JP2014122209A - Olopatadine-containing aqueous composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an olopatadine-containing aqueous composition that achieves the light stabilization of olopatadine.SOLUTION: An aqueous composition contains (A) at least one selected from the group consisting of olopatadine and the salt thereof, and (B) at least one selected from the group consisting of bromfenac and the salt thereof, berberine and the salt thereof, allantoins, and zinc and zinc compounds.

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 Special table 2011-105694 gazette Special table 2011-20960 gazette

  As a result of various studies on the olopatadine-containing aqueous composition, the present inventors have found that olopatadine in the aqueous composition is unstable to light irradiation.

  An object of the present invention is to provide an olopatadine-containing aqueous composition in which light stabilization of olopatadine is achieved. Another object of the present invention is to provide a method for photostabilizing olopatadine in an aqueous composition.

  As a result of intensive studies, the present inventors have found that an aqueous composition containing (A) at least one selected from the group consisting of olopatadine and a salt thereof (hereinafter sometimes referred to as “component (A)”). (B) at least one selected from the group consisting of bromfenac and salts thereof, berberine and salts thereof, allantoins, and zinc and zinc compounds (hereinafter sometimes referred to as “component (B)”). It has been found that the photo-stability is improved by suppressing the photodecomposition of the component (A) in the aqueous composition.

That is, the present invention provides the following [1] to [6].
[1] selected from the group consisting of (A) at least one selected from the group consisting of olopatadine and a salt thereof, and (B) bromfenac and a salt thereof, berberine and a salt thereof, allantoins, and zinc and a zinc compound. An aqueous composition containing at least one of the following.
[2] The aqueous composition according to [1], wherein the component (A) is olopatadine hydrochloride.
[3] The aqueous composition according to [1] or [2], which is a composition applied to mucosa.
[4] The aqueous composition according to [3], wherein the mucosa-applied composition is an ophthalmic composition.
[5] The aqueous composition according to any one of [1] to [4], which is contained in a polyethylene terephthalate container.
[6] (A) selected from the group consisting of at least one selected from the group consisting of olopatadine and salts thereof, and (B) bromfenac and salts thereof, berberine and salts thereof, allantoins, and zinc and zinc compounds. And a method for photostabilizing olopatadine in an aqueous composition.

  In the olopatadine-containing aqueous composition of the present invention, since olopatadine is light-stabilized, the photodegradation of olopatadine is suppressed, and the excellent efficacy of olopatadine can be exhibited over a long period of time.

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

  In the present 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 the present embodiment contains at least one (component (A)) selected from the group consisting of olopatadine and a salt thereof. By containing this together with at least one selected from the group consisting of (B) bromfenac and salts thereof, berberine and salts thereof, allantoins, and zinc and zinc compounds described later (component (B)), an aqueous composition The light stabilization of olopatadine in a product can be achieved.

  Olopatadine is a known compound having a chemical name of (Z) -11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo [b, e] -oxepin-2-acetic acid and synthesized by a known method. Alternatively, it can 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 light 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 this embodiment, the content of the component (A) is not particularly limited, and the type of the component (A), the type and content of the component (B) to be used in combination, the use of the aqueous composition, and the preparation It is appropriately set according to the form, usage method, and the like. As content of (A) component, it is preferable that the total content of (A) component is 0.002-1 w / v% on the basis of the total amount of the aqueous composition which concerns on this embodiment, for example, It is more preferably 0.005 to 0.5 w / v%, still more preferably 0.01 to 0.2 w / v%, and particularly preferably 0.01 to 0.22 w / v%. 0.02 to 0.11 w / v% is even more preferable.
Content of the said (A) component is suitable from a viewpoint of the effect of improving the light stability of the olopatadine in an aqueous composition.

  The aqueous composition according to this embodiment contains (B) bromfenac and a salt thereof, berberine and a salt thereof, allantoin, and at least one selected from the group consisting of zinc and a zinc compound. By containing the component (B), the light stability of olopatadine in the aqueous composition can be improved.

  Bromfenac is a known compound also referred to as 2-amino-3- (4-bromobenzoyl) phenylacetic acid, and may be synthesized by a known method or obtained as a commercial product.

  The salt of bromfenac is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such salts include organic acid salts [for example, monocarboxylate (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polyvalent carboxylate (fumarate, maleate). Acid salt, succinate, malonate, etc.), oxycarboxylate (lactate, tartrate, citrate, etc.), organic sulfonate (methanesulfonate, toluenesulfonate, tosylate, etc.) Etc.], inorganic acid salts (eg, hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc.), salts with organic bases (eg, methylamine, triethylamine, triethanolamine, morpholine, piperazine, Salts with organic amines such as pyrrolidine, tripyridine, picoline, etc.), salts with inorganic bases [eg ammonium salts; alkali metals (sodium, potassium, etc.), alkaline earth metals ( Calcium, magnesium, etc.), include various salts of salt, etc.] or the like with a metal such as aluminum.

