatadine or a salt thereof was evaluated. Except that the storage temperature was 60 ° C., the storage period was changed from 14 days to 30 days, and the aqueous composition was filled in a glass headspace vial (capacity 10 mL), the same as in Test Example 1 above. The residual rate of olopatadine hydrochloride was determined.

  As shown in Table 7, when the aqueous composition containing olopatadine hydrochloride contains d-borneol or cineol, which are terpenoids, as in the case of containing l-menthol, the nonionic surfactant is used. The stability of olopatadine hydrochloride, which was reduced by containing the agent, was improved (Comparative Example 7-1, Example 7-1, and Example 7-2).

[Test Example 8: Test on stability (8)]
In the case where the same test as in the above Test Examples 1 to 7 was performed, and the aqueous composition having a polysorbate 80 concentration of 0.05 w / v% decreased the stability of olopatadine hydrochloride and further contained a terpenoid. It was confirmed that the stability was improved.

[Formulation example]
An aqueous composition was prepared according to Formulation Examples 1 to 13 shown in Tables 8 to 9 below, and those filled in polyethylene terephthalate containers (eye drops or eyewashes) were designated Formulation Examples 1 to 13 and filled in polypropylene containers. (Eye drops or eye wash) were designated as formulation examples 14 to 26. The continuation of Table 8-1 is Table 8-2, and the continuation of Table 9-1 is Table 9-2.

Claims (13)

Housed in any container selected from the group consisting of polyethylene terephthalate, polypropylene and glass,
(A) at least one selected from the group consisting of olopatadine and a salt thereof;
(B) a nonionic surfactant;
A method of stabilizing the component (A) in an aqueous composition containing
(A) component, (B) component, and (C) menthol are mixed, and the aqueous composition containing (A) component, (B) component, and (C) component is obtained,
(A) The method whose total density | concentration of a component is 0.1-0.11 w / v% on the basis of the total amount of an aqueous composition.   (A) component, (B) component, (C) component, and (D) at least 1 sort (s) selected from the group which consists of glycyrrhizic acid and its salt are mixed, (A) component, (B) component, (C The method of Claim 1 which obtains the aqueous composition containing a component) and a component (D).   The method according to claim 2, wherein the total concentration of component (D) is 0.001 to 2 w / v% based on the total amount of the aqueous composition.   The method of Claim 2 that the total content of (D) component is 0.005-100 mass parts with respect to 1 mass part of total content of (A) component contained in an aqueous composition.   (D) The method as described in any one of Claims 2-4 whose component is dipotassium glycyrrhizinate.   (C) The method as described in any one of Claims 1-5 whose total density | concentration of a component is 0.00001-1.0 w / v% on the basis of the total amount of an aqueous composition.   The total content of the component (C) is 0.0005 to 100 parts by mass with respect to 1 part by mass of the total content of the component (A) contained in the aqueous composition. The method according to item.   (B) The method as described in any one of Claims 1-7 whose total density | concentration of a component is 0.001-5.0 w / v% on the basis of the total amount of an aqueous composition.   The total content of the component (B) is 0.01 to 500 parts by mass with respect to 1 part by mass of the total content of the component (A) contained in the aqueous composition. The method according to item.   The component (B) is at least one selected from the group consisting of polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyethylene glycol monostearate and polyoxyethylene / polyoxypropylene block copolymer The method according to any one of claims 1 to 9, which is a nonionic surfactant.   (A) The method as described in any one of Claims 1-10 whose component is olopatadine hydrochloride.   The method according to any one of claims 1 to 11, wherein the aqueous composition is a composition applied to mucosa. The method according to claim 12, wherein the mucosa-applied composition is an ophthalmic composition.