Olopatadine-containing aqueous composition

Abstract

To improve the stability of olopatadine in an aqueous composition that is stored in a predetermined container and contains olopatadine and a nonionic surfactant.SOLUTION: The problem herein is solved by the invention described in the Specifications.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an aqueous composition. [Background technology]

[0002] Olopatadine has anti-allergic as well as anti-histamine activity, and is used in aqueous compositions as a therapeutic agent for allergic or inflammatory disorders (Patent Document 1).

[0003] On the other hand, it is known that olopatadine is degraded over time during storage due to additives such as excipients, disintegrants, binders and lubricants that are frequently used in the manufacture of pharmaceutical preparations for oral administration (Patent Document 2), and there is a need for a formulation design that stabilizes olopatadine (Patent Document 3).

[0004] Patent Document 4 reports a method for improving the stability of an olopatadine-containing solid preparation by deliberately not including crystalline cellulose in the preparation. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Special Publication No. 2004-536096 [Patent Document 2] Patent No. 3828247 [Patent Document 3] JP 2011-105694 A [Patent Document 4] JP 2011-20960 A Summary of the Invention [Problem to be solved by the invention]

[0006] The present inventors have conducted various studies on aqueous compositions containing olopatadine and have found that when an aqueous composition containing olopatadine and a nonionic surfactant is filled into a container selected from the group consisting of polyethylene terephthalate, polyethylene naphthalate, polypropylene, polyarylate, polybutylene terephthalate, polycarbonate, and glass, the stability of olopatadine is significantly reduced.

[0007] Therefore, an object of the present invention is to improve the stability of olopatadine in an aqueous composition that is contained in the above-mentioned container and contains olopatadine and a nonionic surfactant. [Means for solving the problem]

[0008] As a result of extensive research, the present inventors have found that an aqueous composition containing (A) at least one selected from the group consisting of olopatadine and its salts (hereinafter sometimes referred to as "component (A)"), (B) a nonionic surfactant (hereinafter sometimes referred to as "component (B)"), and (C) at least one terpenoid selected from the group consisting of menthol, camphor, borneol, and cineol (hereinafter sometimes referred to as "component (C)"), is inhibited from decreasing in stability of component (A) in the aqueous composition even when contained in the above-mentioned container, and have thus completed the present invention.

[0009] That is, the present invention provides the following [1] to

[10] . [1] An aqueous composition housed in a container selected from the group consisting of polyethylene terephthalate, polyethylene naphthalate, polypropylene, polyarylate, polybutylene terephthalate, polycarbonate, and glass, and containing: (A) at least one selected from the group consisting of olopatadine and salts thereof; (B) a nonionic surfactant; and (C) at least one terpenoid selected from the group consisting of menthol, camphor, borneol, and cineol. [2] The aqueous composition according to [1], wherein component (A) is olopatadine hydrochloride. [3] The aqueous composition according to [1] or [2], wherein component (B) is at least one nonionic surfactant selected from the group consisting of polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyethylene glycol monostearate, and polyoxyethylene-polyoxypropylene block copolymers. [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 member selected from the group consisting of glycyrrhizinic acid and salts thereof. [6] The aqueous composition described in [5], wherein component (D) is dipotassium glycyrrhizinate. [7] The aqueous composition described in any one of [1] to [6], which is a composition for application to mucosa. [8] The aqueous composition described in [7], wherein the composition for application to mucosa is an ophthalmic composition. [9] A method for stabilizing component (A) in an aqueous composition that is contained in a container selected from the group consisting of polyethylene terephthalate, polyethylene naphthalate, polypropylene, polyarylate, polybutylene terephthalate, polycarbonate, and glass and contains (A) at least one selected from the group consisting of olopatadine and salts thereof, and (B) a nonionic surfactant, comprising mixing component (A), component (B), and (C) at least one terpenoid selected from the group consisting of menthol, camphor, borneol, and cineol to obtain an aqueous composition containing component (A), component (B), and component (C).

[10] The method according to [9], comprising mixing the components (A), (B), (C), and (D) at least one selected from the group consisting of glycyrrhizinic acid and salts thereof to obtain an aqueous composition containing the components (A), (B), (C), and (D). Effect of the Invention

[0010] The olopatadine-containing aqueous composition of the present invention contains a nonionic surfactant and is housed in a container selected from the group consisting of polyethylene terephthalate, polyethylene naphthalate, polypropylene, polyarylate, polybutylene terephthalate, polycarbonate, and glass, and further contains at least one terpenoid selected from the group consisting of menthol, camphor, borneol, and cineol, thereby improving the stability of olopatadine. Therefore, even when the aqueous composition is stored for a long period of time or exposed to a high-temperature environment, the pharmaceutical effect of olopatadine can be exhibited.

[0011] Furthermore, the olopatadine-containing aqueous composition of the present invention further contains at least one selected from the group consisting of glycyrrhizinic acid and salts thereof, thereby further improving the stability of olopatadine. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] In this specification, the unit of concentration "%" means "w / v%" and is synonymous with "g / 100 mL."

[0013] In this specification, unless otherwise specified, the abbreviation "POE" means polyoxyethylene. In this specification, unless otherwise specified, the abbreviation "POP" means polyoxypropylene.

[0014] The aqueous composition of this embodiment contains (A) at least one selected from the group consisting of olopatadine and salts thereof, (B) a nonionic surfactant, and (C) at least one terpenoid selected from the group consisting of menthol, camphor, borneol and cineol, and is housed in a container made of polyethylene terephthalate, polyethylene naphthalate, polypropylene, polyarylate, polybutylene terephthalate, polycarbonate, and glass.