  These bromfenac and its salt may be used individually by 1 type, and may be used in combination of 2 or more types arbitrarily. Bromfenac or a salt thereof includes a solvate (eg, hydrate) form. Examples of the solvate include, but are not limited to, 1/2 hydrate, monohydrate, 3/2 hydrate, and the like. As bromfenac and / or a salt thereof, bromfenac, a salt thereof with an inorganic base, or a solvate thereof is preferable from the viewpoint of achieving light stabilization of olopatadine in an aqueous composition, bromfenac or an alkali metal salt thereof, or Those solvates are more preferred, bromfenac sodium or its hydrate is more preferred, and bromfenac sodium 3/2 hydrate is particularly preferred.

  Berberine is a known compound having a benzylisoquinoline skeleton, and may be synthesized by a known method or obtained as a commercial product.

  The berberine salt is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such salts include berberine chloride, berberine sulfate, and berberine tannate.

  These berberine and its salt may be used individually by 1 type, and may be used in combination of 2 or more types arbitrarily. Berberine or a salt thereof includes a solvate (eg, hydrate) form. From the viewpoint of further improving the photostability of olopatadine in the aqueous composition, berberine and / or a salt thereof is preferably berberine sulfate or berberine chloride, more preferably berberine sulfate.

  Allantoin is a known compound also called 5-ureidohydantoin. Examples of allantoins include allantoin or a salt thereof, or an allantoin derivative or a salt thereof.

  Allantoins are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of allantoins include allantoin, allantoindihydroxyaluminum, allantoinchlorohydroxyaluminum, allantoinglycylretin, allantoinacetyl-DL-methionine, allantoin-DL-pantothenyl alcohol, and allantoin polygalacturonic acid.

  These allantoins may be used alone or in any combination of two or more. From the viewpoint of further improving the light stability of olopatadine in the aqueous composition, allantoins are preferably allantoin, allantoindihydroxyaluminum, or allantoinchlorohydroxyaluminum, and more preferably allantoin.

  Zinc or zinc compound is a simple substance or compound containing at least one zinc atom, and can be used in any form such as zinc, inorganic zinc salt, organic zinc salt, and hydrates thereof. .

  Zinc or zinc compounds include zinc, zinc chloride, zinc sulfate, zinc lactate, zinc nitrate, zinc gluconate, zinc citrate, zinc 2-oxoglutarate, zinc oxide, zinc phosphate, zinc aluminate, zinc fluoride, Zinc iodide, zinc hydroxide, zinc carbonate, zinc chromate, zinc benzoate, zinc acetate, zinc paraaminobenzoate, zinc paradimethylaminobenzoate, zinc paraphenolsulfonate, zinc paramethoxycinnamate, 2-mercaptopyridine N-oxide zinc, zinc picrate, zinc aspartate, zinc naphthenate, zinc salicylate, zinc phenolsulfonate, zinc sebacate, sodium tripolyphosphate, zinc stearate, zinc caprate, zinc laurate, zinc myristate, Zinc palmitate, zinc oleate, zinc polyphosphonate, Examples include zinc lecithin sulfate, zinc undecylenate, zinc ascorbate, zinc pyrithione, zinc hinokitiol, zinc dipicolinate, zinc glycerolate complex, bishistidine zinc complex, zinc-3,4-dihydroxybenzoic acid complex, and hydrates thereof. It is done.

  These zinc and zinc compounds may be used alone or in any combination of two or more. Zinc or zinc compounds also include their solvate (eg, hydrate) forms. Examples of the solvate include, but are not limited to, heptahydrate and the like. From the viewpoint of further improving the photostability of olopatadine in an aqueous composition, zinc and / or zinc compounds include zinc chloride, zinc sulfate, zinc lactate, zinc gluconate, zinc citrate, or hydrates thereof. Zinc chloride, zinc sulfate, zinc lactate or their hydrates are more preferred, zinc sulfate, zinc lactate or their hydrates are still more preferred, and zinc sulfate heptahydrate is particularly preferred.

  In the aqueous composition according to this embodiment, the content of the component (B) is not particularly limited, and the type of the component (B), the type and content of the component (A) to be used together, the use of the aqueous composition, and the preparation It is appropriately set according to the form, usage method, and the like. As content of (B) component, it is preferable that the total content of (B) component is 0.0001-5 w / v% on the basis of the total amount of the aqueous composition which concerns on this embodiment, for example, It is more preferably 0.0002 to 3 w / v%, still more preferably 0.0005 to 1 w / v%, and particularly preferably 0.001 to 0.5 w / v%.

