JP6789616B2 - Aqueous pharmaceutical formulation in packaging - Google Patents

Description

The present invention relates to an aqueous pharmaceutical preparation in a package.

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

On the other hand, olopatadine is known to be decomposed over time during storage by additives such as excipients, disintegrants, binders and lubricants, which are frequently used in the production of pharmaceutical preparations for oral administration. (Patent Document 2), a formulation design aimed at stabilizing olopatadine has been studied (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 Japanese Patent No. 3828247 Special Table 2011-105649A Special Table 2011-20960

An object of the present invention is to provide an aqueous pharmaceutical preparation capable of suppressing the decomposition of olopatadine by light. Another object of the present invention is to provide a method for suppressing the decomposition of olopatadine by light.

As a result of diligent studies to solve the above problems, the present inventor has found that the decomposition of olopatadine by light can be suppressed by blocking light rays having a wavelength of 280 to 320 nm. The present invention has been completed by further studies based on such findings.

That is, the present invention comprises a package that blocks light with a wavelength of 280 to 320 nm, and an aqueous pharmaceutical preparation containing at least one selected from the group consisting of olopatadine and a salt thereof contained in the package. , Provide an aqueous pharmaceutical preparation in a package.

The above-mentioned aqueous pharmaceutical preparation in a package can suppress the decomposition of olopatadine by light.

The package preferably has an average light transmittance of 25% or less in the wavelength region of 280 to 320 nm. When the average light transmittance in the wavelength region in the above range is 25% or less, the decomposition of olopatadine can be suppressed more efficiently and more reliably.

The present invention also comprises a package that blocks light rays having a wavelength of 310 to 320 nm, and an aqueous pharmaceutical preparation containing at least one selected from the group consisting of olopatadine and a salt thereof contained in the package. Provided is an aqueous pharmaceutical preparation in a package. The above-mentioned aqueous pharmaceutical preparation in a package can suppress the decomposition of olopatadine by light.

It is preferable that the aqueous pharmaceutical preparation containing the package has an average light transmittance of 25% or less in the wavelength region of the package having a wavelength of 310 to 320 nm. When the average light transmittance in the wavelength region in the above range is 25% or less, the decomposition of olopatadine can be suppressed more efficiently and more reliably.

The maximum light transmittance of the package having a wavelength of 400 to 700 nm is preferably 60% or more. When the maximum light transmittance at a wavelength of 400 to 700 nm is 60% or more, the inside of the package can be easily visually recognized.

The above-mentioned aqueous pharmaceutical preparation in a package can be an eye drop, an eye wash, an injection, an external preparation for skin, a nasal drop, or a composition for contact lenses.

The material of the package is preferably a polyester resin. Further, the material of the package is more preferably polyethylene terephthalate.

Further, the present invention is a method for suppressing decomposition by light of at least one selected from the group consisting of olopatadine and a salt thereof, wherein an aqueous pharmaceutical preparation containing olopatadine or a salt thereof has a wavelength of 280 to 320 nm. Provided is a method including a step of accommodating in a package that blocks light rays. By the method of the present invention, the photodecomposition of olopatadine can be suppressed.

Further, the present invention is a method for improving the drainage of an aqueous pharmaceutical preparation containing at least one selected from the group consisting of olopatadine and a salt thereof, wherein the aqueous pharmaceutical preparation is made of a polyester resin or a styrene resin. Provided is a method including a step of accommodating in a package which is a resin. When the material of the package is the above type, the wettability between the aqueous pharmaceutical preparation and the package can be reduced, and the liquid drainage during use and / or storage can be improved.

According to the present invention, the photodegradation of olopatadine caused by light exposure can be remarkably suppressed, and the storage stability of an aqueous pharmaceutical preparation containing olopatadine can be enhanced.

It is a graph which shows the degree of coloring in Test Example 4.

Hereinafter, the present invention will be described in detail. In the present specification, the aqueous pharmaceutical preparation (or aqueous pharmaceutical composition) refers to water in the preparation (or composition) at least 5% by mass or more, preferably 20% by mass or more, still more preferably 50% by mass or more, particularly preferably. Means that it contains 90% or more, most preferably 95% or more.

In the present specification, the abbreviation "POE" means polyoxyethylene, and the abbreviation "POP" means polyoxypropylene.

The aqueous pharmaceutical preparation containing a package according to an embodiment of the present invention is at least one selected from the group consisting of a package that blocks light having a wavelength of 280 to 320 nm and olopatadine and a salt thereof contained in the package. It is composed of an aqueous pharmaceutical preparation containing (hereinafter, also referred to as “component (A)”). By housing the aqueous pharmaceutical preparation containing the component (A) in a package that blocks light having a wavelength of 280 to 320 nm, photodecomposition of olopatadine in the aqueous pharmaceutical preparation can be suppressed, and the aqueous pharmaceutical preparation Coloring or discoloration and precipitation can be suppressed.

Olopatadine is a known compound having the chemical name (Z) -11- (3-dimethylaminopropanol) -6,11-dihydrodibenzo [b, e] -oxepin-2-acetic acid. Olopatadine may be synthesized by a known method or can be obtained as a commercially available 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, bromine salts, sulfates, phosphates, sodium-orthophosphates, potassium hydrogen sulfates, etc.) and salts with organic acids (eg, salts with organic acids (eg For example, acetate, glycolate, lactate, pyruvate, malonate, succinate, glutarate, fumarate, malate, tartrate, citrate, ascorbate, maleate. , Hydroxymaleate, benzoate, hydroxybenzoate, phenylacetate, cinnamonate, salicylate, 2-phenoxybenzoate, etc.).

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

The content of the component (A) in the aqueous pharmaceutical preparation according to the present embodiment is not particularly limited, and the type of the component (A), the shape of the container in which the aqueous pharmaceutical preparation is stored, the use of the aqueous pharmaceutical preparation, the formulation form, and the like. It is set appropriately according to the usage method and the like. As for the content of the component (A), for example, the total content of the component (A) is preferably 0.002 to 1 w / v% based on the total amount of the aqueous pharmaceutical preparation according to the present embodiment. It is more preferably 0.005 to 0.8 w / v%, further preferably 0.005 to 0.5 w / v%, and even more preferably 0.01 to 0.22 w / v%. It is preferably 0.01 to 0.2 w / v%, and most preferably 0.02 to 0.11 w / v%. From the viewpoint of the effect of suppressing the photodecomposition of olopatadine in the aqueous pharmaceutical preparation, the content of the component (A) is preferably in the above range.

By adding a compound that imparts photostability to olopatadine in addition to the above component (A) to the aqueous pharmaceutical preparation according to the present embodiment, the decomposition of the component (A) by light can be more significantly suppressed. It will be possible.

Examples of the compound that imparts photostability to olopatadine include at least one selected from the group consisting of (B) bromphenac and its salt, berberine and its salt, allantoins, and zinc and zinc compounds.

Bromfenac is a known compound also called 2-amino-3- (4-bromobenzoyl) phenylacetic acid, which may be synthesized by a known method or can be obtained as a commercially available 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, monocarboxylates [acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.], polyvalent carboxylates [fumarate, maleine, etc.] Acid salt, succinate, malonate, etc.], oxycarboxylate [lactate, tartrate, citrate, etc.], organic sulfonate [methanesulfonate, toluenesulfonate, tosilate, etc.] Etc.), inorganic acid salts (eg, hydrochlorides, sulfates, nitrates, hydrobromates, phosphates, etc.), salts with organic bases (eg, methylamine, triethylamine, triethanolamine, morpholine, piperazine, etc.) Salts with organic amines such as pyrrolidine, tripyridine, picolin, etc.), salts with inorganic bases (eg, ammonium salts; alkali metals [sodium, potassium, etc.], alkaline earth metals [calcium, magnesium, etc.], metals such as aluminum Various salts such as (and salt, etc.) can be mentioned.

These bromfenacs and salts thereof may be used alone or in any combination of two or more. Bromfenac or salts thereof also include the form of their solvates (eg, hydrates). Examples of the form of the solvate include, but are not limited to, 1/2 hydrate, monohydrate, 3/2 hydrate and the like. As the bromphenac and / or a salt thereof, bromfenac, a salt with an inorganic base thereof, or a solvate thereof is preferable from the viewpoint of suppressing photodecomposition of olopatadine in an aqueous pharmaceutical preparation, and bromfenac or an alkali metal salt thereof, or a metal salt thereof. These solvates are more preferred, bromfenac sodium, or a hydrate thereof, is even more preferred, and a 3/2 hydrate of bromfenax sodium is particularly preferred.

Berberine is a known compound having a benzylisoquinoline skeleton, may be synthesized by a known method, or can be obtained as a commercially available product.