[0015] Component (A) Olopatadine is a known compound with the chemical name (Z)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenzo[b,e]-oxepin-2-acetic acid, and can be synthesized by known methods or obtained commercially.

[0016] The salt of olopatadine is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical) or physiologically acceptable. Examples of such salts include salts with inorganic acids [e.g., hydrochloride, bromate, sulfate, phosphate, sodium orthophosphate, potassium hydrogen sulfate, etc.] and salts with organic acids [e.g., acetate, glycolate, lactate, pyruvate, malonate, succinate, glutarate, fumarate, malate, tartrate, citrate, ascorbate, maleate, hydroxymaleate, benzoate, hydroxybenzoate, phenylacetate, cinnamate, salicylate, 2-phenoxybenzoate, etc.].

[0017] These olopatadine and / or salts thereof 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.

[0018] The concentration of the (A) component in the aqueous composition according to this embodiment is not particularly limited, and is appropriately set according to the type of the (A) component, the types and concentrations of the (B) and (C) components used in combination, the purpose of the aqueous composition, the formulation form, the method of use, etc. The concentration of the (A) component is, for example, based on the total amount of the aqueous composition according to this embodiment, preferably 0.002 to 1 w / v%, more preferably 0.005 to 0.5 w / v%, even more preferably 0.01 to 0.22 w / v%, and particularly preferably 0.01 to 0.11 w / v%. The above concentration of the (A) component is suitable from the viewpoint of the effect of improving the stability of olopatadine in the aqueous composition.

[0019] (B) Component The nonionic surfactant is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical) or physiologically acceptable. Specific examples of such nonionic surfactants include POE sorbitan fatty acid esters such as POE (20) sorbitan monolaurate (polysorbate 20), POE (20) sorbitan monooleate (polysorbate 80), POE sorbitan monostearate (polysorbate 60), and POE sorbitan tristearate (polysorbate 65); POE hydrogenated castor oils such as 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 60, and POE hydrogenated castor oil 100; and POE castor oil 3, POE castor oil 10, and POE castor oil 35. Examples of such compounds include POE castor oil, polyethylene glycol monostearate such as polyoxyl 40 stearate, polyoxyethylene-polyoxypropylene block copolymers such as POE(196)POP(67) glycol (poloxamer 407, Pluronic F127) and POE(200)POP(70) glycol, POE-POP block copolymer adducts of ethylenediamine such as poloxamine, POE alkyl ethers such as POE(9) lauryl ether, POE·POP alkyl ethers such as POE(20)POP(4) cetyl ether, and POE alkyl phenyl ethers such as POE(10) nonylphenyl ether. The numbers in parentheses indicate the number of moles added.

[0020] These nonionic surfactants may be used alone or in any combination of two or more.

[0021] In the aqueous composition according to this embodiment, as component (B), POE sorbitan fatty acid esters, POE hydrogenated castor oil, POE castor oil, polyethylene glycol monostearate and polyoxyethylene-polyoxypropylene block copolymers are preferred, POE sorbitan fatty acid esters, POE hydrogenated castor oil, POE castor oil and polyethylene glycol monostearate are more preferred, polysorbate 80, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene castor oil 10, polyoxyethylene castor oil 35 and polyoxyl 40 stearate are even more preferred, and polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene castor oil 35 and polyoxyl 40 stearate are particularly preferred.

[0022] The concentration of the (B) component in the aqueous composition according to this embodiment is not particularly limited, and is appropriately set depending on the type of the (B) component, the types and concentrations of the (A) and (C) components used in combination, the purpose of the aqueous composition, the formulation form, the method of use, etc. The concentration of the (B) component is, for example, preferably 0.001 to 5.0 w / v%, more preferably 0.005 to 3.0 w / v%, even more preferably 0.01 to 2.0 w / v%, and particularly preferably 0.05 to 1.5 w / v%, based on the total amount of the aqueous composition according to this embodiment.

[0023] In addition, the content ratio of the (B) component to the (A) component in the aqueous composition according to this embodiment is not particularly limited, and is appropriately set according to the types of the (A) component and the (B) component, the purpose of the aqueous composition, the formulation form, the method of use, etc. The content ratio of the (B) component to the (A) component is, for example, preferably 0.01 to 500 parts by mass, more preferably 0.05 to 200 parts by mass, further preferably 0.1 to 70 parts by mass, and particularly preferably 0.45 to 30 parts by mass, per part by mass of the total content of the (A) component contained in the aqueous composition according to this embodiment. The content ratio of the (B) component to the (A) component is suitable from the viewpoint of further improving the stability of olopatadine in the aqueous composition.

[0024] (C) Component The terpenoid of component (C) may be any of d-, l-, and dl-isomers. However, cineole does not have any optical isomers. In addition, in the aqueous composition according to this embodiment, essential oils or plant extracts containing the above-mentioned terpenoids may be used. Examples of such essential oils include eucalyptus oil, peppermint oil, and peppermint oil. Coolmint No. 71212 and the like may also be used.

[0025] 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 preferred, l-menthol, d-camphor, dl-camphor and cineol are more preferred, and l-menthol is even more preferred.

