JP7136864B2 - Packaged aqueous pharmaceutical preparation - Google Patents

Description

TECHNICAL FIELD The present invention relates to a packaged aqueous pharmaceutical preparation.

Olopatadine has anti-allergic and antihistamine activity, 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 be degraded over time during storage due to excipients, disintegrants, binders, lubricants and other additives that are often used in the manufacture of pharmaceutical formulations for oral administration. (
Patent document 2), formulation design aiming at stabilization of olopatadine is studied (patent document 3).

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

Japanese translation of PCT publication No. 2004-536096 Japanese Patent No. 3828247 Japanese Patent Publication No. 2011-105694 Japanese Patent Application Publication No. 2011-20960

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

As a result of intensive studies aimed at solving the above problems, the inventors of the present invention have found that the decomposition of olopatadine by light can be suppressed by blocking light with a wavelength of 280 to 320 nm. The present invention has been completed through further studies based on such findings.

That is, the present invention consists of a package that blocks light with a wavelength of 280 to 320 nm, and an aqueous pharmaceutical formulation containing at least one selected from the group consisting of olopatadine and salts thereof, contained in the package. provides packaged aqueous pharmaceutical formulations.

The packaged aqueous pharmaceutical formulation can suppress the degradation of olopatadine by light.

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

The present invention also comprises a package that blocks light with a wavelength of 310 to 320 nm, and an aqueous pharmaceutical formulation containing at least one selected from the group consisting of olopatadine and salts thereof, contained in the package. A packaged aqueous pharmaceutical formulation is provided. The packaged aqueous pharmaceutical formulation can suppress the degradation of olopatadine by light.

It is preferable that the packaged aqueous pharmaceutical preparation has an average light transmittance of 25% or less in the wavelength range of 310 to 320 nm. The average light transmittance of the wavelength region in the above range is 25%
Decomposition of olopatadine can be efficiently and reliably suppressed by the following.

The package preferably has a maximum light transmittance of 60% or more at a wavelength of 400 to 700 nm. 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 viewed.

The packaged aqueous pharmaceutical formulation can be an eye drop, an eye wash, an injection, an external skin preparation, a nose drop, or a contact lens composition.

The material of the package is preferably a polyester-based resin. Moreover, it is more preferable that the material of the package is polyethylene terephthalate.

The present invention also provides a method for suppressing photodegradation of at least one selected from the group consisting of olopatadine and salts thereof, wherein an aqueous pharmaceutical preparation containing olopatadine or a salt thereof is treated at a wavelength of 280 to 320 nm. A method is provided that includes encasing in a light-blocking package. The method of the present invention can inhibit photodegradation of olopatadine.

The present invention also provides a method for improving drainage of an aqueous pharmaceutical preparation containing at least one selected from the group consisting of olopatadine and salts thereof, wherein the aqueous pharmaceutical preparation is made of a polyester resin or a styrene resin. A method is provided that includes the step of housing in a resin package. The wettability between the aqueous pharmaceutical preparation and the package is reduced by using the above type of material for the package,
It is possible to improve liquid drain during use and/or storage.

ADVANTAGE OF THE INVENTION According to this invention, the photodecomposition of olopatadine caused by light exposure can be suppressed remarkably, and the storage stability of the aqueous pharmaceutical formulation containing olopatadine can be improved.

4 is a graph showing the degree of coloring in Test Example 4. FIG.

The present invention will be described in detail below. As used herein, the term "aqueous pharmaceutical formulation (or aqueous pharmaceutical composition)" means that the formulation (or composition) contains water at least 5% by mass, preferably 20% by mass or more, more preferably 50% by mass or more, and particularly preferably is 90% or more, most preferably 95%
or more.

As used herein, the abbreviation "POE" means polyoxyethylene and the abbreviation "POP" means polyoxypropylene.

The packaged aqueous pharmaceutical formulation according to one embodiment of the present invention is a package that blocks light with a wavelength of 280 to 320 nm, and at least one selected from the group consisting of olopatadine and salts thereof contained in the package. (hereinafter also referred to as "component (A)"). (A) an aqueous pharmaceutical preparation containing component at a wavelength of 280 to 320 nm
By storing in a light-blocking package, photodegradation of olopatadine in the aqueous pharmaceutical formulation can be suppressed, and coloring or discoloration and precipitation of the aqueous pharmaceutical formulation can be suppressed.

Olopatadine has the chemical name (Z)-11-(3-dimethylaminopropylidene)-6,
11-dihydrodibenzo[b,e]-oxepine-2-acetic acid is a known compound. Olopatadine may be synthesized by a known method, and can also be obtained as a commercial product.