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

These berberine and salts thereof may be used alone or in any combination of two or more. Berberine or salts thereof also include the form of their solvates (eg, hydrates). From the viewpoint of further suppressing the photodegradation of olopatadine in aqueous pharmaceutical preparations, berberine and / or a salt thereof is preferably berberine sulfate or berberine chloride, and more preferably berberine sulfate.

Allantoin is a known compound also referred to as 5-ureidohydantoin. Examples of allantoin species include allantoin or a salt thereof, or an allantoin derivative or a salt thereof.

The allantoins are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of allantoins include allantoin, allantoin dihydroxyaluminum, allantoinchlorohydroxyaluminum, allantoinglycyrrhetin, 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 suppressing the photodegradation of olopatadine in aqueous pharmaceutical preparations, allantoin, allantoin dihydroxyaluminum, or allantoinchlorohydroxyaluminum is preferable, and allantoin is more preferable.

Zinc or a zinc compound is a simple substance or a 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. ..

Examples of 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- Zinc N-oxide, zinc picriate, 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, zinc chondroitin sulfate, zinc undecylate, zinc ascorbate, zinc pyrithione, zinc hinokithiol, zinc dipicolinate, zinc glycerolate complex, bishistidin zinc complex, zinc-3,4-dihydroxybenzoate Examples thereof include acid complexes and hydrates thereof.

These zinc and zinc compounds may be used individually by 1 type, or may be used in any combination of 2 or more type. Zinc or zinc compounds also include the form of their solvates (eg, hydrates). Examples of the form of the solvate include, but are not limited to, heptahydrate and the like. From the viewpoint of further suppressing the photodegradation of olopatadine in aqueous pharmaceutical preparations, zinc and / or zinc compounds include zinc chloride, zinc sulfate, zinc lactate, zinc gluconate, zinc citrate, or hydrates thereof. Preferably, zinc chloride, zinc sulfate, zinc lactate, or a hydrate thereof is more preferable, zinc sulfate, zinc lactate, or a hydrate thereof is further preferable, and zinc sulfate heptahydrate is particularly preferable.

The content of the component (B) in the aqueous pharmaceutical preparation according to the present embodiment is not particularly limited, and the type of the component (B), the type and content of the component (A) to be used in combination, the use of the aqueous pharmaceutical preparation, and the formulation form. , It is set appropriately according to the usage method. As for the content of the component (B), for example, the total content of the component (B) is preferably 0.0001 to 5 w / v% based on the total amount of the aqueous pharmaceutical preparation according to the present embodiment. It is more preferably 0.0002 to 3 w / v%, further preferably 0.0005 to 1 w / v%, and particularly preferably 0.001 to 0.5 w / v%.

As for the 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% based on the total amount of the aqueous pharmaceutical preparation according to this embodiment. It is preferably 0.001 to 0.5 w / v%, more preferably 0.005 to 0.2 w / v%.

As for the 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 pharmaceutical preparation according to the present embodiment. It is preferably 0.0005 to 0.05 w / v%, more preferably 0.001 to 0.025 w / v%.

As for the content of allantoins, for example, the total content of allantoins is preferably 0.001 to 1 w / v%, preferably 0.005 to 1, based on the total amount of the aqueous pharmaceutical preparation according to the present embodiment. It is more preferably 0.5 w / v%, and even more preferably 0.01 to 0.3 w / v%.

As for the content of zinc and / or zinc compound, for example, the total content of zinc and / or zinc compound is 0.0001 to 1 w / v% based on the total amount of the aqueous pharmaceutical preparation according to the present embodiment. It is preferably 0.0002 to 0.7 w / v%, more preferably 0.001 to 0.5 w / v%, and even more preferably 0.01 to 0.25 w / v%. Is even more preferable.

From the viewpoint of further suppressing the photodecomposition of olopatadine in the aqueous pharmaceutical preparation, the content of the component (B) is preferably in the above range.

Further, the content ratio of the component (B) to the component (A) in the aqueous pharmaceutical preparation according to the present embodiment is not particularly limited, and the types of the component (A) and the component (B), the use of the aqueous pharmaceutical preparation, and the preparation. It is appropriately set according to the form, usage, and the like. The content ratio of the component (B) to the component (A) is, for example, the total content of the component (B) with respect to 1 part by mass of the total content of the component (A) contained in the aqueous pharmaceutical preparation according to the present embodiment. The amount is preferably 0.0005 to 2000 parts by mass, more preferably 0.002 to 500 parts by mass, further preferably 0.005 to 100 parts by mass, and 0.01 to 50 parts by mass. It is particularly preferable that it is a part.

From the viewpoint of further suppressing the photodecomposition of olopatadine in the aqueous pharmaceutical preparation, the content ratio of the component (B) to the component (A) is preferably in the above range.

The content ratio of bromfenac and / or its salt to the component (A) is, for example, bromfenac and / or its salt with respect to 1 part by mass of the total content of the component (A) contained in the aqueous pharmaceutical preparation according to the present embodiment. The total content of the salt 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 0. It is particularly preferably 05 to 10 parts by mass.

The content ratio of berberine and / or its salt to the component (A) is, for example, berberine and / or its content with respect to 1 part by mass of the total content of the component (A) contained in the aqueous pharmaceutical preparation according to the present embodiment. The total content of the salt is preferably 0.0001 to 50 parts by mass, more preferably 0.0005 to 10 parts by mass, further preferably 0.002 to 5 parts by mass, and 0. It is particularly preferably 01 to 1 part by mass.

As for the content ratio of allantoins to the component (A), for example, the total content of allantoins is 0 with respect to 1 part by mass of the total content of the component (A) contained in the aqueous pharmaceutical preparation according to the present embodiment. It is preferably .001 to 500 parts by mass, more preferably 0.005 to 100 parts by mass, further preferably 0.02 to 50 parts by mass, and 0.1 to 15 parts by mass. Is particularly preferable.

The content ratio of zinc and / or zinc compound to the component (A) is, for example, zinc and / or zinc with respect to 1 part by mass of the total content of the component (A) contained in the aqueous pharmaceutical preparation according to the present 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, further preferably 0.001 to 50 parts by mass, and 0. It is even more preferably 002 to 50 parts by mass, and particularly preferably 0.1 to 10 parts by mass.

From the viewpoint of further suppressing the photodecomposition of olopatadine in the aqueous pharmaceutical preparation, it is preferable that the content ratio of each component (B) to the component (A) is within the above range.

The aqueous pharmaceutical preparation according to the present embodiment preferably further contains a terpenoid from the viewpoint of exerting the effect of the present application more remarkably. The terpenoid used in the aqueous pharmaceutical preparation according to the present embodiment is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. As the terpenoid used in the aqueous pharmaceutical preparation according to the present embodiment, for example, menthol, menthone, camphor, borneol, geraniol, cineol, citronellol, carboxylic, anator, eugenol, limonene, linalool, linalyl acetate, derivatives thereof and the like are used. Can be done. These compounds may be d-form, l-form or dl-form. Further, in the aqueous pharmaceutical preparation according to the present 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, sparemint oil, peppermint oil, uikyo oil, kehi oil, rose oil, and cypress oil.

These terpenoids may be used alone or in any combination of two or more. From the viewpoint of suppressing photodegradation of olopatadine, menthol, menthol, camphor, borneol and geraniol are preferable, menthol, camphor and borneol are more preferable, menthol and camphor are more preferable, and l-menthol and dl-menthol are more preferable. Such as menthol is even more preferable.

The content of the terpenoid in the aqueous pharmaceutical preparation according to the present embodiment is not particularly limited, and depends on the type and content of the components (A) and (B) to be used in combination, the use, formulation form, usage method, etc. of the aqueous pharmaceutical preparation. It is set appropriately according to it. As the content of the terpenoid, for example, the total content of the terpenoid is preferably 0.0001 to 0.2 w / v%, preferably 0.0005 to 0, based on the total amount of the aqueous pharmaceutical preparation according to the present embodiment. .1 w / v% is more preferable, and 0.001 to 0.08 w / v% is further preferable. When an essential oil containing a terpenoid is used, the terpenoid in the essential oil contained in the aqueous pharmaceutical preparation can be set to satisfy the above content. From the viewpoint of suppressing the photodecomposition of olopatadine, the content of the terpenoid can be within the above range.