  As content of bromfenac and / or its salt, for example, the total content of bromfenac and / or its salt is 0.0005 to 1 w / v% on the basis of the total amount of the aqueous composition according to this embodiment. It is preferably 0.001 to 0.5 w / v%, more preferably 0.005 to 0.2 w / v%.

  As content of berberine and / or its salt, for example, the total content of berberine and / or its salt is 0.0001 to 0.1 w / v% based on the total amount of the aqueous composition according to the present embodiment. It is preferable that it is 0.0005-0.05 w / v%, and it is still more preferable that it is 0.001-0.025 w / v%.

  As content of allantoin, it is preferable that the total content of allantoin is 0.001-1 w / v% on the basis of the total amount of the aqueous composition which concerns on this embodiment, for example, 0.005- More preferably, it is 0.5 w / v%, and still more preferably 0.01-0.3 w / v%.

  As content of zinc and / or a zinc compound, the total content of zinc and / or a zinc compound is 0.0001-1 w / v% on the basis of the total amount of the aqueous composition which concerns on this embodiment, for example. It is preferably 0.001 to 0.5 w / v%, and more preferably 0.01 to 0.25 w / v%.

  The content of the component (B) is preferable from the viewpoint of further improving the photostability of olopatadine in the aqueous composition.

Further, the content ratio of the component (B) to the component (A) in the aqueous composition according to this embodiment is not particularly limited, and the types of the component (A) and the component (B), the use of the aqueous composition, and the preparation It is appropriately set according to the form, usage method, and the like. 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 0.0005 to 2000 parts by mass, more preferably 0.002 to 500 parts by mass, still more preferably 0.005 to 100 parts by mass, and 0.01 to 50 parts by mass. Part is particularly preferred.
The content ratio of the component (B) relative to the component (A) is preferable from the viewpoint of further improving the light stability of olopatadine in the aqueous composition.

  As a content ratio with respect to (A) component of bromfenac and / or its salt, for example with respect to 1 mass part of total content of (A) component contained in the aqueous composition which concerns on this embodiment, bromfenac and / or its The total salt content is preferably 0.0005 to 500 parts by mass, more preferably 0.002 to 100 parts by mass, still more preferably 0.01 to 20 parts by mass, and It is especially preferable that it is 05-10 mass parts.

  As a content ratio with respect to (A) component of berberine and / or its salt, for example with respect to 1 mass part of total content of (A) component contained in the aqueous composition which concerns on this embodiment, berberine and / or its The total salt content is preferably 0.0001 to 50 parts by mass, more preferably 0.0005 to 10 parts by mass, still more preferably 0.002 to 5 parts by mass, and It is especially preferable that it is 01-1 mass part.

  As a content ratio with respect to (A) component of allantoin, the total content of allantoin is 0 with respect to 1 mass part of total content of (A) component contained in the aqueous composition which concerns on this embodiment, for example. 0.001 to 500 parts by mass, more preferably 0.005 to 100 parts by mass, still more preferably 0.02 to 50 parts by mass, and 0.1 to 15 parts by mass. Is particularly preferred.

  The content ratio of zinc and / or zinc compound to component (A) is, for example, zinc and / or zinc with respect to 1 part by mass of the total content of component (A) contained in the aqueous composition according to this embodiment. The total content of the compound is preferably 0.0001 to 500 parts by mass, more preferably 0.0005 to 100 parts by mass, still more preferably 0.002 to 50 parts by mass, and It is particularly preferably 1 to 10 parts by mass.

  The content ratio of the component (B) to the component (A) is preferable from the viewpoint of further improving the photostability 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. Examples of the tris buffer include trishydroxymethylaminomethane (trometamol). 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 buffers, borate buffer, phosphate buffer, and Tris buffer are preferable, borate buffer (for example, a combination of boric acid and borax, etc.), phosphate buffer (for example, hydrogen phosphate) Particularly preferred is a combination of disodium and sodium dihydrogen phosphate.

  When a buffering agent is blended in the aqueous composition according to the present embodiment, the content includes the type of the buffering agent, the type and content of other blending components, the use of the aqueous composition, the formulation form, the method of use, etc. It is set appropriately according to As the content of the buffering agent, for example, the total content of the buffering agent 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% is more preferable, 0.1 to 7.5 w / v% is still more preferable, and 0.5 to 5 w / v% is particularly preferable.

  The aqueous composition according to the present embodiment can further contain a terpenoid. The terpenoid used in the aqueous composition according to this embodiment is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. As the terpenoid used in the aqueous composition according to the present embodiment, for example, menthol, menthone, camphor, borneol, geraniol, cineol, citronellol, carvone, anethole, eugenol, limonene, linalool, linalyl acetate, and derivatives thereof Can do. These compounds may be any of d-form, l-form and dl-form. In the aqueous composition according to this embodiment, an essential oil containing the above compound may be used as the terpenoid. Examples of such essential oils include eucalyptus oil, bergamot oil, peppermint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, rose oil, camphor oil and the like.