[0026] The concentration of the (C) component in the aqueous composition according to this embodiment is not particularly limited, and is appropriately set according to the type of the (C) component, the type and concentration of the (A) and (B) components used in combination, the purpose of the aqueous composition, the formulation form, the method of use, etc. As the concentration of the (C) component, for example, based on the total amount of the aqueous composition according to this embodiment, the total concentration of the (C) component is preferably 0.00001 to 1.0 w / v%, more preferably 0.0005 to 0.5 w / v%, even more preferably 0.001 to 0.1 w / v%, and particularly preferably 0.004 to 0.1 w / v%. In addition, when an essential oil containing the (C) component is used, the (C) component in the essential oil contained in the aqueous composition can be set to satisfy the above concentration. The concentration of the (C) component is suitable from the viewpoint of improving the stability of olopatadine.

[0027] In addition, the content ratio of the (C) component to the (A) component in the aqueous composition according to this embodiment is not particularly limited, and is appropriately set according to the types of the (A) component and the (C) component, the purpose of the aqueous composition, the formulation form, the method of use, etc. The content ratio of the (C) component to the (A) component is, for example, preferably 0.0005 to 100 parts by weight, more preferably 0.001 to 50 parts by weight, further preferably 0.005 to 20 parts by weight, and particularly preferably 0.04 to 10 parts by weight, per 1 part by weight of the total content of the (A) component contained in the aqueous composition according to this embodiment. The content ratio of the (C) component to the (A) component is suitable from the viewpoint of further improving the stability of olopatadine in the aqueous composition.

[0028] The aqueous composition according to the present embodiment is contained in a container selected from the group consisting of polyethylene terephthalate (PET), polyethylene naphthalate (PEN), polypropylene (PP), polyarylate (PAR), polybutylene terephthalate (PBT), polycarbonate (PC) and glass. The containers are preferably made of PET, PEN, PP, PAR, PC and glass, and more preferably made of PET, PP and glass.

[0029] In this specification, the container mainly means a container (primary container) that directly contains the olopatadine-containing aqueous composition. The container may also have a lid or an extraction port attached to the container body. The above-mentioned material mainly means the material of the container body.

[0030] When the container for containing the aqueous composition according to the present embodiment is made of synthetic resin, the container may be formed from only a single synthetic resin, or may be formed by combining a plurality of synthetic resins. When combining a plurality of synthetic resins, the above synthetic resins (PET, PEN, PP, PAR, PBT, and PC) may be combined, or a synthetic resin that is usually used to mold a synthetic resin container may be combined in addition to the above synthetic resin. Examples of such synthetic resins include polyester-based resins (polyethylene terephthalate resin, polyethylene naphthalate resin, polybutylene terephthalate, etc.), olefin-based resins (polyethylene, polypropylene, etc.), polyarylate-based resins, polyphenylene ether-based resins, polycarbonate-based resins, polysulfone-based resins, polyamide-based resins, polyimides, hard vinyl chloride resins, styrene-based resins (polystyrene, acrylonitrile-styrene copolymers, etc.), and cellulose acetates. In addition, when combining a plurality of synthetic resins, the method is not limited, and the synthetic resins may be copolymers of these synthetic resins, or these synthetic resins may simply be mixed, or copolymers may be mixed. The copolymer may be any of an alternating copolymer, a random copolymer, a block copolymer and a graft copolymer.

[0031] 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 relative to the total weight of the constituent materials of the container is not particularly limited, but the total weight of PET, PEN, PP, PAR, PBT and PC relative to the total weight of the constituent materials of the container is preferably 50 w / w% or more, more preferably 65 w / w% or more, and particularly preferably 80 w / w% or more. In a more preferred embodiment, the weight of any one of the synthetic resins PET, PEN, PP, PAR, PBT and PC relative to the total weight of the constituent materials of the container is 50 w / w% or more, 65 w / w% or more, or 80 w / w% or more.

[0032] The container for containing the aqueous composition according to the present embodiment may be a container to which an ultraviolet blocking agent has been added or coated. For example, a container molded after adding an ultraviolet blocking agent to a resin, a container molded after processing a resin into a sheet shape and coating it with an ultraviolet blocking agent, or a container molded into a final container shape and then coating it with an ultraviolet blocking agent may be mentioned. In addition, the sheet-shaped resin to which an ultraviolet blocking agent has been added or coated may be shrink-wrapped or labeled into the molded container.

[0033] Examples of ultraviolet blocking agents include zinc oxide, titanium oxide, triazole compounds, benzoate compounds, substituted acrylonitrile compounds, cyanoacrylate compounds, triazine compounds, oxalic acid anilide compounds, and nickel complex compounds; cinnamic acid ultraviolet absorbers such as methyl diisopropylcinnamate, cinoxate, di-paramethoxycinnamate mono-2-ethylhexanoate glyceryl, isopropyl paramethoxycinnamate-diisopropylcinnamate mixture, 2-ethylhexyl paramethoxycinnamate, and benzyl cinnamate; benzoic acid ester ultraviolet absorbers such as paraaminobenzoic acid, ethyl paraaminobenzoate, glyceryl paraaminobenzoate, amyl paradimethylaminobenzoate, 2-ethylhexyl paradimethylaminobenzoate, and ethyl 4-[N,N-di(2-hydroxypropyl)amino]benzoate; ethylene glycol salicylate, octyl salicylate, and the like. salicylic acid UV absorbers such as salicylic acid, dipropylene glycol salicylate, phenyl salicylate, homomenthyl salicylate, and methyl salicylate, guaiazulene, dimethoxybenzylidene dioxoimidazolidinepropionate 2-ethylhexyl, 2,4,6-tris[4-(2-ethylhexyloxycarbonyl)anilino]1,3,5-triazine, parahydroxyanisole, 2-(2-hydroxy-5-methylphenyl)benzotriazole, 4-tert-butyl-4'-methoxydibenzoylmethane, phenylbenzimidazole sulfonic acid, 2-(4-diethylamino-2-hydroxybenzoyl)-hexyl benzoate, hindered amines, riboflavin, anthraquinone dyes (1-amino-4-methylanthraquinone, 1,4-diaminoanthraquinone, anthraquinone yellow, etc.), phthalocyanine dyes (phthalocyanine blue (CI Pigment Blue 15; CI 74160; Blue No. 404), Phthalocyanine Green (CI Pigment Green 7), etc.