The aqueous pharmaceutical preparation according to the present embodiment may further contain a buffering agent. Thereby, the pH of the aqueous pharmaceutical preparation 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, carbonic acid buffer, citric acid buffer, acetate buffer, tris buffer, aspartic acid, aspartate, epsilon-aminocaproic acid and the like. Be done. These buffers may be used alone or in any combination of two or more. Examples of the boric acid buffer include borate, or borates such as an alkali metal boric acid salt and an alkaline earth metal boric acid salt. Examples of the phosphoric acid buffer include phosphates, or phosphates such as alkali metal phosphates and alkaline earth metal phosphates. Examples of the carbonic acid buffer include carbonic acid, or carbonates such as alkali metal carbonate and alkaline earth metal carbonate. Examples of the citric acid buffer include citric acid, an alkali metal citrate salt, and an alkaline earth metal citrate salt. Examples of the tris buffer include trishydroxymethylaminomethane (tromethamole) and the like. Moreover, borate or phosphate hydrate may be used 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, boar sand, etc.) as a borate buffer; phosphoric acid or a salt thereof as a phosphate buffer. Salts (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); carbonic acid as a carbon dioxide buffer Or its salt (sodium hydrogen carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate, magnesium carbonate, etc.); as a citrate buffer, citric acid or its salt (sodium citrate, potassium citrate, citrus) Calcium acidate, sodium dihydrogen citrate, disodium citrate, etc.); acetic acid or a salt thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.) as an acetate buffer; aspartic acid or a salt thereof (sodium aspartate, sodium aspartate, etc.) (Magnetic aspartate, potassium aspartate, etc.) and the like can be exemplified. Among these buffers, boric acid buffer, phosphate buffer, and Tris buffer are preferable, boric acid buffer (for example, a combination of boric acid and boric acid), and phosphate buffer (for example, hydrogen phosphate). A combination of disodium and sodium dihydrogen phosphate, etc.) is particularly preferable, and a boric acid buffer is most preferable.

When a buffer is added to the aqueous pharmaceutical preparation according to the present embodiment, the content thereof includes the type of the buffer, the type and content of other compounding ingredients, the use, formulation form, usage method, etc. of the aqueous pharmaceutical preparation. 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 pharmaceutical preparation according to the present embodiment, preferably 0.05. It is more preferably 10 w / v%, further preferably 0.1 to 7.5 w / v%, particularly preferably 0.5 to 5 w / v%, and 0.5 to 2. Most preferably, it is 5 w / v%.

The pH of the aqueous pharmaceutical preparation according to the present embodiment is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable range. The pH of the aqueous pharmaceutical preparation 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. , 6.5-8.0 is particularly preferable, and 6.8-7.8 is most preferable. The pH may be 6.0-8.0.

Further, the osmotic pressure of the aqueous pharmaceutical preparation 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 pharmaceutical preparation is, for example, preferably 0.5 to 5.0, more preferably 0.6 to 3.0, and further preferably 0.7 to 2.0. It is preferably 0.9 to 1.55, and particularly preferably 0.9 to 1.55. The osmotic pressure can be adjusted by a method known in the art using inorganic salts, polyhydric alcohols, sugar alcohols, sugars and the like. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (osmotic pressure of 0.9 w / v% sodium chloride aqueous solution) based on the 16th revised Japanese Pharmacy, and the osmotic pressure is the osmotic pressure measurement method described in the Japanese Pharmacy. Measure with reference to (freezing point descent method). For the standard solution for measuring the osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution), sodium chloride (standard reagent of the Japanese Pharmacopoeia) is dried at 500 to 650 ° C. for 40 to 50 minutes, and then in a desiccator (silica). It can be allowed to cool in, and 0.900 g thereof can be accurately weighed and dissolved in purified water to prepare exactly 100 mL, or a commercially available standard solution for measuring osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution) can be used. ..

The viscosity of the aqueous pharmaceutical preparation according to the present embodiment is not particularly limited as long as it is within the range 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 preferably, for example, 0.01 to 1000 mPa · s, preferably 0.05. It is more preferably ~ 100 mPa · s, and further preferably 0.1 to 10 mPa · s.

Further, the aqueous pharmaceutical preparation according to the present embodiment may contain various pharmacologically active ingredients or physiologically active ingredients in combination in an appropriate amount as long as the effects of the present invention are not impaired. The type of such an ingredient is not particularly limited, and for example, the active ingredient in various pharmaceutical products described in the 2012 edition of the OTC drug manufacturing and marketing approval standard (supervised by the Japan Regulatory Science Society) can be exemplified. Specifically, the following components can be mentioned as components used in ophthalmic drugs.

Anti-histamine or anti-allergic agent: for example, ketotifen, iproheptine, diphenhydramine, chlorpheniramine maleate, potassium pemirolast, sodium cromoglycate, tranilast and the like.

Decongestant: for example, tetrahydrozoline, naphazoline, epinephrine, ephedrine, methylephedrine and the like.

Eye muscle regulators: For example, cholinesterase inhibitors having an active center similar to acetylcholine, specifically neostigmine methylsulfate, tropicamide, atropine heleniensulfate and the like.

Disinfectants: for example, acrinol, cetylpyridinium, benzalkonium, benzethonium, chlorhexidine, polyhexamethylene biguanide and the like.

Vitamins: For example, flavin adenine dinucleotide sodium, cyanocobalamin, retinyl acetate, retinol palmitate, pyridoxine hydrochloride, panthenol, calcium pantothenate, tocopherol acetate and the like.

Amino acids: For example, potassium aspartate, magnesium aspartate, magnesium / potassium aspartate (equal mixture), aminoethylsulfonic acid and the like.

Anti-inflammatory agents: For example, glycyrrhetinic acid, glycyrrhizinic acid, methyl salicylate, glycol salicylate, azulene sulfonic acid, tranexamic acid, epsilon-aminocaproic acid, lysozyme, licorice, pranoprofen and the like.

Others: For example, sodium hyaluronate, sulfametoxazole, indomethacin, ibuprofen, ibuprofen piconol, bufexamac, butylflufenamic acid, bendazac, piroxicam, ketoprofen, felbinac, purple root, horse chestnut, and salts thereof.

In addition, for the aqueous pharmaceutical preparation according to the present embodiment, various additives are appropriately selected according to a conventional method according to the use and the preparation form as long as the effects of the invention are not impaired, and one kind or the same. The above may be used in combination to contain an appropriate amount. Examples of these additives include various additives described in the Encyclopedia of Pharmaceutical Additives 2007 (edited by the Japan Pharmaceutical Additives Association). The following additives can be mentioned as typical components.

Carrier: An aqueous carrier such as water or hydrous ethanol.
Sugars: For example, glucose, cyclodextrin, etc.
Sugar alcohols: For example, xylitol, sorbitol, mannitol and the like. These may be D-form, L-form or DL-form.

Preservatives, bactericides or antibacterial agents: for example, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalconium 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, biganide compounds (specifically, polyhexamethylene biganide, etc.), Glokill (Rhodia products) First name) etc.

Stabilizers: for example, tromethamole, sodium formaldehyde sulfoxylate (longalit), tocopherol, sodium metabisulfite, monoethanolamine, aluminum monostearate, glycerin monostearate, dibutylhydroxytoluene and the like.

Surface active agents: For example, POE monolaurate (20) sorbitan (polysorbate 20), POE monopalmitate (20) sorbitan (polysorbate 40), POE monostearate (20) sorbitan (polysorbate 60), POE tristearate (20). ) POE sorbitan fatty acid esters such as sorbitan (polysorbate 65), monooleic acid POE (20) sorbitan (polysorbate 80); POE (40) hardened castor oil (polyoxyethylene cured castor oil 40), POE (60) cured castor oil POE cured castor oil such as (polyoxyethylene cured castor oil 60); POE castor oil such as POE castor oil 10, POE castor oil 35; POE alkyl ether such as POE (9) lauryl ether; POE (20) POP (4) ) POE-POP alkyl ethers such as cetyl ether; POE / POP block copolymers such as POE (196) POP (67) glycols (poroxummer 407, sorbonic F127), POE (200) POP (70) glycols; polyoxyl 40 stearate, etc. Nonionic surfactants such as polyethylene glycol monostearate (in the compounds exemplified above, the number in parentheses indicates the number of added moles), alkyldiaminoethylglycine or a salt thereof (for example, hydrochloride, etc.), etc. Amphoteric surfactants, cationic surfactants such as benzalkonium chloride and benzethonium chloride, alkylbenzene sulfonates, alkyl sulfates, polyoxyethylene alkyl sulfates, α-sulfofatty acid ester salts, α-olefin sulfonic acid Anionic surfactants and the like.

Viscosant: For example, polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone (K25, K30, K90, etc.), carboxyvinyl polymer, polyoxyethylene-polyoxypropylene block copolymer (BASF Wyandotte Coporation, Pluronic, Tetronic, etc.) ), 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, gum arabic, tragant, dextran (40, 70, etc.), alginic acid, sodium alginate, glucose, sorbitol, etc.

Isotonic agents: 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 hydrogen carbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, glycerin, propylene glycol, polyethylene glycol, glucose, mannitol, sorbitol, etc.