  These terpenoids may be used alone or in any combination of two or more. From the viewpoint of improving the photostability of olopatadine, the terpenoid is preferably menthol, menthone, camphor, borneol or geraniol, more preferably menthol or camphor, and even more preferably menthol such as l-menthol or dl-menthol.

  The content of the terpenoid in the aqueous composition according to the present embodiment is not particularly limited, and the (A) component to be used in combination, the type and content of the component (B), the use of the aqueous composition, the formulation form, the method of use, etc. It is set appropriately according to As the terpenoid content, for example, based on the total amount of the aqueous composition according to this embodiment, the total terpenoid content is preferably 0.0001 to 0.2 w / v%, and is preferably 0.0005 to 0. 0.1 w / v% is more preferable, and 0.001 to 0.08 w / v% is further more preferable. In addition, when using the essential oil containing a terpenoid, it can set so that the terpenoid in the essential oil contained in an aqueous composition may satisfy | fill the said content. The terpenoid content is suitable from the viewpoint of improving the photostability of olopatadine.

  The aqueous composition according to this embodiment can further contain a surfactant. The surfactant is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable, and is non-ionic surfactant, amphoteric surfactant, anionic surfactant. Either an agent or a cationic surfactant may be used.

  Specific examples of the nonionic surfactant include monolauric acid POE (20) sorbitan (polysorbate 20), monopalmitic acid POE (20) sorbitan (polysorbate 40), and monostearic acid POE (20) sorbitan (polysorbate 60). ), POE sorbitan fatty acid esters such as tristearic acid POE (20) sorbitan (polysorbate 65), monooleic acid POE (20) sorbitan (polysorbate 80); POE (40) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 40) POE hydrogenated castor oil such as POE (60) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 60); POE castor oil such as POE castor oil 10 and POE castor oil 35; POE alkyl ethers such as POE (9) lauryl ether ; POE 20) POE-POP alkyl ethers such as POP (4) cetyl ether; polyoxyethylene polyoxy such as POE (196) POP (67) glycol (poloxamer 407, Pluronic F127), POE (200) POP (70) glycol, etc. Examples include propylene block copolymers; polyethylene glycol monostearate such as polyoxyl 40 stearate. In the compounds exemplified above, the numbers in parentheses indicate the number of added moles.

Specific examples of amphoteric surfactants include alkyldiaminoethylglycine or a salt thereof (for example, hydrochloride).
Specific examples of the cationic surfactant include benzalkonium chloride and benzethonium chloride.
Furthermore, specific examples of the anionic surfactant include alkylbenzene sulfonate, alkyl sulfate, polyoxyethylene alkyl sulfate, α-sulfo fatty acid ester salt, α-olefin sulfonic acid and the like.

  These surfactants may be used individually by 1 type, and may be used in combination of 2 or more type. The surfactant is preferably a nonionic surfactant, more preferably POE sorbitan fatty acid ester, POE hydrogenated castor oil, POE castor oil, or POE / POP block copolymer, polyethylene glycol monostearate, polysorbate 80, polyoxy More preferred are ethylene hydrogenated castor oil 60, polyoxyethylene castor oil 10, polyoxyethylene castor oil 35, or poloxamer 407 and polyoxyl 40 stearate.

  When a surfactant is blended in the aqueous composition according to the present embodiment, the content of the surfactant is the kind of the surfactant, the kind and content of other blending components, the use of the aqueous composition, the formulation form, and the use It is set appropriately according to the method and the like. As the content of the surfactant, for example, the total content of the surfactant other than the component (A) is 0.001 to 3 w / v% on the basis of the total amount of the aqueous composition according to this embodiment. It is preferably 0.005 to 2 w / v%, more preferably 0.01 to 1 w / v%, and particularly preferably 0.05 to 1 w / v%.

  The aqueous composition which concerns on this embodiment can contain a thickener further. Thereby, the viscosity of the aqueous composition which concerns on this embodiment can be adjusted. As the thickener, for example, polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone (K25, K30, K90 etc.), carboxyvinyl polymer, polyoxyethylene-polyoxypropylene block copolymer (BASF Wyandotte Corporation, Pluronic, Tronic, etc.), cellulose derivatives [methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (2208, 2906, 2910, etc.), carboxymethylcellulose, carboxyethylcellulose, nitrocellulose or their salts], polyethylene glycol (macrogol) 300, macro goal 400, macro goal 1500, macro goal 40 00, macrogol 6000, etc.), chondroitin sodium sulfate, gum arabic, tragacanth, dextran (40, 70, etc.), alginic acid, sodium alginate, glucose, sorbitol, etc., 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), Chondroy And more preferably polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone (K25, K30, K90), carboxyvinyl polymer, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose (2208, 2906, 2910), carboxy Methyl cellulose or a salt thereof, polyethylene glycol (macrogol 300, macrogol 400, macrogol 4000, macrogol 6000), dextran (70), and sodium chondroitin sulfate. These thickening agents may be used alone or in any combination of two or more.