[0034] Preferred examples of the ultraviolet blocking agent include zinc oxide, titanium oxide, 2-ethylhexyl paramethoxycinnamate, glyceryl di-paramethoxycinnamate mono-2-ethylhexanoate, 2,4,6-tris[4-(2-ethylhexyloxycarbonyl)anilino]1,3,5-triazine, phenylbenzimidazole sulfonic acid, hexyl 2-(4-diethylamino-2-hydroxybenzoyl)-benzoate, and 2-ethylhexyl dimethoxybenzylidene dioxoimidazolidinepropionate. Zinc oxide and titanium oxide may be further coated with silica, silicon, zinc silicate, or the like.

[0035] The container for storing the aqueous composition according to the present embodiment may be a transparent container that allows the inside of the container to be seen, or may be an opaque container that makes it difficult to see the inside of the container. Here, the term "transparent container" includes both colorless transparent containers and colored transparent containers.

[0036] The aqueous composition according to this embodiment preferably further contains (D) at least one selected from the group consisting of glycyrrhizinic acid and salts thereof.

[0037] (D) Component Glycyrrhizic acid is a known compound also known as 20β-carboxy-11-oxo-30-norolean-12-en-3β-yl-2-O-β-D-glucopyranuronosyl-α-D-glucopyranosiduronic acid, and can be synthesized by known methods or obtained as a commercially available product.

[0038] The salt of glycyrrhizinic acid is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical) or physiologically acceptable, but specifically, the same form as the salt that component (A) can take is exemplified. Among these salts, salts with inorganic bases are preferred, alkali metal salts and / or ammonium salts are more preferred, sodium salts, potassium salts and / or ammonium salts are even more preferred, and potassium salts are particularly preferred. These salts of glycyrrhizinic acid may be used alone or in any combination of two or more.

[0039] Among glycyrrhizinic acid and its salts, from the viewpoint of obtaining a greater stability improving effect, glycyrrhizinic acid, its alkali metal salts and / or its ammonium salts are preferred, disodium glycyrrhizinate, trisodium glycyrrhizinate, dipotassium glycyrrhizinate, tripotassium glycyrrhizinate and / or monoammonium glycyrrhizinate are more preferred, and dipotassium glycyrrhizinate is particularly preferred.

[0040] The concentration of the (D) component in the aqueous composition according to this embodiment is not particularly limited, and is appropriately set according to the type of the (D) component, the types and concentrations of the (A), (B) and (C) components used in combination, the purpose of the aqueous composition, the formulation form, the method of use, etc. The concentration of the (D) component is, for example, based on the total amount of the aqueous composition according to this embodiment, preferably 0.001 to 2 w / v%, more preferably 0.005 to 1 w / v%, even more preferably 0.01 to 0.5 w / v%, and particularly preferably 0.01 to 0.25 w / v%. The above concentration of the (D) component is suitable from the viewpoint of improving the stability of olopatadine.

[0041] In addition, the content ratio of the (D) component to the (A) component in the aqueous composition according to this embodiment is not particularly limited, and is appropriately set according to the types of the (A) component and the (D) component, the purpose of the aqueous composition, the formulation form, the method of use, etc. The content ratio of the (D) component to the (A) component is, for example, preferably 0.005 to 100 parts by mass, more preferably 0.01 to 50 parts by mass, further preferably 0.05 to 25 parts by mass, and particularly preferably 0.5 to 25 parts by mass, per 1 part by mass of the total content of the (A) component contained in the aqueous composition according to this embodiment. The content ratio of the (D) component to the (A) component is suitable from the viewpoint of further improving the stability of olopatadine in the aqueous composition.

[0042] The aqueous composition according to the present embodiment may further contain a buffering agent. This allows the pH of the aqueous composition to be adjusted. The buffering agent is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical) or physiologically acceptable. Examples of such buffering agents include borate buffering agents, phosphate buffering agents, carbonate buffering agents, citrate buffering agents, acetate buffering agents, Tris buffering agents, aspartic acid, aspartic acid salts, and epsilon-aminocaproic acid. These buffering agents may be used alone or in any combination of two or more. Examples of borate buffering agents include boric acid, or borates such as alkali metal borates and alkaline earth metal borates. Examples of phosphate buffering agents include phosphoric acid, or phosphates such as alkali metal phosphates and alkaline earth metal phosphates. Examples of carbonate buffering agents include carbonic acid, or carbonates such as alkali metal carbonates and alkaline earth metal carbonates. Examples of citrate buffering agents include citric acid, or alkali metal citrates and alkaline earth metal citrates. In addition, borate or phosphate hydrates may be used as borate buffers or phosphate buffers. More specific examples include borate buffers such as boric acid or its salts (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.); phosphate buffers such as phosphoric acid or its salts (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); carbonate buffers such as carbonic acid or its salts (sodium hydrogen carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate, magnesium carbonate, etc.); citrate buffers such as citric acid or its salts (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.); acetic acid buffers such as acetic acid or its salts (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.); aspartic acid or its salts (sodium aspartate, magnesium aspartate, potassium aspartate, etc.), etc. can be exemplified.Among these buffers, boric acid buffers (for example, a combination of boric acid and borax) and phosphate buffers (for example, a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate) are preferred, with boric acid buffers being more preferred.