Chelating agent: For example, ethylenediamine diacetic acid (EDDA), ethylenediamine triacetic acid, ethylenediaminetetraacetic acid (edetic acid, EDTA), N- (2-hydroxyethyl) ethylenediamine triacetic acid (HEDTA), diethylenetriamine pentaacetic acid (DTPA) and the like.

The aqueous pharmaceutical preparation according to the present embodiment is prepared by adding the above component (A), and if necessary, the component (B) and other compounding components to the carrier so as to have a desired concentration. For example, in the case of an ophthalmic preparation, it can be prepared by dissolving or suspending the component in purified water, adjusting the pH and osmotic pressure to a predetermined value, and sterilizing by filtration sterilization or the like. When a highly hydrophobic component is blended, it may be dissolved or suspended by adding purified water after stirring in advance with a component having a dissolution assisting action such as a surfactant.

(Packaging body)
The container for accommodating the aqueous pharmaceutical preparation will be described below. The container is a package that blocks light rays having a wavelength of 280 to 320 nm.

The package mainly means a package (primary package) that directly contains the aqueous pharmaceutical preparation, but further contains a primary package that contains the aqueous pharmaceutical preparation, and doubles or more the aqueous pharmaceutical preparation. It also includes a packaging body (secondary packaging body) for packaging. Further, the package may include only the main body of the package, or may include the main body of the package, the lid, and / or the extraction port.

In the case of an aqueous pharmaceutical preparation containing a package having a secondary package, at least one of the primary package and the secondary package may block the above-mentioned light rays. From the viewpoint of suppressing the decomposition of olopatadine in the package, it is desirable that the primary package blocks the above-mentioned light rays not only during distribution and storage but also during use.

The form of the package is not particularly limited as long as it can accommodate the aqueous pharmaceutical preparation, and can be appropriately selected depending on the form and use of the aqueous pharmaceutical preparation to be accommodated, the type of primary package or secondary package, and the like. .. Examples of the form of the package include a tube-shaped container, a bottle-shaped container, an eye drop container and the like as the primary package, and a pillow, a packaging bag and the like as the secondary package.

For pharmaceutical preparations such as eye drops, eye wash agents, and injections, a foreign matter confirmation test is stipulated in the Pharmaceutical Affairs Law (by the Japanese Pharmacopoeia) in quality control, and the container of the pharmaceutical preparation is a transparent package (container) that allows the inside to be observed. ) Is required. In addition, it can be said that it is desirable for the user to have a package (container) having transparency enough to observe the inside with the naked eye in order to confirm the residual amount. Therefore, from the viewpoint of the foreign matter confirmation test in quality control, the package is preferably a package having internal visibility (transparency) to which the inside can be observed with the naked eye. A package having internal visibility (transparency) is particularly suitable for eye drops, eye wash agents, injections, etc., for which a foreign substance confirmation test is stipulated in the Pharmaceutical Affairs Law (by the Japanese Pharmacopoeia) in quality control. On the other hand, from the viewpoint of confirming the residual amount, it is preferable that all kinds of aqueous pharmaceutical preparations are contained in a package having internal visibility (transparency).

As a package having internal visibility (transparency), specifically, the maximum value of light transmittance in the visible light region of a wavelength of 400 to 700 nm (hereinafter, also referred to as “maximum light transmittance”) is 60%. As described above, a package having preferably 70% or more, more preferably 80% or more, and particularly preferably 90% or more can be exemplified. In the present invention, the method for measuring the light transmittance conforms to the method described in Examples. Further, the maximum transmittance in the visible light region having a wavelength of 400 to 700 nm can be obtained from each obtained light transmittance by measuring the light transmittance every 10 nm between wavelengths of 400 to 700 nm, for example.

In the present embodiment, when the package is a package having visibility, the preparation in the package can be visually recognized if at least a part of the package has the above-mentioned internal visibility (transparency). Therefore, the internal visibility (transparency) of the package does not necessarily have to be ensured on the entire surface of the package. For example, when the aqueous pharmaceutical preparation to be contained is an eye drop or an injection, the container (package) is used from the viewpoint of implementing the general rules for the preparation of eye drops in the Japanese Pharmacopoeia and the insoluble foreign substance inspection method for the injection. The transparent portion may occupy at least 20% or more, preferably 50% or more, more preferably 70% or more, still more preferably 80% or more, particularly preferably 90% or more of the total area of the above. Further, for example, in the distribution stage, the package used in the present embodiment has a label for displaying the component and the product name on the surface of the package, so that the internal visibility (transparency) of the package is achieved. However, it is desirable that the portion of the package having internal visibility (transparency) is secured to such an extent that the user can confirm the amount of the preparation inside the package. .. Further, when the packaged preparation is double-packed or more, it is preferable that all the packages have the above-mentioned transparency.

In the present invention, blocking light having a wavelength of 280 to 320 nm means that, for example, the average light transmittance in the entire range of wavelengths 280 to 320 nm (hereinafter, also referred to as “average light transmittance”) is 25% or less. means. Here, the light transmittance in the wavelength region of 280 to 320 nm can be measured according to the method specified in the examples of the present application, as in the case of the maximum light transmittance in the visible light region having a wavelength of 400 to 700 nm. Further, for the average light transmittance in the wavelength region of 280 to 320 nm, for example, the light transmittance is measured every 10 nm between 280 to 320 nm, and the average value thereof is calculated from each obtained light transmittance. Can be obtained by.

From the viewpoint of more effectively suppressing the decomposition of olopatadine by light, the average light transmittance of the package in the wavelength region of 280 to 320 nm is preferably 25% or less, more preferably 20% or less, still more preferably 10. % Or less, particularly preferably 5% or less, further particularly preferably 2% or less, and most preferably 1% or less.

In order for the aqueous pharmaceutical preparation containing the component (A) to have an even more excellent photodecomposition suppressing effect, it is desirable that the package can block light with a wavelength of 300 to 320 nm. That is, the average light transmittance (average light transmittance) at a wavelength of 300 to 320 nm is preferably 35% or less, more preferably 30% or less, still more preferably 20% or less, still more preferably 10% or less, particularly preferably. Is more preferably 5% or less, more preferably 2% or less, and most preferably 1% or less. Here, the method for measuring the average light transmittance at a wavelength of 300 to 320 nm is the same as the method for measuring the average light transmittance at 280 to 320 nm.

In order for the aqueous pharmaceutical preparation containing the component (A) to have a particularly excellent photodecomposition suppressing effect, it is desirable that the package can block light with a wavelength of 310 to 320 nm. That is, the average light transmittance (average light transmittance) at a wavelength of 310 to 320 nm is preferably 45% or less, more preferably 40% or less, still more preferably 25% or less, still more preferably 20% or less, particularly preferably. Is more preferably 10% or less, still more preferably 5% or less, even more particularly preferably 2% or less, and most preferably 1% or less. Here, the method for measuring the average light transmittance at a wavelength of 310 to 320 nm is the same as the method for measuring the average light transmittance at 280 to 320 nm.

In this way, the package blocks light having a wavelength of 280 to 320 nm (preferably 300 to 320 nm, more preferably 310 to 320 nm) to prevent light in the wavelength region from being transmitted into the container. It is possible to suppress the photodecomposition of olopatadine in the package.

An aqueous pharmaceutical preparation containing a package according to another embodiment of the present invention comprises a package that blocks light having a wavelength of 310 to 320 nm and an aqueous pharmaceutical preparation containing the component (A) contained in the package. It will be. By housing the aqueous pharmaceutical preparation containing the component (A) in a package that blocks light having a wavelength of 310 to 320 nm, photodecomposition of olopatadine in the aqueous pharmaceutical preparation can be suppressed, and the aqueous pharmaceutical preparation can also be used. Coloring or discoloration and precipitation can be suppressed. Regarding the type of olopatadine or a salt thereof used in the present embodiment, the content ratio in the aqueous pharmaceutical preparation, other components contained in the aqueous pharmaceutical preparation, the form of the aqueous pharmaceutical preparation, the package, etc., the light beam blocked by the package. Other than the wavelength of, the same aspects as those detailed above can be applied.

In order to equip the aqueous pharmaceutical preparation containing the component (A) with a particularly excellent photodecomposition suppressing effect, the package blocks light having a wavelength of 280 to 320 nm and emits light having a wavelength of 310 to 320 nm. It is desirable to block it. Blocking light with a wavelength of 280 to 320 nm and blocking light with a wavelength of 310 to 320 nm means that the average light transmittance in the entire range of wavelengths from 280 to 320 nm is, for example, 25% or less, 20% or less, 10% or less, 5%. Below, 2% or less, 1% or less, and the average light transmittance in the entire range of wavelengths of 310 to 320 nm is, for example, 45% or less, 40% or less, 25 or less, 20% or less, 10% or less, 5% or less. It means that it is 2% or less and 1% or less.