  When a thickening agent is blended in the aqueous composition according to the present embodiment, the content thereof includes the type of the thickening agent, the type and content of other blending components, the use of the aqueous composition, the formulation form, and the use It is set appropriately according to the method and the like. As the content of the thickener, for example, the total content of the thickener is preferably 0.01 to 10 w / v% based on the total amount of the aqueous composition according to the present embodiment. More preferably, it is 0.05-5 w / v%, and still more preferably 0.1-3 w / v%.

  Moreover, the aqueous composition according to the present embodiment may further contain an isotonic agent. 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 an isotonic agent is blended in the aqueous composition according to the present embodiment, the content is the type of the tonicity agent, the type and content of other compounding ingredients, the use of the aqueous composition, the formulation form It is set as appropriate according to the method of use. As the content of the tonicity agent, for example, based on the total amount of the aqueous composition according to the present embodiment, the total content of the tonicity agent is preferably 0.01 to 10 w / v%. 0.05 to 5 w / v% is more preferable, and 0.1 to 3 w / v% is still more preferable.

  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 medicines described in the Occupational Drug Manufacturing and Marketing Approval Standards 2012 edition (supervised by the Japanese Society for Regulatory Science). Specifically, the following components are listed as components used in ophthalmic drugs.
Antihistamine or antiallergic agent: for example, ketotifen, iproheptin, diphenhydramine, chlorpheniramine maleate, pemirolast potassium, sodium cromoglycate and the like.
Decongestant: For example, tetrahydrozoline, naphazoline, epinephrine, ephedrine, methylephedrine 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, benzethonium, chlorhexidine, polyhexamethylene biguanide and the like.
Vitamins: For example, flavin adenine dinucleotide sodium, cyanocobalamin, retinol acetate, retinol palmitate, pyridoxine hydrochloride, panthenol, calcium pantothenate, tocopherol acetate and the like.
Amino acids: For example, potassium aspartate, magnesium aspartate, magnesium and potassium aspartate (a mixture of equal amounts), aminoethylsulfonic acid and the like.
Anti-inflammatory agents: for example, glycyrrhetinic acid, glycyrrhizic acid, methyl salicylate, glycol salicylate, azulene sulfonic acid, tranexamic acid, epsilon-aminocaproic acid, lysozyme, licorice, pranoprofen and the like.
Other: For example, sodium hyaluronate, sulfamethoxazole, indomethacin, ibuprofen, ibuprofen piconol, bufexamac, butyl flufenamate, bendazac, piroxicam, ketoprofen, felbinac, purple root, tochinoki, and salts thereof.

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.
Stabilizer: For example, trometamol, sodium formaldehyde sulfoxylate (Longalite), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, glyceryl monostearate, dibutylhydroxytoluene and the like.
Chelating agents: for example, ethylenediaminediacetic acid (EDDA), ethylenediaminetriacetic acid, ethylenediaminetetraacetic acid (edetic acid, EDTA), N- (2-hydroxyethyl) ethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), and the like.

  The aqueous composition according to this embodiment is prepared by adding the component (A), the component (B), and, if necessary, other compounding components to the carrier so as to have a desired concentration. For example, in the case of an ophthalmic composition, it can be prepared by dissolving or suspending the 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 (A), component (B) and other highly hydrophobic components, stir in advance with a component having a solubilizing action such as a surfactant, and then dissolve by adding purified water. Alternatively, it may be suspended.

  From another point of view, this embodiment includes (A) an aqueous composition containing at least one selected from the group consisting of olopatadine and salts thereof, (B) bromfenac and salts thereof, berberine and salts thereof, allantoins, In addition, the present invention provides a method for photostabilizing olopatadine in an aqueous composition by blending at least one selected from the group consisting of zinc and zinc compounds.

  In this embodiment, the aqueous composition means a composition having a water content of 85 w / v% or more based on the total amount of the aqueous composition. The water content 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%. The above is particularly preferable. 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 revised Japanese Pharmacopoeia.