Salts of olopatadine are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. Such salts include, for example, salts with inorganic acids (e.g., hydrochloride, bromate, sulfate, phosphate, sodium-orthophosphate, potassium hydrogen sulfate, etc.), salts with organic acids ( Acetate, glycolate, lactate, pyruvate, malonate, succinate, glutarate, fumarate, malate, tartrate, citrate, ascorbate, maleate , hydroxymaleate, benzoate, hydroxybenzoate, phenylacetate, cinnamate, salicylate, 2-phenoxybenzoate, etc.).

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

The content of component (A) in the aqueous pharmaceutical preparation according to this embodiment is not particularly limited, and (A)
The type of ingredients, the shape of the container in which the aqueous pharmaceutical preparation is accommodated, the use of the aqueous pharmaceutical preparation, the formulation form,
It is appropriately set according to the method of use and the like. The content of component (A) is, for example, based on the total amount of the aqueous pharmaceutical preparation according to the present embodiment, and the total content of component (A) is 0.002 to 1 w/
v%, more preferably 0.005 to 0.8 w/v%, 0
. 005 to 0.5 w/v%, even more preferably 0.01 to 0.22 w/v%, particularly preferably 0.01 to 0.2 w/v%, 0.
02 to 0.11 w/v% is most preferred. From the viewpoint of the effect of suppressing the photodegradation of olopatadine in the aqueous pharmaceutical formulation, it is preferable to set the content of the component (A) within the above range.

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

As compounds that impart photostability to olopatadine, (B) bromfenac and salts thereof,
At least one selected from the group consisting of berberine and its salts, allantoins, and zinc and zinc compounds can be exemplified.

Bromfenac is a known compound also called 2-amino-3-(4-bromobenzoyl)phenylacetic acid, and may be synthesized by a known method or commercially available.

The salt of bromfenac is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. Such salts include organic acid salts (e.g., monocarboxylic acid salts [acetate, trifluoroacetate, butyric acid salt, palmitate, stearate, etc.], polycarboxylic acid salts [fumarate, maleic acid acid, succinate, malonate, etc.], oxycarboxylate [lactate, tartrate, citrate, etc.], organic sulfonate [methanesulfonate, toluenesulfonate, tosylate, etc.] etc.), inorganic acid salts (e.g., hydrochlorides, sulfates, nitrates, hydrobromides, phosphates, etc.), salts with organic bases (e.g., methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, salts with organic amines such as picoline, etc.), salts with inorganic bases (e.g., ammonium salts; alkali metals [sodium, potassium, etc.], alkaline earth metals [calcium, magnesium, etc.], metals such as aluminum and the like), and various salts such as

These bromfenac and salts thereof may be used singly or in any combination of two or more. Bromfenac or its salts include their solvates (
For example, hydrates) forms are also included. Examples of solvate forms include, but are not limited to, hemihydrate, monohydrate, and trihydrate. 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 suppressing photodegradation of olopatadine in an aqueous pharmaceutical preparation, bromfenac or an alkali metal salt thereof, or Solvates thereof are more preferred, bromfenac sodium, or hydrates thereof are even 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 commercially available.

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

These berberines and salts thereof may be used singly or in any combination of two or more. Berberine or its salts include solvates thereof (e.g.
hydrate) forms are also included. Berberine sulfate or berberine chloride is preferable as berberine and/or a salt thereof, and berberine sulfate is more preferable, from the viewpoint of further suppressing photodegradation of olopatadine in an aqueous pharmaceutical preparation.

Allantoin is a known compound also called 5-ureidohydantoin. Allantoins include allantoin or salts thereof, or allantoin derivatives or salts thereof.

Allantoins are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. Specific examples of allantoins include allantoin, allantoin dihydroxyaluminum, allantoin chlorohydroxyaluminum, allantoin glycyrrhetin, allantoin acetyl-DL-methionine, allantoin-
DL-pantothenyl alcohol, allantoin polygalacturonic acid, and the like.

These allantoins may be used singly or in any combination of two or more. From the viewpoint of further suppressing the photodegradation of olopatadine in the aqueous pharmaceutical preparation, the allantoins are preferably allantoin, allantoindihydroxyaluminum, or allantoinchlorohydroxyaluminum, and more preferably allantoin.

Zinc or a zinc compound is an element or compound containing at least one zinc atom, and can be used in any form such as zinc, inorganic zinc salts, organic zinc salts, 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 para-aminobenzoate, zinc para-dimethylaminobenzoate, zinc para-phenolsulfonate, zinc para-methoxycinnamate, 2-mercaptopyridine Zinc N-oxide, zinc picrate, zinc aspartate, zinc naphthenate, zinc salicylate, zinc phenolsulfonate, zinc sebacate, zinc sodium tripolyphosphate, zinc stearate, zinc caprate, zinc laurate, zinc myristate, Zinc palmitate, zinc oleate, zinc polyphosphonate, zinc chondroitin sulfate, zinc undecylenate, zinc ascorbate, zinc pyrithione, zinc hinokitiol, zinc dipicolinate, zinc glycerolate complex, zinc bishistidine complex, zinc-3,4-dihydroxybenzoate acid complexes, hydrates thereof, and the like.