In order for the aqueous pharmaceutical preparation containing the component (A) to have a particularly excellent photodecomposition inhibitory effect of olopatadine, the package has a wavelength of 280 to 320 nm (preferably 300 to 320 nm, more preferably 310 to 320 nm). ), It is preferable that the light having a wavelength of 340 nm to 350 nm can also be blocked. That is, in addition to the fact that the package can block light with a wavelength of 280 to 320 nm (preferably 300 to 320 nm, more preferably 310 to 320 nm), the average light transmittance (average light transmittance) of a wavelength of 340 to 350 nm is determined. It is more preferably 40% or less, more preferably 30% or less, still more preferably 10% or less, particularly preferably 5% or less, and most preferably 1% or less. Here, the method for measuring the average light transmittance at a wavelength of 340 to 350 nm is the same as the method for measuring the average light transmittance at 280 to 320 nm.

As described above, the means for blocking light having a wavelength of 280 to 320 nm is not particularly limited, but for example, a method of kneading a substance that blocks light having a wavelength of 280 to 320 nm into the material constituting the package, the package. Examples include a method of applying a substance that blocks light rays having a wavelength of 280 to 320 nm, a method of attaching a film kneaded with a substance that blocks light rays having a wavelength of 280 to 320 nm, and the like, and one of these methods is used alone. Or in combination of two or more. As a method of attaching the film to a container, specifically, a heat-shrinkable film (shrink film) that blocks light having a wavelength of 280 to 320 nm is put on the package, and the film is heated to attach the film to the package. An example of a method of close contact coating. The other means for blocking light having a wavelength of 340 to 350 nm is the same as the above method except that the wavelength to be blocked is made to correspond to the target wavelength in the above method.

The material of the package used in the present embodiment is not limited, and may be any of glass, plastic, cellulose, pulp, rubber and the like. From the viewpoint of exerting the effect of the present application more remarkably, and from the viewpoint of squeeze property and durability, a plastic package is preferable.

The resin used for the plastic packaging used in the present embodiment is preferably a thermoplastic resin, for example, an olefin resin (polyethylene, polypropylene, etc.), a polyester resin, a polyphenylene ether resin, a polycarbonate resin, or a polysulfone. Examples thereof include based resins, polyamide resins, hard vinyl chloride resins, and styrene resins (polystyrene (PS), acrylonitrile-styrene copolymer (AS resin), etc.). Preferred resins are polyethylene, polypropylene, polyester resins or polycarbonate resins, and since the effects of the present invention are remarkably exhibited, more preferred resins are polyester resins or polycarbonate resins, and particularly preferred resins are polyesters. It is a based resin.

As the polyester-based resin, a resin obtained by using a component containing a dicarboxylic acid component (aromatic dicarboxylic acid component such as phthalic acid, terephthalic acid, naphthalene dicarboxylic acid, etc.) and a diol component can be used. Specifically, aromatic polyester-based resins such as polyalkylene terephthalate (poly C2-4 alkylene terephthalate such as polyethylene terephthalate (PET) and polybutylene terephthalate (PBT)) and polyalkylene naphthalate (polyethylene naphthalate (PEN)). ), Poly C2-4 alkylene naphthalate such as polybutylene naphthalate), polycycloalkylene terephthalate (poly (1,4-cyclohexylene methylene terephthalate) (PCT), etc.), polyarylates (bisphenols [bisphenol- A etc.] and phthalates [resin composed of phthalic acid, terephthalic acid])) homopolyester and the like can be mentioned. Further, the polyester-based resin also includes a copolyester containing the homopolyester unit as a main component (for example, 50% by weight or more), a copolymer of the homopolyester (a copolymer of PET and PCT, etc.) and the like. .. The polycarbonate-based resin is, for example, an aromatic polycarbonate based on bisphenols (bisphenol-A, etc.).

In the present embodiment, the plastic package may contain a polymer alloy (polymer blend or the like) as long as it does not adversely affect the strength, light transmission, gas or water vapor barrier property (moisture permeability) and the like. Preferred polymer alloys include polymer blends of multiple synthetic resins, such as polymer blends of PET and PEN. When the material of the package is a polymer alloy, it is preferable that the polyester resin is contained as a main component (for example, 50% or more). It is preferable that the resin constituting the package has good squeeze property and can be a package having durability against repeated pressing.

Among polyester resins, the material of the package is preferably polyalkylene terephthalate or polyalkylene naphthalate, more preferably polyethylene terephthalate (PET) or polybutylene terephthalate (PBT), because the effect of the present invention is remarkably exhibited. ) Or polyethylene terephthalate (PEN). The material of the package may be a homopolyester or copolyester containing these, or may be a polymer alloy containing the homopolyester or copolyester.

Further, from the viewpoint of improving the liquid drainage of the aqueous pharmaceutical preparation, the material of the package is preferably a polyester resin or a styrene resin, more preferably PET or PS, and further preferably PET. preferable. By using a package made of these resins as a material, the wettability between the aqueous pharmaceutical preparation containing the component (A) and the package is reduced, the liquid drainage during use and / or storage is improved, and the aqueous solution is used. It is possible to prevent liquid residue in the container of the pharmaceutical preparation.

The package according to the present embodiment may be a package to which a UV blocking agent has been added, or may be a package coated with a UV blocking agent. For example, a package, glass or synthetic resin, etc., which is molded after adding an ultraviolet blocking agent to glass or synthetic resin, is processed into a sheet, coated with an ultraviolet blocking agent, and then molded. Examples thereof include a package body coated with an ultraviolet blocking agent after being molded into a package body shape. Further, a sheet-shaped synthetic resin or the like to which an ultraviolet blocking agent has been added or coated may be shrink-wrapped in a package after molding.

UV blocking agents include zinc oxide, titanium oxide, triazole compounds, benzoate compounds, substituted acrylonitrile compounds, cyanoacrylate compounds, triazine compounds, oxalic acid anilide compounds, nickel complex compounds, and trade name tinubin (registered). Benzophenone compounds such as 328, chinubin (R) 384-2, chinubin (R) 400, chinubin (R) 400-2, chinubin (R) 900, chinubin (R) 928, chinubin (R) 1130; Methyl diisopropylsilicate, synoxate, mono-2-ethylhexarate diparamethoxycinerate, glyceryl paramethoxycinerate isopropyl-diisopropylsilicate ester mixture, 2-ethylhexyl paramethoxycinerate, benzyl silicate , Etc.; benzophenone-based UV absorbers such as oxybenzone, hydroxymethoxybenzophenone sulfonic acid, sodium hydroxymethoxybenzophenone sulfonate, dihydroxydimethoxybenzophenone, dihydroxydimethoxybenzophenone disulfonate, dihydroxybenzophenone, tetrahydroxybenzophenone; Paraaminobenzoic acid, ethyl paraaminobenzoate, glyceryl paraaminobenzoate, amyl paradimethylaminobenzoate, 2-ethylhexyl paradimethylaminobenzoate, 4- [N, N-di (2-hydroxypropyl) amino] ethyl benzoate, etc. Benzophenone ester-based UV absorbers; Salicylic acid-based UV absorbers such as ethylene glycol salicylate, octyl salicylate, dipropylene glycol salicylate, phenyl salicylate, homomentyl salicylate, methyl salicylate, guaiazulene, 2-ethylhexyl dimethoxybenzylenedioxoimidazolidinepropionate. , 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 and the like can be mentioned. In addition, riboflavin, anthraquinone dyes (1-amino-4-methylanthraquinone, 1,4-diaminoanthraquinone, anthraquinone yellow, etc.), phthalocyanine dyes (phthalocyanine blue (CI Pigment Blue15; CI 74160;) Blue No. 404), phthalocyanine green (CI Pigment Green7), etc.) and the like.

The ultraviolet blocking agent is preferably zinc oxide, titanium oxide, chinubin (registered trademark) 328, chinubin (R) 384-2, chinubin (R) 400, chinubin (R) 400-2, chinubin (R) 900, chinubin ( R) 928, Tinubin (R) 1130, 2-ethylhexyl paramethoxycinnamate, glyceryl mono-2-ethylhexanate diparamethoxycinnamate, 2,4,6-tris [4- (2-ethylhexyloxycarbonyl) ) Anilino] 1,3,5-triazine, phenylbenzimidazoline sulfonic acid, 2- (4-diethylamino-2-hydroxybenzoyl) -hexyl benzoate, dimethoxybenzylidene dioxoimidazolidine propionate 2-ethylhexyl, in particular. Preferably, zinc oxide, titanium oxide, chinubin (R) 328, chinubin (R) 384-2, chinubin (R) 400, chinubin (R) 400-2, chinubin (R) 900, chinubin (R) 928, chinubin ( R) 1130. Zinc oxide and titanium oxide may be further coated with silica, silicon, zinc silicate and the like.