[0043] When the aqueous composition according to the present embodiment contains a buffer, the concentration is appropriately set depending on the type of buffer, the type and concentration of other components, the purpose of the aqueous composition, the formulation form, the method of use, etc. The concentration of the buffer is, for example, preferably 0.01 to 15 w / v%, more preferably 0.05 to 10 w / v%, further preferably 0.1 to 7.5 w / v%, and particularly preferably 0.5 to 5 w / v%, based on the total amount of the aqueous composition of the present invention.

[0044] The aqueous composition according to this embodiment may further contain a thickening agent. This allows the viscosity of the aqueous composition according to this embodiment to be adjusted. Examples of the thickening agent include polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone (K25, K30, K90, etc.), carboxyvinyl polymer, cellulose derivatives [methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose (2208, 2906, 2910, etc.), carboxymethyl cellulose, carboxyethyl cellulose, nitrocellulose or salts thereof, etc.], polyethylene glycol (macrogol 300, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000, etc.), sodium chondroitin sulfate, sodium hyaluronate, gum arabic, tragacanth, dextran (40, 70, etc.), glucose, sorbitol, etc. are preferred. ), carboxyvinyl polymer, cellulose derivatives (methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (2208, 2906, 2910), carboxymethylcellulose or its salts, etc.), 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, hydroxyethylcellulose, hydroxypropylmethylcellulose (2208, 2906, 2910), carboxymethylcellulose or its salts, 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.

[0045] When the aqueous composition according to the present embodiment contains a thickener, the concentration thereof is appropriately set according to the type of thickener, the type and concentration of other components contained, the purpose of the aqueous composition, the formulation form, the method of use, etc. The concentration of the thickener is, for example, preferably 0.0001 to 5 w / v%, more preferably 0.0005 to 3 w / v%, further preferably 0.001 to 1 w / v%, and particularly preferably 0.01 to 0.2 w / v%, based on the total amount of the aqueous composition of the present invention.

[0046] In addition, the aqueous composition according to the present embodiment may further contain an isotonicity agent. The isotonicity agent is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical) or physiologically acceptable. Specific examples of such isotonicity agents include 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 hydrogen carbonate, sodium thiosulfate, magnesium sulfate, glycerin, propylene glycol, polyethylene glycol, glucose, mannitol, sorbitol, and the like. Among these isotonicity agents, glycerin, propylene glycol, glucose, sodium chloride, potassium chloride, calcium chloride, or magnesium chloride is preferred, sodium chloride or glycerin is more preferred, and sodium chloride is even more preferred. These isotonicity agents may be used alone or in any combination of two or more.

[0047] When the aqueous composition according to this embodiment contains an isotonicity agent, the concentration thereof is appropriately set depending on the type of isotonicity agent, the types and concentrations of other components contained, the purpose of the aqueous composition, the formulation form, the method of use, etc. The concentration of the isotonicity agent is, for example, preferably 0.01 to 10 w / v%, more preferably 0.05 to 5 w / v%, and even more preferably 0.1 to 3 w / v%, based on the total amount of the aqueous composition according to this embodiment.

[0048] The pH of the aqueous composition according to the present embodiment is not particularly limited as long as it is within a medicamentously, pharmacologically (pharmaceutical) or physiologically acceptable range. The pH of the aqueous composition is, for example, preferably 4.0 to 9.5, more preferably 5.0 to 9.0, and even more preferably 5.5 to 8.5.

[0049] In addition, the osmotic pressure of the aqueous composition according to the present embodiment is not particularly limited as long as it is within the range acceptable to the living body. The osmotic pressure ratio of the aqueous composition is, for example, preferably 0.5 to 5.0, more preferably 0.6 to 3.0, even more preferably 0.7 to 2.0, and particularly preferably 0.9 to 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, or a sugar. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (the osmotic pressure of a 0.9 w / v% sodium chloride aqueous solution) based on the 16th revised Japanese Pharmacopoeia, and the osmotic pressure is measured with reference to the osmotic pressure measurement method (freezing point depression method) described in the Japanese Pharmacopoeia. For the standard solution for measuring osmolality ratios (0.9 w / v% sodium chloride aqueous solution), sodium chloride (Japanese Pharmacopoeia standard reagent) is dried at 500-650°C for 40-50 minutes, then allowed to cool in a desiccator (silica gel), and 0.900 g of the solution is accurately weighed out and dissolved in purified water to make exactly 100 mL; alternatively, a commercially available standard solution for measuring osmolality ratios (0.9 w / v% sodium chloride aqueous solution) can be used.

[0050] The viscosity of the aqueous composition according to the present embodiment is not particularly limited as long as it is within a range that is acceptable to the living body. The viscosity at 25°C measured with a rotational viscometer (RE550 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1°34'xR24) is, for example, preferably 0.01 to 1000 mPa s, more preferably 0.05 to 100 mPa s, and even more preferably 0.1 to 10 mPa s.