  Further, the aqueous composition according to the present embodiment expresses not only pharmacological action based on olopatadine or a salt thereof, but also pharmacological action based on bromfenac or a salt thereof, berberine or a salt thereof, allantoins, or zinc or a zinc compound. Therefore, it is effective for anti-inflammatory and anti-allergic applications, especially inflammatory diseases of the external and anterior eyes (blinditis, conjunctivitis, keratitis, scleritis, superior scleritis, anterior eye) It can be used as a pharmaceutical or quasi-drug formulation in applications such as symptomatic treatment of uveitis, 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 aqueous composition according to the present embodiment includes eye drops (also referred to as eye drops or eye drops. The eye drops include eye drops that can be applied while wearing contact lenses), artificial tears, Ophthalmic compositions such as eyewashes (also called eyewashes or eyewashes. Eyewashes include eyewashes that can be washed while wearing contact lenses), eye ointments, etc .; contact lens compositions [contact lens wearing Solutions, contact lens care compositions (contact lens disinfectants, contact lens preservatives, contact lens cleaners, contact lens cleaners, etc.)]; nasal compositions such as nasal drops and nasal rinses; oral cavity It can be used as a composition for oral cavity such as a pharyngeal drug and a mouthwash (an gargle); In view of the pharmacological action of the components (A) and (B), the aqueous composition according to this embodiment is preferably a mucosa-applied composition, more preferably an ophthalmic composition, and an eye drop. Is more preferable.
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).

  The aqueous composition according to the present embodiment is provided in a container generally used in the pharmaceutical field and provided as a pharmaceutical product. The container for storing the aqueous composition according to the present embodiment may be made of glass or plastic. Moreover, the transparent container which can visually recognize the inside of a container may be sufficient as the container which accommodates the aqueous composition which concerns on this embodiment, and the opaque container where it is difficult to visually recognize the inside of a container may be sufficient as it. Here, the “transparent container” includes both a colorless transparent container and a colored transparent container.

  When a plastic container is used as a container for containing the aqueous composition according to the present embodiment, the constituent material of the plastic container is not particularly limited. For example, polyester (polyethylene naphthalate, polybutylene naphthalate, Polyethylene terephthalate, polybutylene terephthalate, etc.), polyarylate, polypropylene, polyethylene, polyimide, polycarbonate, or a mixture of two or more thereof. In addition, as a constituent material of the plastic container, for example, a copolymer containing any of 2,6-naphthalate unit, terephthalate unit, ethylene-2,6-naphthalate unit, ethylene terephthalate unit, propylene unit, ethylene unit, and imide unit. A coalescence can also be used. From the viewpoint of improving the light stability of olopatadine, polyester, polypropylene, polyethylene, polyimide, and polycarbonate are preferable as the material for the container that contains the aqueous composition according to the present embodiment, and polyethylene naphthalate, polyarylate, and polyethylene terephthalate. Is more preferable, and polyethylene terephthalate (PET) is particularly preferable. In this specification, unless otherwise specified, for example, when “polyethylene terephthalate” is described, in addition to the case where polyethylene terephthalate is contained in the container constituent material, the container shrink constituent material The case of containing polyethylene terephthalate is also included. From the standpoint of achieving the effects of the present application, it is preferable that polyethylene terephthalate is contained in an amount of 30 w / w% or more, more preferably 50 w / w% or more, based on the total weight of the constituent material of the container or shrink. preferable.

  Further, the container containing the aqueous composition according to the present embodiment may be added or coated with an additive such as an ultraviolet blocking agent, or may be a sheet-like composition added or coated with an additive such as an ultraviolet blocking agent. The resin may be shrink-wrapped in a container.

  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.

[ Test Example 1 Photostability Test (1) ]
An aqueous composition having the composition shown in Table 1 below was prepared by a conventional method, and the light stability was evaluated. The prepared aqueous composition was filled into 5 mL portions of 10 mL clear glass vials. Using a light stability tester (“Light-Tron LT-120 D3CJ type”, manufactured by Nagano Kagaku Co., Ltd.), using a D65 lamp as a light source, 5000 lx of light was continuously irradiated for 120 hours at room temperature. Was exposed to light having an integrated irradiation amount of 600,000 lx · hr. After exposure, the content of olopatadine hydrochloride in the aqueous composition was quantified using HPLC, and the residual ratio of olopatadine hydrochloride was calculated according to the following formula (I).
Formula (I)
Residual rate (%) = (Olopatadine hydrochloride content after light irradiation) / (Olopatadine hydrochloride content before light irradiation) × 100
Furthermore, the light stability improvement rate (%) was calculated using the following formula (II). The calculation results are also shown in Table 1.
Formula (II)
Light stability improvement rate (%) = {(residual rate of each example / residual rate of corresponding comparative example) -1} × 100
In addition, the corresponding comparative example is the comparative example 1 about Example 1-1, 1-2, for example.

  As shown in Table 1, compared with the aqueous composition containing olopatadine hydrochloride (Comparative Example 1), bromfenac sodium (Example 1-1) or berberine sulfate (Example 1-2) together with olopatadine hydrochloride. It was confirmed that the residual ratio of olopatadine hydrochloride was remarkably improved in the aqueous composition containing, and the light stability in the aqueous composition was improved.

[ Test Example 2 Photostability Test (2) ]
An aqueous composition was prepared according to Table 2 below, and the stability of olopatadine or its salt against light was evaluated. Specific experimental methods and results are shown below.