In the package according to the present embodiment, when an ultraviolet blocking agent is added to the material constituting the packaging, the ratio of the added ultraviolet blocking agent is, for example, 0.05 to 5.0% by weight based on the total amount of the material. It is preferably 0.1 to 3.0% by weight. A package coated with an ultraviolet blocking agent can be produced, for example, by applying a coating paint containing an ultraviolet absorber to the molded package or a synthetic resin sheet. Here, as the coating coating material, a radical polymerization type acrylic type (for example, polyester polyacrylate, urethane polyacrylate, epoxy polyacrylate, polyether polyacrylate, side chain acryloyl type acrylic resin, etc.), thiolene type (for example, polythiol acrylic) Type oligomers, polythiol spiroacetal types, etc.), unsaturated polyesters, cationically polymerized epoxy resins, and the like can be used. Further, the material constituting the package may be spread in the form of a film and molded from a sheet in which this film is adhered and laminated.

The package according to this embodiment may be made of a material (package) to which a colorant is added or coated. As the colorant, inorganic pigments, lake pigments, organic pigments and the like can be used.

Since the aqueous pharmaceutical preparation of the present invention has excellent photostability, it is packaged in a form of being administered multiple times and is useful as a multi-dose eye drop that is continuously used by the user. It can also be used as an eye drop.

As described above, the package that blocks light rays having a wavelength of 280 to 320 nm can suppress the decomposition of olopatadine by light. Therefore, the present invention further comprises a step of accommodating an aqueous pharmaceutical preparation containing at least one selected from the group consisting of olopatadine and a salt thereof in a package that blocks light having a wavelength of 280 to 320 nm. Provided is at least one method for suppressing photodecomposition selected from the group consisting of salts. The present invention also comprises a step of accommodating an aqueous pharmaceutical preparation containing at least one selected from the group consisting of olopatadine and a salt thereof in a package that blocks light having a wavelength of 310 to 320 nm. Provided is at least one method for suppressing photodecomposition selected from the group consisting of.

In the above method, the type of olopatadine or a salt thereof to be used, the content ratio in the aqueous pharmaceutical preparation, other components contained in the aqueous pharmaceutical preparation, the form of the aqueous pharmaceutical preparation, the packaging body that blocks light rays having a wavelength of 280 to 320 nm, etc. The same aspects as those described in detail for the above-mentioned aqueous pharmaceutical preparation in a package can be applied.

The present invention is also a method for improving the drainage of an aqueous pharmaceutical preparation containing at least one selected from the group consisting of olopatadine and a salt thereof, wherein the aqueous pharmaceutical preparation is made of a styrene resin or a polyester resin. Provided is a method including a step of accommodating in a packaging body. By using a package whose material is the above type as a container for accommodating the aqueous pharmaceutical preparation containing the component (A), the wettability between the aqueous pharmaceutical preparation and the package is reduced, and the liquid drainage during use is improved. It is possible to reduce the amount of liquid remaining in the container of the aqueous pharmaceutical preparation. Excellent liquid drainage is particularly useful in ophthalmic compositions, especially eye drops, which are used in small amounts at one time. The details of the styrene-based resin or the polyester-based resin are the same as those described in detail with respect to the aqueous pharmaceutical preparation containing the package. Further, in the above method, by increasing the content of the component (A), it is possible to further improve the liquid drainage during use.

The aqueous pharmaceutical preparation according to the present embodiment can be used as a pharmaceutical product, a quasi-drug, or the like, and can be used, for example, as an ophthalmic pharmaceutical preparation or an otolaryngological pharmaceutical preparation. Ophthalmic pharmaceutical preparations include, for example, eye drops (also referred to as eye drops or eye drops; the eye drops include eye drops that can be instilled while wearing contact lenses), artificial tears, and eye wash (eye wash). Also referred to as eye drops. The eye drops include eye drops that can be washed while wearing contact lenses), ophthalmic compositions such as eye ointments; composition for contact lenses (contact lens wearing solution, contact lenses). Care compositions [contact lens disinfectants, contact lens preservatives, contact lens cleaning agents, contact lens cleaning preservatives], etc.) are included. The above composition for contact lenses can be applied to all contact lenses including hard contact lenses and soft contact lenses. Otorhinolaryngological pharmaceutical preparations include, for example, nasal drops, nasal lavage fluid and the like.

The aqueous pharmaceutical preparation may be an injection, a suppository, an oral medicine, an inhalation preparation, or the like, or may be a locally applied aqueous pharmaceutical preparation that is easily exposed to light when applied to a patient. It is an aqueous pharmaceutical preparation that is applied not only to the skin but also to mucous membranes that are easily irritated (eye mucosa such as cornea and conjunctiva, gums, tongue, lips, oral mucosa, nasal mucosa, pharyngeal mucosa, etc.). May be good. For example, as an example of the above-mentioned aqueous pharmaceutical preparation, an external preparation for skin (ointment for outer skin, cream for outer skin, liquid for outer skin, etc.), eye drops (eye drops), eye wash (eye wash), eye ointment, contact lens wearing solution , Contact lens preparations (cleaning solution, preservative solution, disinfectant solution, multipurpose solution, etc.), nasal drops (nasal drops), nasal cleaning solution, oropharyngeal drug, mouthwash, ear drops, etc. In addition, in this specification, a contact lens includes all types of contact lenses such as a hard contact lens (including an oxygen permeable hard contact lens) and a soft contact lens. Among these, preferably, eye drops (eye drops), eye wash (eye wash), injections, external skin preparations, nasal drops and contact lens preparations can be mentioned.

In particular, when the package is a highly visible package, it is possible to inspect the presence or absence of foreign substances by visually observing the pharmaceutical preparation in the container from the outside, and the Japanese Pharmacopoeia provides general rules for eye drop preparation. In view of the effect of the present invention that the insoluble foreign matter test method for an injection can be suitably carried out, examples of preferable pharmaceutical preparations include eye drops, eye wash, injection and the like. In addition, a preparation containing a plurality of doses is suitable because the user can visually recognize the residual amount of the preparation for each use. Specific examples of the preparation containing a plurality of doses include eye drops, eye wash agents, external preparations for skin, nasal drops, and contact lens preparations.
When the package is a package having visibility, eye drops and eye wash are particularly preferable for the above reasons.

Hereinafter, the present invention will be described in detail based on examples, but the present invention is not limited thereto.

[Test Example 1-1: Photodegradation suppression confirmation test of olopatadine]
An olopatadine-containing aqueous pharmaceutical preparation (eye drops) was prepared according to Formulation Example 1 shown in Table 1, and 5 mL each was placed in various containers shown in Table 2 and sealed. The ratio of each component of the prescription example in Table 1 is based on the total amount of the aqueous pharmaceutical preparation, and the unit is w / v%. The containers include colorless or colored polyethylene terephthalate (PET) containers, polyethylene naphthalate (PEN) containers, polycarbonate (PC) containers, polyethylene (PE) containers, polypropylene (PP) containers or glass containers. Was used. A light stability test device (“Light-Tron LT-120 D3CJ type”, manufactured by Nagano Scientific Co., Ltd.) was used for the various containerized olopatazine-containing aqueous pharmaceutical preparations thus obtained, and a D65 fluorescent lamp was used as a light source. Light of an integrated irradiation amount of 600,000 lx · h was exposed by continuously irradiating light of 5,000 lpx for 120 hours at a room temperature of 25 ° C. Then, the concentration of olopatadine in each aqueous pharmaceutical preparation was analyzed by high performance liquid chromatography, and the residual concentration of olopatadine was quantified. From the measured residual concentration of olopatadine, the residual rate (%) with respect to the residual concentration of olopatadine before light irradiation was calculated. The results are shown in Table 2.

In order to evaluate the light transmittance of the container used for the test, a part of each container was cut out and used as a sample with a microplate reader (“SH-9000”, manufactured by Corona Electric Co., Ltd.) at a wavelength of 200 to 700 nm. The light transmittance was measured every 10 nm in the range, and the average light transmittance at a predetermined wavelength of the container and the maximum transmittance at a wavelength of 400 to 700 nm were determined. If there are labels or the like on the measurement part that interfere with the measurement, the measurement was performed after removing them.

The internal visibility of the container used in the test was evaluated based on the following evaluation criteria. The evaluation was carried out by visual observation using a white light source at a position having a brightness of 3000 to 5000 lp. The results are shown in Table 2.
<Evaluation criteria>
◎ The amount of aqueous pharmaceutical preparation inside and foreign matter can be clearly seen ○ The amount of aqueous pharmaceutical preparation inside and foreign matter can be visually recognized △ The amount of aqueous pharmaceutical preparation inside can be visually recognized, but foreign matter is difficult to see × Internal The amount of aqueous pharmaceutical preparation and foreign matter cannot be visually recognized.