[0051] In addition, the aqueous composition according to the present embodiment may contain various pharmacologically active ingredients and physiologically active ingredients in combination in appropriate amounts in addition to the above-mentioned ingredients, as long as the effects of the present invention are not hindered. Such ingredients are not particularly limited, and examples thereof include active ingredients in various medicines listed in the 2000 edition of the General Drug Manufacturing (Import) Approval Standards (supervised by the Pharmaceutical Affairs Research Association). Specifically, the following ingredients are used in ophthalmic drugs. Antihistamines or antiallergic agents: for example, ketotifen fumarate, iproheptin, diphenhydramine hydrochloride, chlorpheniramine maleate, pemirolast potassium, sodium cromoglycate, etc. Decongestants: tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, naphazoline hydrochloride, naphazoline nitrate, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, and the like. Ocular muscle regulating drugs: For example, cholinesterase inhibitors having an active center similar to that of acetylcholine, specifically, neostigmine methylsulfate, tropicamide, atropine helenien sulfate, etc. 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 (equal mixture), aminoethylsulfonic acid, etc. Anti-inflammatory agents: for example, allantoin, berberine chloride, berberine sulfate, zinc sulfate, zinc lactate, glycyrrhetinic acid, methyl salicylate, glycol salicylate, sodium azulene sulfonate, tranexamic acid, epsilon-aminocaproic acid, lysozyme, licorice, pranoprofen, etc. Others: For example, sodium hyaluronate, sulfamethoxazole, sulfamethoxazole sodium, indomethacin, ibuprofen, ibuprofen piconol, bufexamac, butyl flufenamate, bendazac, piroxicam, ketoprofen, felbinac, lilac root, horse chestnut, and salts thereof.

[0052] In addition, the aqueous composition according to the present embodiment may contain various additives selected appropriately according to the application and formulation form in a conventional manner, and may contain one or more additives in appropriate amounts in combination, as long as the effects of the invention are not impaired. Examples of such additives include those listed in the Pharmaceutical Additives Encyclopedia 2007 (edited by the Japan Pharmaceutical Additives Association). Representative components include the following additives. Carrier: For example, an aqueous carrier such as water or aqueous ethanol. Sugars: for example, glucose, cyclodextrin, etc. Sugar alcohols: for example, xylitol, sorbitol, mannitol, etc. These may be in any of the D-, L- and DL-forms. Preservatives, disinfectants, or antibacterial agents: for example, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide, etc.), Glokill (trade name, manufactured by Rhodia), etc. Stabilizers: trometamol, sodium formaldehyde sulfoxylate (Rongalit), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, glyceryl monostearate, etc. Fragrance: Menthone, geraniol, citronellol, carvone, anethole, eugenol, limonene, linalool, linalyl acetate, bergamot oil, spearmint oil, fennel oil, cinnamon oil, rose oil, camphor oil, etc.

[0053] The aqueous composition according to the present embodiment is prepared by adding the above-mentioned (A), (B) and (C) components, and if necessary, the (D) component and other components to a carrier to obtain a desired concentration. For example, in the case of an ophthalmic composition, the above-mentioned components are dissolved or suspended in purified water, adjusted to a predetermined pH and osmotic pressure, and sterilized by filtration sterilization or the like to prepare the composition. Regarding the dissolution of the above-mentioned (C) component and other highly hydrophobic components, they may be mixed with a component having a dissolution-assisting effect such as a surfactant (including the (B) component) and stirred in advance, and then further dissolved or suspended by adding purified water.

[0054] In this embodiment, the aqueous composition means a composition in which the concentration of water is 85 w / v% or more with respect to 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, even more preferably 94 w / v% or more, and particularly preferably 96 w / v% or more. As the water used in the aqueous composition according to this embodiment, any water that is medicamentally, pharmacologically (pharmaceutical) or physiologically acceptable may be used, and specific examples of such water include distilled water, ordinary water, purified water, sterile purified water, water for injection, distilled water for injection, etc. In addition, the dosage form of the aqueous composition in this embodiment is not particularly limited, but includes liquid agents, semi-solid agents (ointments, etc.), etc., and is preferably liquid. These definitions are based on the 16th revised Japanese Pharmacopoeia.

[0055] Furthermore, the aqueous composition according to this embodiment can exert a pharmacological action based on the component (A), and when the aqueous composition also contains the component (D), can also exert the pharmacological action of the component (D), and is therefore effective for applications such as anti-inflammatory and anti-allergic effects, and can be used in particular as formulations of medicines, quasi-drugs, and the like for the symptomatic treatment of inflammatory diseases of the external and anterior eye (blepharitis, conjunctivitis, keratitis, scleritis, episcleritis, anterior uveitis, postoperative inflammation), and for the treatment of allergic conjunctivitis and vernal conjunctivitis.

[0056] The aqueous composition according to the present embodiment can be used as a formulation for pharmaceuticals and quasi-drugs, and can be used for various purposes, such as compositions for application to mucous membranes (ophthalmic compositions, nasal compositions, etc.), oral compositions, ear drop compositions, compositions for subcutaneous administration, and compositions for topical application to the skin.

[0057] The aqueous composition according to this embodiment is useful as a composition for application to mucous membranes, such as ocular mucosa including the cornea and conjunctiva, oral mucosa, nasal mucosa, and pharyngeal mucosa.