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

The content of component (B) in the aqueous pharmaceutical preparation according to the present embodiment is not particularly limited, and (B)
type of component, type and content of component (A) to be used in combination, use of the aqueous pharmaceutical formulation, formulation form,
It is appropriately set according to the method of use and the like. As the content of component (B), for example, the total content of component (B) is 0.0001 to 5 w based on the total amount of the aqueous pharmaceutical preparation according to the present embodiment.
/v%, more preferably 0.0002 to 3 w/v%, 0
. 0005 to 1 w/v%, and particularly preferably 0.001 to 0.5 w/v%.

The content of bromfenac and/or a salt thereof is, for example, based on the total amount of the aqueous pharmaceutical preparation according to the present embodiment, and the total content of bromfenac and/or a salt thereof is 0.000.
It is preferably 5 to 1 w/v%, more preferably 0.001 to 0.5 w/v%, even more preferably 0.005 to 0.2 w/v%.

As the content of berberine and/or salts thereof, for example, the total content of berberine and/or salts thereof based on the total amount of the aqueous pharmaceutical preparation according to the present embodiment is 0.0001-0.
It is preferably 1 w/v %, more preferably 0.0005 to 0.05 w/v %, even more preferably 0.001 to 0.025 w/v %.

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

As the content of zinc and/or zinc compounds, for example, based on the total amount of the aqueous pharmaceutical preparation according to the present embodiment, the total content of zinc and/or zinc compounds is 0.0001 to 1 w/v.
%, more preferably 0.0002 to 0.7 w/v%, 0
. 001 to 0.5 w/v%, and even more preferably 0.01 to 0.25 w/v%.

From the viewpoint of further suppressing the photodegradation of olopatadine in aqueous pharmaceutical formulations, (B
) is preferably within the above range.

In addition, the content ratio of component (B) to component (A) in the aqueous pharmaceutical preparation according to the present embodiment is not particularly limited, and the types of components (A) and (B), the use of the aqueous pharmaceutical preparation, the formulation It is appropriately set according to the form, method of use, 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, even more preferably 0.005 to 100 parts by mass, and 0.01 to 50 parts by mass Part is particularly preferred.

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

The content ratio of bromfenac and/or its salt to component (A) is, for example, bromfenac and/or The total salt content is preferably 0.0005 to 500 parts by mass, more preferably 0.002 to 100 parts by mass, even more preferably 0.01 to 20 parts by mass, and 0.01 to 20 parts by mass. 05 to 10 parts by mass is particularly preferred.

The content ratio of berberine and/or a salt thereof to component (A) is, for example, berberine and/or its salt per part by mass of the total content of component (A) contained in the aqueous pharmaceutical preparation according to the present embodiment The total salt content is preferably 0.0001 to 50 parts by mass, and 0.0001 to 50 parts by mass.
0005 to 10 parts by mass, more preferably 0.002 to 5 parts by mass, and particularly preferably 0.01 to 1 part by mass.

As 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 0.001 to 500 parts by mass, more preferably 0.005 to 100 parts by mass, even more preferably 0.02 to 50 parts by mass, and 0.1 to 15 parts by mass.
Parts by mass are 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 pharmaceutical preparation according to the present embodiment. The total content of the compounds is preferably 0.0001 to 500 parts by mass, and 0.0
005 to 100 parts by mass, more preferably 0.001 to 50 parts by mass, even more preferably 0.002 to 50 parts by mass, and 0.1 to 10 parts by mass is particularly preferred.

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

The aqueous pharmaceutical preparation according to the present embodiment preferably further contains a terpenoid from the viewpoint of exhibiting the effects of the present application more significantly. The terpenoid used in the aqueous pharmaceutical preparation according to this embodiment is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. Examples of terpenoids used in the aqueous pharmaceutical preparation according to this embodiment include:
menthol, menthone, camphor, borneol, geraniol, cineol, citronellol, carvone, anethole, eugenol, limonene, linalool, linalyl acetate,
These derivatives and the like can be used. These compounds may be any of d-, l- and dl-isomers. Moreover, in the aqueous pharmaceutical formulation 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, and camphor oil.