Among the various containers used in the test, those having a maximum light transmittance of 60% or more at a wavelength of 400 to 700 nm were able to visually recognize the aqueous pharmaceutical preparation contained therein from the outside and had sufficient transparency. ..

The residual rate of olopatadine after light irradiation was remarkably high in the olopatadine-containing aqueous pharmaceutical preparation contained in a container in which light having a wavelength of 280 to 320 nm was blocked. It was confirmed that even within the wavelength range of 280 to 320 nm, the lower the light transmittance in the wavelength range of 300 to 320 nm and 310 to 320 nm, the more the decomposition of olopatadine is suppressed and the olopatadine is stably retained in the container. Was done. Incidentally, this is, for example, can be confirmed by comparing the average light transmittance of each wavelength range shown in the above Table 2, the coefficient of determination R ² in olopatadine residual ratio. Further, it was confirmed that the decomposition of olopatadine was further suppressed and stably maintained in the container in which the light having a wavelength of 280 to 320 nm was blocked and the light having a wavelength of 340 to 350 nm was also blocked. It was.

From the above results, it is clear that light rays having a wavelength of 280 to 320 nm are involved in the decomposition of olopatadine by light exposure, and it is possible to suppress the decomposition of olopatadine by light exposure by blocking the light in the above wavelength region. confirmed. Furthermore, it was confirmed that good visibility inside can be ensured if the maximum light transmittance of the container containing the olopatadine-containing aqueous pharmaceutical preparation at a wavelength of 400 to 700 nm is 60% or more.

[Test Example 1-2: Photodegradation suppression confirmation test of olopatadine]
An olopatadine-containing aqueous pharmaceutical preparation (eye drops) was prepared according to Formulation Examples 2 and 3 shown in Table 3, and Examples 6-1-1 (colorless polyethylene terephthalate (PET) container) and Example 7- shown in Table 2 were prepared. 5 mL each was placed in a container of the same type as that used in 1-1 (polycarbonate (PC) container) and sealed. The ratio of each component of the prescription example in Table 3 is based on the total amount of the aqueous pharmaceutical preparation, and the unit is w / v%. With respect to the obtained various container-containing olopatadine-containing aqueous pharmaceutical preparations, the residual concentration of olopatadine after light irradiation and exposure was quantified by the same method as in Test Example 1-1 described above, and the residual ratio with respect to the olopatadine concentration before light irradiation ( %) Was calculated. The results are shown in Table 4. Also in Formulation Examples 2 and 3 in which the pH was changed from Formulation Example 1, the residual rate of olopatadine after light irradiation was remarkably high by using the container of Example.

[Test Example 2 Photodegradation suppression confirmation test of olopatadine]
Olopatadine-containing aqueous solution containing 0.11 w / v% olopatadine hydrochloride, benzalkonium chloride, anhydrous sodium monohydrogen phosphate, a pH regulator and an isotonic agent, pH 7.0, and an osmotic pressure ratio of 0.9 to 1.1. A container of the same type as that used in Example 6-1-1 and Comparative Example 3-1 shown in Table 2 using a pharmaceutical preparation (Patanol ophthalmic solution 0.1% manufacturer: Alcon Japan). It was housed in and sealed, and used as Example 6-2 and Comparative Example 3-2, respectively.

A light stability test device (“Light-Tron LT-120 D3CJ type”, manufactured by Nagano Scientific Co., Ltd.) was used for the various containerized olopatazine-containing aqueous pharmaceutical preparations thus obtained, and a D65 fluorescent lamp was used as a light source. Light of an integrated irradiation amount of 600,000 lx · h was exposed by continuously irradiating light of 5,000 lpx for 120 hours at a room temperature of 25 ° C. Then, the concentration of olopatadine in each aqueous pharmaceutical preparation was analyzed by high performance liquid chromatography, and the residual concentration of olopatadine was quantified. From the measured residual concentration of olopatadine, the residual rate (%) with respect to the residual concentration of olopatadine before light irradiation was calculated.

Table 5 shows the results of the residual rate of olopatadine after light irradiation. Even if the composition of the aqueous pharmaceutical preparation is different, in the olopatadine-containing aqueous pharmaceutical preparation contained in a container in which light having a wavelength of 280 to 320 nm is blocked, the residual rate of olopatadine after light irradiation is similar to that in Test Example 1-1. It showed a remarkably high value.

[Test Example 3 Photodegradation suppression confirmation test of olopatadine]
An aqueous pharmaceutical preparation was prepared according to the formulation examples shown in Table 6 below, and the decomposition of olopatadine or a salt thereof with light was evaluated. Specific experimental methods and results are shown below. The ratio of each component of the prescription example in Table 6 is based on the total amount of the aqueous pharmaceutical preparation, and the unit is w / v%.

First, each aqueous pharmaceutical preparation shown in Table 6 was prepared by a conventional method. Next, each aqueous pharmaceutical preparation was filled in a 10 mL volume transparent glass vial (the same type as the glass (colorless) container used in Comparative Example 3-1 shown in Table 2) or a 13 mL volume PET container by 5 mL each. Table 7 shows the average light transmittance and the maximum light transmittance at a predetermined wavelength of the PET container. Using a light stability test device (“Light-Tron LT-120 D3CJ type”, manufactured by Nagano Kagaku Co., Ltd.), a D65 lamp is used as a light source, and 5000 lp of light is continuously irradiated for 120 hours at room temperature to obtain an aqueous pharmaceutical preparation. After exposing the light to an integrated irradiation dose of 600,000 xl · hr, the residual concentration of olopatadine was quantified by the same method as in Test Example 1-1, and the photostability of olopatadine was determined according to the following formulas (I) and (II). The improvement rate was calculated. The results are shown in Table 6.
Residual rate (%) = (Olopatadine hydrochloride content after light irradiation) / (Olopatadine hydrochloride content before light irradiation) × 100 ... (I)
Photostability improvement rate (%) = {(Residual rate of each Example or Comparative Example / Residual rate of Comparative Example 4) -1} × 100 ... (II)

As shown in Table 6, olopatadine was contained and was filled in a PET container (transparent) and contained bromfenac sodium and berberine sulfate together with olopatadine as compared with Comparative Examples 4 to 6 filled in a glass vial. It was confirmed that the residual rate of olopatadine was improved in the aqueous pharmaceutical preparation and the photostability of olopatadine in the aqueous pharmaceutical preparation was improved.

[Test Example 4: Olopatadine coloring and precipitation suppression confirmation test]
Similar to Test Example 1-1, 5 mL each of Formulation Example 1 in Table 1 was placed in the container in Table 2 (a typical container was selected) and sealed. The containers used in Examples 1-1, 5-1 and 6-1-1 and Comparative Examples 1-1, 2-1 and 3-1 were filled with Examples 1-4, 5-4, respectively. 6-4, Comparative Examples 1-4, 2-4, 3-4.

The olopatadine-containing aqueous pharmaceutical preparations in various containers thus obtained were irradiated with a photostability test device (Suntester (SUNTEST XLS +: manufactured by ATLAS)) at 765 W / m ² for 19 hours for integration. Light with an irradiation amount of 52,000 kJ / m ² was exposed. 200 μL of each sample before and after light irradiation was placed in a 96-well plate, and the absorbance at 420 nm was measured with a microplate reader (“SH-9000” manufactured by Corona Electric Co., Ltd.). Then, the value obtained by subtracting the absorbance of the sample before light irradiation from the absorbance of the sample after light irradiation was calculated and used as the degree of coloring. The results are shown in FIG.

The color of the sample after light irradiation and the presence or absence of precipitation were visually inspected and evaluated according to the following criteria to obtain a property score. The results are shown in Table 8.
<Evaluation criteria>
◎ Colorless, no precipitation ○ Very slightly yellow, no precipitation △ Light yellow, no precipitation × dark yellow, no precipitation × × dark yellow, with precipitation

The color tone of the olopatadine-containing aqueous pharmaceutical preparation after light irradiation was completely absent or only slightly yellow when it was housed in a container in which light having a wavelength of 280 to 320 nm was blocked. On the other hand, in a comparative example in which light having a wavelength of 280 to 320 nm was housed in a container in which light was not blocked, it was confirmed that the aqueous pharmaceutical preparation was colored and precipitated in deep yellow.

Further, it was confirmed that coloring was further suppressed in the aqueous pharmaceutical preparation contained in the container in which the light having a wavelength of 280 to 320 nm was blocked and the light having a wavelength of 340 to 350 nm was also blocked. It was. On the other hand, even if the light transmittance at a wavelength of 260 to 270 nm is low, the olopatazine-containing aqueous pharmaceutical preparation contained in a container having a high light transmittance at a wavelength of 280 to 320 nm cannot suppress coloring and precipitation of the preparation due to light irradiation. It was confirmed that.