[0058] Specific examples of the composition for application to mucosa according to the present embodiment include ophthalmic compositions such as eye drops (also called eye drops or eye drops. Eye drops include eye drops that can be applied while wearing contact lenses), artificial tears, eyewash (also called eyewash or eyewash. Eyewash includes eyewash that can be applied while wearing contact lenses), and eye ointments; contact lens compositions [contact lens wetting solution, contact lens care compositions (contact lens disinfectants, contact lens preservatives, contact lens cleaners, contact lens cleaning preservatives), etc.]; nasal compositions such as nasal drops and nasal washes; oral compositions such as oropharyngeal medicines and mouthwashes (gargles); and ear drops. In view of the pharmacological actions of the components (A) and (D), the aqueous composition according to the present embodiment is preferably an ophthalmic composition, and more preferably an eye drop.

[0059] The contact lens composition can be applied to any contact lens, including hard contact lenses and soft contact lenses. Soft contact lenses include both ionic and non-ionic contact lenses, and also include silicone hydrogel contact lenses (hereinafter sometimes abbreviated as SHCL) and non-silicone hydrogel contact lenses (soft contact lenses that are not silicone hydrogel lenses).

[0060] From another viewpoint, the present embodiment provides a method for stabilizing component (A) in an aqueous composition containing components (A) and (B) contained in a container selected from the group consisting of polyethylene terephthalate, polyethylene naphthalate, polypropylene, polyarylate, polybutylene terephthalate, polycarbonate, and glass, by mixing components (A), (B), and (C) to obtain an aqueous composition containing components (A), (B), and (C). Components (A), (B), and (C) may be mixed in any order, and as long as the finally obtained aqueous composition contains components (A), (B), and (C), component (A) is stabilized. In the above method, component (D) is preferably also mixed to obtain an aqueous composition containing components (A), (B), (C), and (D). The components (A), (B), (C), and (D) may be mixed in any order, and as long as the final aqueous composition contains the components (A), (B), (C), and (D), the component (A) will be stabilized. From another viewpoint, the present embodiment provides a method for producing an aqueous composition in which component (A) is stabilized, by containing component (A), component (B), and component (C) in the aqueous composition and storing the aqueous composition in a container selected from the group consisting of polyethylene terephthalate, polyethylene naphthalate, polypropylene, polyarylate, polybutylene terephthalate, polycarbonate, and glass. EXAMPLES

[0061] The present invention will be described in detail below with reference to examples and test examples, but the present invention is not limited to these examples, etc. When tests were performed using plastic containers, the weight of the sample was measured before and after storage to determine the evaporation rate, and the concentration change due to evaporation was corrected.

[0062] [Test Example 1: Stability Test (1)] Aqueous compositions were prepared according to Table 1 below, and the stability of olopatadine or a salt thereof was evaluated.

[0063] First, each aqueous composition shown in Table 1 was prepared by a conventional method. Next, 5 mL of the prepared aqueous composition was filled 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), and the aqueous composition was sealed and stored in a thermostatic chamber at 50° C. under light shielding. After 14 days from 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 rate of olopatadine hydrochloride was calculated according to the following formula (I). Formula (I) Residual rate (%) = (Olopatadine hydrochloride content after storage) / (Olopatadine hydrochloride content before storage) × 100

[0064] [Table 1]

[0065] As shown in Table 1, when an aqueous composition containing olopatadine hydrochloride was stored in a polyethylene terephthalate container, if the aqueous composition contained polysorbate 80, which is a nonionic surfactant, the residual rate of olopatadine hydrochloride decreased, and the stability of olopatadine hydrochloride decreased (Reference Example 1-1 and Comparative Example 1-1). However, if the aqueous composition further contained l-menthol, which is a terpenoid, the residual rate of olopatadine hydrochloride increased, and the stability of olopatadine hydrochloride improved (Example 1-1). A similar phenomenon was also observed when an aqueous composition containing olopatadine hydrochloride was stored in a polypropylene container (Reference Example 1-2, Comparative Example 1-2, and Example 1-2).

[0066] On the other hand, when an aqueous composition containing olopatadine hydrochloride was stored in a polyethylene container, the residual rate of olopatadine hydrochloride was hardly decreased and the stability of olopatadine hydrochloride was hardly decreased (Reference Examples 1-3 to 1-5) even when the aqueous composition contained polysorbate 80. A similar phenomenon was also observed when an aqueous composition containing olopatadine hydrochloride was stored in a polystyrene container.

[0067] [Test Example 2: Stability Test (2)] An aqueous composition was prepared according to Table 2 below, and the stability of olopatadine or a salt thereof was evaluated. The remaining rate of olopatadine hydrochloride was determined in the same manner as in Test Example 1 above, except that the aqueous composition was filled in a glass headspace vial (volume 10 mL).

[0068] [Table 2]

[0069] As shown in Table 2, when an aqueous composition containing olopatadine hydrochloride was stored in a glass container, it was found that if the aqueous composition contained polysorbate 80, the residual rate of olopatadine hydrochloride decreased and the stability of olopatadine hydrochloride decreased (Reference Example 2 and Comparative Example 2). In addition, if the aqueous composition further contained 1-menthol, the residual rate of olopatadine hydrochloride increased and the stability of olopatadine hydrochloride improved (Example 2).

[0070] [Test Example 3: Stability Test (3)] Aqueous compositions were prepared according to Table 3 below, and the stability of olopatadine or a salt thereof was evaluated. The remaining rate of olopatadine hydrochloride was determined in the same manner as in Test Example 1 above, except that the storage temperature was changed from 50°C to 70°C, and the aqueous composition was filled in a glass headspace vial (volume 10 mL). Storage at 70°C for 14 days corresponds to storage at room temperature for about 3 years.