  First, each aqueous composition shown in Table 2 was prepared by a conventional method. Next, 5 mL of the prepared aqueous composition was filled into a 10 mL transparent glass vial. Using a light stability tester (“Light-Tron LT-120 D3CJ type”, manufactured by Nagano Kagaku Co., Ltd.), using a D65 lamp as a light source, 5000 lx light was continuously irradiated at room temperature for 40 hours. Then, the light stability improvement rate of olopatadine hydrochloride was calculated according to the above formulas (I) and (II) in the same manner as in Test Example 1 after exposing light with an integrated irradiation amount of 200,000 lx · hr. The calculation results are also shown in Table 2.

  As shown in Table 2, the aqueous composition containing olopatadine hydrochloride was adjusted to pH 6.0 (Comparative Example 2) or adjusted to pH 6.0 using a phosphate buffer (Comparative Example 3). In addition, the residual ratio of olopatadine hydrochloride decreased after light irradiation, and the degradation of olopatadine hydrochloride by exposure was observed. In comparison with this, in the aqueous composition containing zinc sulfate (Example 2) or allantoin (Example 3) together with olopatadine hydrochloride, the residual ratio of olopatadine hydrochloride is improved, and the light of olopatadine hydrochloride in the aqueous composition is improved. It was confirmed that the stability was improved.

[ Test Example 3 Test on Light Stability (3) ]
An aqueous composition was prepared according to Table 3 below, and the stability of olopatadine or its salt against light was evaluated. Specific experimental methods and results are shown below.

  First, each aqueous composition shown in Table 3 was prepared by a conventional method. Next, 5 mL of the prepared aqueous composition was filled into a 10 mL transparent glass vial. Using a light stability tester (“Light-Tron LT-120 D3CJ type”, manufactured by Nagano Kagaku Co., Ltd.), using a D65 lamp as a light source, 5000 lx of light was continuously irradiated for 120 hours at room temperature. Then, the light stability improvement rate of olopatadine hydrochloride was calculated according to the above formulas (I) and (II) by the same method as in Test Example 1 after exposing light with an integrated irradiation amount of 600,000 lx · hr.

  The calculation results are also shown in Table 3. As shown in Table 3, the aqueous composition containing olopatadine hydrochloride was adjusted to pH 6.0 (Comparative Example 4) or adjusted to pH 7.5 using a phosphate buffer (Comparative Example 5). In addition, the residual ratio of olopatadine hydrochloride decreased after light irradiation, and the degradation of olopatadine hydrochloride by exposure was observed. In comparison with this, in the aqueous composition containing zinc sulfate (Example 4-1) or allantoin (Examples 4-2 and 5) together with olopatadine hydrochloride, the residual ratio of olopatadine hydrochloride is improved, It was confirmed that the photostability of olopatadine hydrochloride in the composition was improved.

[ Test Example 4 Photostability Test (4) ]
An aqueous composition was prepared according to Table 4 below, and the stability of olopatadine or its salt against light was evaluated. Specific experimental methods and results are shown below.

  First, each aqueous composition shown in Table 4 was prepared by a conventional method. Subsequently, each aqueous composition was filled into a 10 mL capacity transparent glass vial or a 13 mL capacity PET (polyethylene terephthalate: average absorbance 0.218 at 340 to 365 nm) 5 mL each. Using a light stability tester (“Light-Tron LT-120 D3CJ type”, manufactured by Nagano Kagaku Co., Ltd.), using a D65 lamp as a light source, 5000 lx of light was continuously irradiated for 120 hours at room temperature. Then, the light stability improvement rate of olopatadine hydrochloride was calculated according to the above formulas (I) and (II) by the same method as in Test Example 1 after exposing light with an integrated irradiation amount of 600,000 lx · hr.

  The calculation results are also shown in Table 4. As shown in Table 4, in the aqueous composition containing olopatadine hydrochloride (Comparative Example 6), the residual ratio of olopatadine hydrochloride decreased after irradiation with light, and decomposition of olopatadine hydrochloride by exposure was observed. In comparison with this, in the aqueous composition containing bromfenac sodium (Example 6-1) and berberine sulfate (Example 6-2) together with olopatadine hydrochloride, the residual ratio of olopatadine hydrochloride is improved, It was confirmed that the photostability of olopatadine hydrochloride in the composition was improved. Furthermore, in the aqueous composition containing bromfenac sodium (Example 6-3) or berberine sulfate (Example 6-4) contained in a PET container, the residual ratio of olopatadine hydrochloride was further significantly improved. .

[ Test Example 5 : Test on light stability (5) ]
An aqueous composition was prepared according to Table 5 below, and the stability of olopatadine or its salt against light was evaluated. Specific experimental methods and results are shown below.