These terpenoids may be used singly or in any combination of two or more. From the viewpoint of suppressing the photodegradation of olopatadine, the terpenoids are preferably menthol, menthone, camphor, borneol and geraniol, more preferably menthol, camphor and borneol, still more preferably menthol and camphor, l-menthol and dl-menthol. and menthol are even more preferred.

The content of terpenoids in the aqueous pharmaceutical preparation according to the present embodiment is not particularly limited, and the types and contents of the components (A) and (B) used in combination, the application of the aqueous pharmaceutical preparation, the formulation form,
It is appropriately set according to the method of use and the like. As the content of terpenoids, for example, based on the total amount of the aqueous pharmaceutical preparation according to the present embodiment, the total content of terpenoids is 0.0001 to 0.2.
It is preferably w/v%, more preferably 0.0005 to 0.1 w/v%, even more preferably 0.001 to 0.08w/v%. When using essential oils containing terpenoids, the amount of terpenoids in the essential oils contained in the aqueous pharmaceutical formulation can be set to satisfy the above content. From the viewpoint of suppressing the photodegradation of olopatadine, the content of the terpenoid can be within the above range.

The aqueous pharmaceutical formulation according to this embodiment can further contain a buffer. This will
The pH of the aqueous pharmaceutical formulation can be adjusted. The buffering agent is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. Examples of such buffers include borate buffers, phosphate buffers, carbonate buffers, citrate buffers, acetate buffers, Tris buffers, aspartic acid, aspartate, epsilon-aminocaproic acid, and the like. be done. These buffering agents may be used singly or in any combination of two or more. Examples of the borate buffer include boric acid and borates such as alkali metal borates and alkaline earth metal borates. Phosphate buffers include phosphoric acid and phosphates such as alkali metal phosphates and alkaline earth metal phosphates. Carbonic acid buffers include carbonic acid and carbonates such as alkali metal carbonates and alkaline earth metal carbonates. Citric acid buffers include citric acid, alkali metal citrate salts, alkaline earth metal citrate salts, and the like. Tris buffers include trishydroxymethylaminomethane (trometamol) and the like. Borate or phosphate hydrates may also be used as the borate buffer or phosphate buffer. More specific examples include boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.) as a borate buffer; Salts (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); or salts thereof (sodium hydrogen carbonate, sodium carbonate, ammonium carbonate,
potassium carbonate, calcium carbonate, potassium hydrogen carbonate, magnesium carbonate, etc.); citric acid or its salts as a citric acid buffer (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.) ); as an acetate buffer,
Acetic acid or salts thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.); aspartic acid or salts thereof (sodium aspartate, magnesium aspartate, potassium aspartate, etc.); Among these buffers, borate buffers, phosphate buffers, and Tris buffers are preferred, and borate buffers (e.g., a combination of boric acid and borax), phosphate buffers (e.g., hydrogen phosphate disodium and sodium dihydrogen phosphate) are particularly preferred, with borate buffers being most preferred.

When a buffering agent is added to the aqueous pharmaceutical preparation according to the present embodiment, the content thereof includes the type of the buffering agent, the type and content of other ingredients, the application of the aqueous pharmaceutical preparation, the formulation form, the method of use, etc. is set as appropriate. As the content of the buffer, for example, based on the total amount of the aqueous pharmaceutical preparation according to the present embodiment, the total content of the buffer is preferably 0.01 to 15 w / v%, and 0.05 It is more preferably 10 w/v%, still more preferably 0.1-7.5 w/v%, particularly preferably 0.5-5 w/v%, and 0.5-2. 5
w/v % is most preferred.

The pH of the aqueous pharmaceutical formulation according to this embodiment is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable range. As the pH of the aqueous pharmaceutical formulation,
For example, it is preferably 4.0 to 9.5, more preferably 5.0 to 9.0, even more preferably 5.5 to 8.5, and 6.5 to 8.0. is particularly preferred, and 6.8 to 7.8 is most preferred. The pH may be 6.0-8.0.

In addition, the osmotic pressure of the aqueous pharmaceutical preparation according to this embodiment is not particularly limited as long as it is within a range that is tolerated by living organisms. The osmotic pressure ratio of the aqueous pharmaceutical formulation is, for example, 0.5 to 5.0
is preferably 0.6 to 3.0, more preferably 0.7 to 2.0, and particularly preferably 0.9 to 1.55. Osmotic pressure adjustment
It can be carried out by methods known in the art using inorganic salts, polyhydric alcohols, sugar alcohols, sugars and the like. The osmotic pressure ratio is 286 mOsm (0.9
The osmotic pressure is the ratio of the osmotic pressure of the sample to the osmotic pressure of w/v % sodium chloride aqueous solution), and the osmotic pressure is measured with reference to the osmotic pressure measurement method (freezing point depression method) described in the Japanese Pharmacopoeia. In addition, for 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 to 650 ° C. for 40 to 50 minutes, in a desiccator (silica gel) Allow to cool, accurately weigh 0.900 g, dissolve in purified water to prepare exactly 100 mL, or use a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution). .