From the above results, it was clarified that light having a wavelength of 280 to 320 nm is involved in the coloring of the olopatadine-containing aqueous preparation by light exposure, and by blocking the light in the above wavelength region, the olopatadine-containing preparation is exposed to light. It was confirmed that the coloring and precipitation due to the above can be suppressed.

[Test Example 5: Photodegradation suppression confirmation test of olopatadine]
Olopatadine-containing aqueous pharmaceutical preparations (eye drops) were prepared according to Formulation Examples 4 and 5 shown in Table 9, and Examples 6-1-1 (colorless polyethylene terephthalate (PET) container) and Example 7- shown in Table 2 were prepared. 5 mL each was placed in a container of the same type as that used in 1-1 (polycarbonate (PC) container) and sealed. The ratio of each component of the prescription example in Table 9 is based on the total amount of the aqueous pharmaceutical preparation, and the unit is w / v%. Prescription Examples 4 and 5 correspond to those in which a predetermined amount of menthol is further added to Prescription Examples 2 and 3, respectively. With respect to the obtained various container-containing olopatadine-containing aqueous pharmaceutical preparations, the residual concentration of olopatadine after light irradiation and exposure was quantified by the same method as in Test Example 1-1 described above, and the residual ratio with respect to the olopatadine concentration before light irradiation ( %) Was calculated.

In the above-mentioned Examples using Formulation Examples 4 and 5 containing menthol, the residual rate of olopatadine after light irradiation was higher than that in Examples in Test Example 1-2 using Formulation Examples 2 and 3, respectively. It was confirmed that the photostability of olopatadine was further increased by adding menthol.

[Test Example 6: Liquid drainage improvement confirmation test]
An olopatadine-containing aqueous pharmaceutical preparation was prepared according to Formulation Examples 6, 7 and 8 shown in Table 11. In addition, aqueous pharmaceutical preparations were prepared in the same manner as in Formulation Examples 6, 7 and 8 except that they did not contain olopatadine hydrochloride and l-menthol, and were designated as Comparative Formulation Examples 6', 7'and 8', respectively. As the aqueous pharmaceutical preparations of Formulation Example 8 and Comparative Formulation Example 8', those stored in a 10 mL volume glass vial at 70 ° C. for 5 days were used in the following test.

Using the contact angle meter DM-501 (manufactured by Kyowa Interface Science Co., Ltd.), the forward contact angle, which is the contact angle when the interface between solid and liquid moves, is measured according to the measurement procedure of the expansion / contraction method of the measuring device. did.
Specifically, each container material shown in Table 12 was placed on the stage of the contact angle meter, and the test solution was set in the dispenser so as to be a combination of the formulation example shown in Table 13 and the container material. 1 μL of a droplet of the test solution was dropped onto the surface of the container material and dropped into a hemispherical shape. Next, the tip of the liquid discharge portion of the dispenser was promptly landed on the upper part of the hemisphere. In that state, the test solution was continuously discharged at a discharge rate of 2 μL / sec, and the shape of the droplet was photographed 15 times every 0.1 second from the side surface. The comparative prescription examples corresponding to each prescription example were also continuously measured at the same room temperature using the same container material, and photographed by the same method.

Next, the left and right contact angles were obtained for each image using the analysis software FAMAS of the above measuring device. Here, the contact angle is the angle formed by the tangent line drawn to the test solution from the contact point P of the container material surface, the test solution and air, and the tangent line drawn to the surface of the container material, whichever side contains the test solution. Means. As the droplet expanded by discharging the test solution, the contact angle changed and then became almost constant. The average value of the left and right contact angles was calculated for each image, and the average value of the left and right contact angles was arranged in the order in which the images were taken. Five consecutive values were selected and the first contact angle with a standard deviation of 2.5 ° or less was defined as the forward contact angle in this test. The droplet shape was photographed and the forward contact angle was calculated three times for each test solution, and the average value of the three forward contact angles was taken as the forward contact angle between the test solution and the container material. The forward contact angle was calculated in the same manner when the forward contact angle did not change in the process of expanding the droplet.

From the following formula (1), the rate of increase of the forward contact angle of each prescription example from the forward contact angle of the corresponding comparative prescription example was calculated when the same type of container material was used. The results are shown in Table 13.
Increase rate of forward contact angle (%)
= {(Advance contact angle of each prescription example / Advance contact angle of comparative prescription example) -1} × 100 ... (1)

As shown in Table 13, when polyethylene (PE) was used as the material, the forward contact angle of the aqueous pharmaceutical preparation containing the component (A) was lower than that in the case where the component (A) was not contained. On the other hand, when a container material of polyethylene terephthalate (PET) or polystyrene (PS) is used, it is quite surprising that the forward contact angle of the aqueous pharmaceutical preparation containing the component (A) does not contain the component (A). It was significantly higher than that. It was confirmed that the aqueous pharmaceutical preparation containing the component (A) had a significantly lower wettability when the liquid flowed than the PET and PS container materials. That is, when an aqueous pharmaceutical preparation containing the component (A) is contained in a PET or PS container, particularly a PET container, the liquid drainage is improved when the aqueous pharmaceutical preparation is used, and the container or the like is wetted. It was shown that the advantageous effect of suppressing the rest can be obtained. Further, in Formulation Example 7 in which the concentration of the component (A) in the aqueous pharmaceutical preparation was high, the rate of increase in the forward contact angle was even higher than in the case where the component (A) was not contained.

(Formulation example)
Examples of the preparation are given below. Each example was prepared so that the osmotic pressure ratio was 0.5 to 2.0. Formulation Examples 9 to 23 are filled in the same type of container as Example 1-1 (PET + UV blocking agent, colorless), and Formulation Examples 1 to 15 are filled, and Formulation Examples 9 to 23 are the same type of container as Example 2-1 (PET + UV blocking agent, colorless). Formulation Examples 16 to 30 and Formulation Examples 9 to 23 filled in PET + UV blocking agent + colorant, brown) in the same type of container (PEN, colorless) as in Example 5-1. 45, Formulation Examples 9 to 23 were filled in a container (PET, colorless) of the same type as Example 6-1-1 as Preparation Examples 46 to 60.

Claims (12)

A package that blocks light with a wavelength of 280 to 320 nm,
It comprises an aqueous pharmaceutical preparation containing at least one selected from the group consisting of olopatadine and a salt thereof contained in the package.
The material of the package is a polyester resin, and the package directly contains the aqueous pharmaceutical preparation (however, the aqueous pharmaceutical preparation is made from pranoprofen and a salt thereof). Excludes those containing at least one selected from the group.) . The aqueous pharmaceutical preparation containing a package according to claim 1, wherein the average light transmittance in the wavelength region of 280 to 320 nm of the package is 25% or less. A package that blocks light with a wavelength of 310 to 320 nm,
It comprises an aqueous pharmaceutical preparation containing at least one selected from the group consisting of olopatadine and a salt thereof contained in the package.
The material of the package is a polyester resin, and the package directly contains the aqueous pharmaceutical preparation (however, the aqueous pharmaceutical preparation is made from pranoprofen and a salt thereof). Excludes those containing at least one selected from the group.) . The aqueous pharmaceutical preparation containing a package according to claim 3, wherein the average light transmittance in the wavelength region of the package having a wavelength of 310 to 320 nm is 25% or less. The aqueous pharmaceutical preparation containing a package according to any one of claims 1 to 4, wherein the maximum light transmittance of the package having a wavelength of 400 to 700 nm is 60% or more. The aqueous pharmaceutical preparation containing a package according to any one of claims 1 to 5, wherein the average light transmittance in the wavelength region of the package having a wavelength of 340 to 350 nm is 30% or less. The aqueous pharmaceutical preparation in a package according to any one of claims 1 to 6, which is a composition for eye drops, eye wash, injection, external preparation for skin, nasal drops or contact lenses. The aqueous pharmaceutical preparation containing a package according to any one of claims 1 to 7, wherein the material of the package is polyethylene terephthalate. The packaged aqueous pharmaceutical preparation according to any one of claims 1 to 8, wherein the aqueous pharmaceutical preparation further contains menthol. A method for suppressing photodegradation of at least one selected from the group consisting of olopatadine and a salt thereof, which comprises at least one selected from the group consisting of olopatadine and a salt thereof. A method comprising a step of accommodating in a package that blocks light of 280 to 320 nm, the material of the package being a polyester resin, and the package directly accommodating the aqueous pharmaceutical preparation (however, the aqueous solution). Pharmaceutical formulations include those containing at least one selected from the group consisting of planoprofen and salts thereof.) The method according to claim 10, wherein the average light transmittance of the package in a wavelength region of 340 to 350 nm is 30% or less. The method according to claim 10 or 11, wherein the material of the package is polyethylene terephthalate.

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