[0071] [Table 3]

[0072] As shown in Table 3, even when an aqueous composition containing olopatadine hydrochloride was stored at 70°C, if the aqueous composition contained polysorbate 80, the residual rate of olopatadine hydrochloride decreased, and the stability of olopatadine hydrochloride decreased (Reference Example 3 and Comparative Example 3-1). In addition, if the aqueous composition further contained l-menthol, the residual rate of olopatadine hydrochloride increased, and the stability of olopatadine hydrochloride improved (Example 3-1-1). If the aqueous composition contained dipotassium glycyrrhizinate in addition to l-menthol, the stability was further improved compared to when the aqueous composition contained l-menthol (Example 3-1-2). Similarly, when polyoxyl 40 stearate was contained as a nonionic surfactant, the residual rate of olopatadine hydrochloride was decreased, and when 1-menthol was further contained, the residual rate of olopatadine hydrochloride was increased, and the stability was improved (Comparative Example 3-2, Example 3-2).

[0073] [Test Example 4: Stability Test (4)] Aqueous compositions were prepared according to Table 4 below, and the stability of olopatadine or a salt thereof was evaluated. The remaining rate of olopatadine hydrochloride was determined in the same manner as in 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 in a glass headspace vial (volume 10 mL).

[0074] [Table 4]

[0075] When the aqueous composition containing olopatadine hydrochloride contains d-borneol or cineol, which are terpenoids, the stability of olopatadine hydrochloride, which was reduced by the inclusion of a nonionic surfactant, was improved, as in the case of the aqueous composition containing l-menthol (Comparative Example 4, Example 4-1, 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 was further improved (Example 4-1, Example 4-2).

[0076] [Test Example 5 Stability Test (5)] Aqueous compositions were prepared according to the following Table 5, and the stability of olopatadine or a salt thereof was evaluated. The remaining rate of olopatadine hydrochloride was determined in the same manner as in Test Example 1 above, except that the storage temperature was changed from 50°C to 70°C, and the aqueous composition was filled in a polyethylene terephthalate container (volume 15 mL).

[0077] [Table 5]

[0078] As shown in Table 5, even when the aqueous composition containing olopatadine hydrochloride contained polyoxyethylene hydrogenated castor oil 60 or polyoxyethylene castor oil 35 as a nonionic surfactant, the stability of olopatadine hydrochloride, which was reduced by the inclusion of a nonionic surfactant, was improved when it contained a terpenoid, as in Test Examples 1 to 4.

[0079] [Test Example 6 Stability Test (6)] An aqueous composition was prepared according to the following Table 6, and the stability of olopatadine or a salt thereof was evaluated. The remaining rate of olopatadine hydrochloride was determined in the same manner as in Test Example 1 above, except that the aqueous composition was filled in a glass headspace vial (volume 10 mL).

[0080] [Table 6]

[0081] As shown in Table 6, when the aqueous composition containing olopatadine hydrochloride contained the terpenoids d-borneol or cineol, the stability of olopatadine hydrochloride, which was reduced due to the inclusion of a nonionic surfactant, was improved, as in the case of the aqueous composition containing l-menthol (Comparative Example 6-1, Example 6-1, Example 6-2).

[0082] [Test Example 7 Stability Test (7)] Aqueous compositions were prepared according to Table 7 below, and the stability of olopatadine or a salt thereof was evaluated. The remaining rate of olopatadine hydrochloride was determined in the same manner as in Test Example 1 above, except that the storage temperature was changed to 60°C, the storage period was changed from 14 days to 30 days, and the aqueous composition was filled in a glass headspace vial (volume 10 mL).

[0083] [Table 7]

[0084] As shown in Table 7, when the aqueous composition containing olopatadine hydrochloride contained the terpenoids d-borneol or cineol, the stability of olopatadine hydrochloride, which was reduced due to the inclusion of a nonionic surfactant, was improved, as in the case of the aqueous composition containing l-menthol (Comparative Example 7-1, Example 7-1, Example 7-2).

[0085] [Test Example 8 Stability Test (8)] Tests similar to those in Test Examples 1 to 7 above were carried out, and it was confirmed that even in an aqueous composition containing 0.05 w / v% polysorbate 80, the stability of olopatadine hydrochloride was reduced, and that the stability was improved when a terpenoid was further contained.

[0086] [Formulation example] Aqueous compositions were prepared according to Formulation Examples 1 to 13 in Tables 8 and 9 below, and filled in polyethylene terephthalate containers (eye drops or eye washes) were Preparation Examples 1 to 13, and filled in polypropylene containers (eye drops or eye washes) were Preparation Examples 14 to 26. Table 8-1 is a continuation of Table 8-2, and Table 9-1 is a continuation of Table 9-2.

[0087] [Table 8-1]

[0088] [Table 8-2]

[0089] [Table 9-1]

[0090] [Table 9-2]

Claims

[Claim 1] The container is contained in a container selected from the group consisting of polyethylene terephthalate, polyethylene naphthalate, polypropylene, polyarylate, polybutylene terephthalate, polycarbonate, and glass; (A) at least one selected from the group consisting of olopatadine and its salts; (B) a nonionic surfactant; and (C) at least one terpenoid selected from the group consisting of menthol, camphor, borneol, and cineol; 1. An aqueous composition comprising:

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