The viscosity of the aqueous pharmaceutical preparation according to this embodiment is not particularly limited as long as it is within the range acceptable to living organisms. Rotational viscometer (RE550 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1 ° 34
The viscosity at 25 ° C. measured by 'xR24) is, for example, 0.01 to 1000 mPa s
is preferably 0.05 to 100 mPa s, more preferably 0.1
More preferably, it is up to 10 mPa·s.

In addition, the aqueous pharmaceutical preparation according to the present embodiment may contain various pharmacologically active ingredients or physiologically active ingredients in combination in appropriate amounts in addition to the above ingredients, as long as the effects of the present invention are not impaired. The types of such ingredients are not particularly limited, and examples thereof include active ingredients in various drugs described in the 2012 version of the Standards for Approval for Manufacturing and Marketing of OTC Drugs (supervised by the Japanese Society of Regulatory Science). Specifically, the components used in ophthalmic drugs include the following components.

Antihistamines or antiallergic agents: for example, ketotifen, iproheptine, diphenhydramine, chlorpheniramine maleate, pemirolast potassium, sodium cromoglycate, tranilast and the like.

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

Ocular muscle modulating agents: For example, cholinesterase inhibitors having an active center similar to that of acetylcholine, specifically neostigmine methyl sulfate, tropicamide, atropine helenien sulfate, and the like.

Bactericides: for example acrinol, cetylpyridinium, benzalkonium, benzethonium, chlorhexidine, polyhexamethylenebiguanide 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-potassium aspartate (equal mixture), aminoethylsulfonic acid and the like.

Antiphlogistic 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.

Others: For example, sodium hyaluronate, sulfamethoxazole, indomethacin, ibuprofen, ibuprofen piconol, bufexamac, butyl flufenamate, bendazac, piroxicam, ketoprofen, felbinac, purple root, horse chestnut, and salts thereof.

In addition, in the aqueous pharmaceutical preparation according to the present embodiment, various additives are appropriately selected according to the conventional method according to the application and formulation form, as long as the effects of the invention are not impaired. The above may be used in combination and contained in an appropriate amount. Examples of these additives include various additives described in the Encyclopedia of Pharmaceutical Excipients 2007 (edited by the Japan Pharmaceutical Excipients Association). Typical ingredients include the following additives.

Carrier: For example, 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 are D
Any of isomers, L isomers and DL isomers may be used.

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 parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide, etc.),
Glowkill (manufactured by Rhodia, product name), etc.

Stabilizers: for example trometamol, sodium formaldehyde sulfoxylate (Rongalite), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, glyceryl monostearate, dibutylhydroxytoluene and the like.

Surfactants: e.g. POE(20) sorbitan monolaurate (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) hydrogenated castor oil (
POE hydrogenated castor oils such as polyoxyethylene hydrogenated castor oil 40) and POE (60) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 60); POE castor oils such as POE castor oil 10 and POE castor oil 35; POE (9 ) POE alkyl ethers such as lauryl ether;
POE-POP alkyl ethers such as POE(20)POP(4) cetyl ether; PO
E(196) POP(67) glycol (Poloxamer 407, Pluronic F127)
POE-POP block copolymers such as POE(200)POP(70) glycol;
Nonionic surfactants such as polyethylene glycol monostearate such as polyoxyl 40 stearate (In the compounds exemplified above, the numbers in parentheses indicate the number of added moles.)
, Alkyldiaminoethylglycine or salts thereof (e.g., hydrochloride), etc., amphoteric surfactants, benzalkonium chloride, benzethonium chloride, etc., cationic surfactants, alkylbenzenesulfonates, alkylsulfates, polyoxyethylene Anionic surfactants such as alkyl sulfates, α-sulfo fatty acid ester salts, α-olefinsulfonic acids, and the like.

Thickening agents: for example, polyvinyl alcohol (fully or partially saponified), polyvinylpyrrolidone (K25, K30, K90, etc.), carboxyvinyl polymer, polyoxyethylene-
Polyoxypropylene block copolymer (BASF Wyandotte Copro
ration, Pluronic, Tetronic, etc.), cellulose derivatives (methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose [2208, 2906, 2910, etc.], carboxymethylcellulose, carboxyethylcellulose, nitrocellulose or salts thereof, etc.),
Polyethylene glycol (Macrogol 300, Macrogol 400, Macrogol 15
00, Macrogol 4000, Macrogol 6000, etc.), sodium chondroitin sulfate, gum arabic, tragacanth, dextran (40, 70, etc.), alginic acid, sodium alginate, glucose, sorbitol and the like.