  First, each aqueous composition shown in Table 5 was prepared by a conventional method. Each aqueous composition was then filled into 5 mL portions of 10 mL clear glass vials. Using a light stability tester (“Light-Tron LT-120 D3CJ type”, manufactured by Nagano Kagaku Co., Ltd.), using a D65 lamp as a photogen and continuously irradiating 5000 lx light at room temperature for 240 hours, After exposing the product to light with an integrated irradiation amount of 1,200,000 lx · hr, the light stability improvement rate of olopatadine hydrochloride was calculated according to the above formulas (I) and (II) in the same manner as in Test Example 1.

  The calculation results are also shown in Table 5. As shown in Table 5, in the aqueous composition containing olopatadine hydrochloride (Comparative Example 7), the residual ratio of olopatadine hydrochloride decreased after light irradiation, and the decomposition of olopatadine hydrochloride by exposure was observed. In comparison with this, in the aqueous composition containing bromfenac sodium (Example 7-1) or berberine sulfate (Example 7-2) together with olopatadine hydrochloride, the residual ratio of olopatadine hydrochloride is improved. It was confirmed that the photostability of olopatadine hydrochloride in the aqueous composition was improved.

[ Test Example 6: Light stability test (6) ]
An aqueous composition was prepared according to Table 6 below, and the stability of olopatadine or its salt against light was evaluated. Specific experimental methods and results are shown below.

  First, each aqueous composition shown in Table 6 was prepared by a conventional method. Each aqueous composition was then filled into 5 mL portions of 10 mL clear glass vials. Using a light stability tester (“Light-Tron LT-120 D3CJ type”, manufactured by Nagano Kagaku Co., Ltd.), a D65 lamp is used as a photogen, and 5000 lx light is continuously irradiated for 120 hours at room temperature. After exposing the product to light having an integrated irradiation amount of 600,000 lx · hr, the light stability improvement rate of olopatadine hydrochloride was calculated according to the above formulas (I) and (II) in the same manner as in Test Example 1.

  The calculation results are also shown in Table 6. As shown in Table 6, the aqueous composition containing olopatadine hydrochloride (Comparative Example 8) had the same percentage of olopatadine hydrochloride after irradiation with light even when the content of olopatadine hydrochloride was 0.22 (w / v)%. The degradation of olopatadine hydrochloride by exposure was observed. In comparison, in the aqueous composition containing bromfenac sodium (Example 8-1) or berberine sulfate (Example 8-2) together with olopatadine hydrochloride, bromfenac sodium or berberine sulfate Similarly, when the blending amounts are 0.025 (w / v)% and 0.01%, respectively, the residual ratio of olopatadine hydrochloride is improved, and the photostability of olopatadine hydrochloride in the aqueous composition is improved. confirmed. Moreover, when trometamol (Tris buffer) was used as a buffer, the same tendency was confirmed (Comparative Example 9, Examples 9-1 and 9-2). In addition, the aqueous composition containing 0.11 (w / v)% olopatadine hydrochloride (Comparative Example 10) showed a decrease in the residual ratio of olopatadine hydrochloride after light irradiation, and decomposition of olopatadine hydrochloride by exposure was observed. In comparison with this, in the aqueous composition containing bromfenac sodium (Example 10-1) or allantoin (Example 10-2) together with olopatadine hydrochloride, the residual ratio of olopatadine hydrochloride is improved, It was confirmed that the photostability of olopatadine hydrochloride in the composition was improved. Furthermore, when l-menthol was added as a terpenoid in addition to allantoin, a tendency was observed that the light stability of olopatadine hydrochloride in the aqueous composition was more significantly improved (Example 10-3).

[Formulation example]
In the formulations described in Tables 7 to 14, eye drops (Formulation Examples 1-7, 9-18, 20-29, 31-40, 42-44) and eyewashes (Formulation Examples 8, 19, 30, 41) Prepared.

Claims (6)

  (A) at least one selected from the group consisting of olopatadine and a salt thereof; and (B) at least one selected from the group consisting of bromfenac and a salt thereof, berberine and a salt thereof, allantoins, and zinc and a zinc compound. An aqueous composition comprising a seed.   The aqueous composition according to claim 1, wherein the component (A) is olopatadine hydrochloride.   The aqueous composition according to claim 1 or 2, which is a composition applied to mucosa.   The aqueous composition according to claim 3, wherein the mucosa-applied composition is an ophthalmic composition.   The aqueous composition according to any one of claims 1 to 4, which is contained in a container made of polyethylene terephthalate.   (A) at least one selected from the group consisting of olopatadine and a salt thereof; and (B) at least one selected from the group consisting of bromfenac and a salt thereof, berberine and a salt thereof, allantoins, and zinc and a zinc compound. A method for photostabilizing olopatadine in an aqueous composition, comprising blending a seed with the aqueous composition.