Tonicity 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 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 pharmaceutical formulation according to the present embodiment is prepared by adding the above component (A), optionally component (B), and other ingredients to a carrier to achieve a desired concentration. For example, ophthalmic preparations can be prepared by dissolving or suspending the above-mentioned components in purified water, adjusting the pH and osmotic pressure to a predetermined level, and sterilizing by filtration or the like. When a highly hydrophobic component is blended, it may be mixed in advance with a component having a dissolution-assisting action such as a surfactant, and then purified water may be added to dissolve or suspend.

(package)
The container for containing the above aqueous pharmaceutical preparation will be described below. The container has a wavelength of 280-3
It is a package that blocks light of 20 nm.

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

In the case of a packaged aqueous pharmaceutical formulation having a secondary package, at least one of the primary package and the secondary package should block the light beam. From the viewpoint of suppressing the decomposition of olopatadine in the package not only during distribution and storage but also during use, it is desirable that the primary package block the light.

The form of the package is not particularly limited as long as it can accommodate the aqueous pharmaceutical preparation, and can be appropriately selected according to the form and application of the aqueous pharmaceutical preparation to be accommodated, primary packaging or secondary packaging, and the like. . Examples of the form of the package include tube-shaped containers, bottle-shaped containers, eye drop containers, etc. as primary packages, and pillows, packaging bags, etc. as secondary packages.

For pharmaceutical formulations such as eye drops, eye washes, and injections, foreign matter confirmation tests are stipulated in the Pharmaceutical Affairs Law (Japanese Pharmacopoeia) as part of quality control. ). In addition, it can be said that a package (container) having transparency to the extent that the inside can be observed with the naked eye is desirable for users to confirm the remaining amount. Therefore, from the viewpoint of a foreign matter confirmation test in quality control, the package is preferably a package having internal visibility (transparency) to the extent that the inside can be observed with the naked eye. Internal visibility (transparency)
is particularly suitable for eye drops, eye washes, injections, etc., for which a foreign matter confirmation test is regulated under the Pharmaceutical Affairs Law (in the Japanese Pharmacopoeia) in quality control. On the other hand, also from the viewpoint of confirming the remaining 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 with a wavelength of 400 to 700 nm (hereinafter also referred to as "maximum light transmittance") is 60%. that's all,
An example of a package is preferably 70% or more, more preferably 80% or more, and particularly preferably 90% or more. In addition, 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 with a wavelength of 400 to 700 nm is, for example,
It can be obtained from each light transmittance obtained by measuring the light transmittance every 10 nm between wavelengths of 400 to 700 nm.

In the present embodiment, when the package is a package having visibility, the formulation in the package can be visually recognized as long as the above internal visibility (transparency) is ensured in at least a part of the package. Therefore, the internal visibility (transparency) of the package does not necessarily have to be ensured over the entire surface of the package. For example, when the aqueous pharmaceutical formulation to be accommodated is an eye drop or an injection, the container (packaging body) is required from the viewpoint of implementing the general formulation rules for eye drops in the Japanese Pharmacopoeia and the insoluble foreign matter inspection method for injections. At least 20% or more, preferably 50% or more, more preferably 70% or more, still more preferably 80% or more, and particularly preferably 90% or more of the total area of is occupied by the transparent portion. Also, for example, in the distribution stage,
The package used in the present embodiment does not prevent the internal visibility (transparency) of the package from being impaired due to the label for displaying the ingredients and product name on the surface of the package. In the package, it is desirable that a portion having internal visibility (transparency) is secured to such an extent that the user can confirm the amount of the preparation inside the package. Moreover, when the packaged formulation is packaged in two or more layers, it is preferable that all the packages have the above transparency.

In the present invention, blocking light with a wavelength of 280 to 320 nm means, for example,
It means that the average light transmittance over the entire range of up to 320 nm (hereinafter also referred to as "average light transmittance") is 25% or less. Here, the light transmittance in the wavelength region of 280 to 320 nm is 4
As in the case of the maximum light transmittance in the visible light region of 00 to 700 nm, it can be measured according to the method specified in the examples of the present application. In addition, the average light transmittance in the wavelength region of 280 to 320 nm, for example, measures the light transmittance every 10 nm between 280 and 320 nm, and calculates the average value from each light transmittance obtained. can be obtained by

From the viewpoint of more effectively suppressing the photodegradation of olopatadine, the package 28
The average light transmittance in the wavelength region of 0 to 320 nm is preferably 25% or less, more preferably 2
0% or less, more preferably 10% or less, particularly preferably 5% or less, even more preferably 2
% or less, most preferably 1% or less.

In order to make the aqueous pharmaceutical formulation containing component (A) even more effective in inhibiting photodegradation, it is desirable that the package can block light with a wavelength of 300 to 320 nm. That is, the average light transmittance at a wavelength of 300 to 320 nm (average light transmittance) is preferably 35% or less, more preferably 30% or less, still more preferably 20% or less, still more preferably 10% or less, and particularly preferably is 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 a wavelength of 280 to 320 nm.

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

In this way, the package blocks light with a wavelength of 280 to 320 nm (preferably 300 to 320 nm, more preferably 310 to 320 nm) and prevents light in this wavelength region from penetrating into the container, It is possible to suppress photodegradation of olopatadine in the package.

A packaged aqueous pharmaceutical formulation according to another embodiment of the present invention comprises a package that blocks light with a wavelength of 310 to 320 nm, and an aqueous pharmaceutical formulation containing component (A) contained in the package. It will be. (A) By housing the aqueous pharmaceutical formulation containing the component in a package that blocks light with a wavelength of 310 to 320 nm, it is possible to suppress the photodegradation of olopatadine in the aqueous pharmaceutical formulation. Coloring or discoloration and precipitation can be suppressed. The type of olopatadine or a salt thereof used in this embodiment, the content ratio in the aqueous pharmaceutical preparation, other ingredients blended in the aqueous pharmaceutical preparation, the form of the aqueous pharmaceutical preparation, the package, etc., are the light rays blocked by the package. Aspects similar to those detailed above can be applied, except for the wavelength of .

(A) In order to provide an aqueous pharmaceutical preparation containing component (A) with even more excellent photodegradation inhibiting effect, the package should block light with a wavelength of 280 to 320 nm and have a wavelength of 310 to 32 nm.
It is desirable to block 0 nm light. 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, or 5%. 2% or less, 1% or less, and the average light transmittance in the entire wavelength range 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, 2% or less, or 1% or less.

(A) In order to provide an aqueous pharmaceutical preparation containing component (A) with even more excellent photodegradation inhibitory action of olopatadine, the package should have a wavelength of 280 to 320 nm (preferably 300 to 32 nm).
0 nm, more preferably 310 to 320 nm), and in addition, it is preferable that it can also block light with a wavelength of 340 nm to 350 nm. That is, the package has a wavelength of 280 to 320 nm (preferably 300 to 320 nm, more preferably 310 nm).
320 nm), and the average light transmittance at a wavelength of 340 to 350 nm (average light transmittance) is preferably 40% or less, more preferably 30% or less, and still more preferably 10% or less. More preferably, it is 5% or less, and most preferably 1% or less. Here, regarding the method for measuring the average light transmittance at a wavelength of 340 to 350 nm,
It is the same as the method for measuring the average light transmittance from 280 to 320 nm.

As described above, the means for blocking light with a wavelength of 280 to 320 nm is not particularly limited. Examples include a method of applying a substance that blocks light with a wavelength of 280 to 320 nm, and a method of attaching a film kneaded with a substance that blocks light with a wavelength of 280 to 320 nm to the package. or in combination of two or more. As a method for attaching the film to the container, specifically, the package is covered with a heat-shrinkable film (shrink film) that blocks light with a wavelength of 280 to 320 nm, and the film is attached to the package by heating. A method of close contact coating can be exemplified. Wavelength 340-35
Other means for blocking light such as 0 nm are the same as the above method except that the wavelength to be blocked corresponds to the target wavelength in the above method.

The material of the package used in this embodiment is not limited, and may be glass, plastic, cellulose, pulp, rubber, or the like. A plastic packaging body is preferable from the viewpoint of exhibiting the effects of the present application more remarkably, and from the viewpoint of squeezability and durability.

Thermoplastic resins are preferable as the resin used in the plastic package used in the present embodiment, and examples include olefin resins (polyethylene, polypropylene, etc.), polyester resins, polyphenylene ether resins, polycarbonate resins, polysulfone. -based resin, polyamide-based resin, rigid vinyl chloride resin, styrene-based resin (polystyrene (PS
), acrylonitrile-styrene copolymer (AS resin), etc.). Preferable resins are polyethylene, polypropylene, polyester-based resins, or polycarbonate-based resins, and more preferable resins are polyester-based resins or polycarbonate-based resins, and particularly preferable resins are polyester-based resins, since the effects of the present invention are exhibited remarkably. It is a system resin.

As the polyester-based resin, a resin obtained using a component containing a dicarboxylic acid component (such as an aromatic dicarboxylic acid component such as phthalic acid, terephthalic acid and naphthalenedicarboxylic acid) and a diol component can be used. Specifically, aromatic polyester resins, for example, polyalkylene terephthalate (polyethylene terephthalate (PET), polybutylene terephthalate (PBT) and other poly C2-4 alkylene terephthalate), polyalkylene naphthalate (polyethylene naphthalate (PEN ), poly C2-4 alkylene naphthalate such as polybutylene naphthalate, etc.), polycycloalkylene terephthalate (poly (
1,4-Cyclohexylene dimethylene terephthalate) (PCT), etc.), homopolyesters of polyarylates (resins composed of bisphenols [bisphenol-A, etc.] and phthalic acids [phthalic acid, terephthalic acid], etc.)) etc. 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 (such as a copolymer of PET and PCT), and the like. . Polycarbonate-based resins are, for example, aromatic polycarbonates based on bisphenols (such as bisphenol-A).

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

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

In addition, from the viewpoint of improving the drainage of the aqueous pharmaceutical formulation, the material of the package is preferably a polyester-based resin or a styrene-based resin, more preferably PET or PS, and further preferably PET. preferable. By using a package made of these resins, the wettability between the aqueous pharmaceutical preparation containing component (A) and the package is reduced, and during use and/or
Alternatively, it is possible to improve liquid drainage during storage and prevent liquid residue in the container of the aqueous pharmaceutical preparation.

The packaging body according to the present embodiment may be one using a material to which an ultraviolet blocking agent is added, or may be a packaging body coated with an ultraviolet blocking agent. For example, a package formed by adding an ultraviolet blocker to glass or synthetic resin and then molded, a package formed by processing synthetic resin into a sheet, coated with a UV blocker, and then molded, and glass or synthetic resin are finally used. Examples thereof include a package formed by molding into a package shape and then coated with an ultraviolet shielding agent.
Alternatively, a sheet-like synthetic resin to which an ultraviolet blocking agent is added or coated may be shrink-wrapped in a molded package.

Examples of UV blockers include zinc oxide, titanium oxide, triazole compounds, benzoate compounds, substituted acrylonitrile compounds, cyanoacrylate compounds, triazine compounds, oxalic acid anilide compounds, nickel complex compounds, and Tinuvin (trade name). Trademark) 328, Tinuvin (R) 384-2, Tinuvin (R) 400, Tinuvin (R) 400-
2, benzotriazole compounds such as Tinuvin (R) 900, Tinuvin (R) 928, Tinuvin (R) 1130; Isopropyl methoxycinnamate
Diisopropyl cinnamate mixture, 2-ethylhexyl paramethoxycinnamate, cinnamic acid UV absorbers such as benzyl cinnamate; oxybenzone, hydroxymethoxybenzophenone sulfonic acid, sodium hydroxymethoxybenzophenone sulfonate, dihydroxydimethoxybenzophenone, dihydroxy Benzophenone UV absorbers such as sodium dimethoxybenzophenonedisulfonate, dihydroxybenzophenone, tetrahydroxybenzophenone; para-aminobenzoic acid, ethyl para-aminobenzoate, glyceryl para-aminobenzoate, amyl para-dimethylaminobenzoate, 2-ethylhexyl para-dimethylaminobenzoate, Benzoic acid ester ultraviolet absorbers such as 4-[N,N-di(2-hydroxypropyl)amino]ethyl benzoate; ethylene glycol salicylate, octyl salicylate, dipropylene glycol salicylate, phenyl salicylate, homomenthyl salicylate, methyl salicylate, etc. salicylic acid-based UV absorber, guaiazulene, dimethoxybenzylidene dioxoimidazolidine 2-ethylhexylpropionate, 2,4,6-
Tris[4-(2-ethylhexyloxycarbonyl)anilino]1,3,5-triazine, parahydroxyanisole, 2-(2-hydroxy-5-methylphenyl)benzotriazole, 4-tert-butyl-4'-methoxy Dibenzoylmethane, phenylbenzimidazole sulfonic acid, 2-(4-diethylamino-2-hydroxybenzoyl)-
and hexyl benzoate. In addition, riboflavin, anthraquinone dyes (1-
amino-4-methylanthraquinone, 1,4-diaminoanthraquinone, anthraquinone yellow, etc.), phthalocyanine dyes (phthalocyanine blue (C.I. Pigme
C.nt Blue 15; I. 74160; blue No. 404), phthalocyanine green (
C. I. Pigment Green 7), etc.).

The UV blocker is preferably zinc oxide, titanium oxide, Tinuvin (registered trademark) 328, Tinuvin (R) 384-2, Tinuvin (R) 400, Tinuvin (R) 400-2, Tinuvin (R) 900, Tinuvin ( R) 928, Tinuvin (R) 1130, 2-ethylhexyl paramethoxycinnamate, glyceryl mono-2-ethylhexanoate di-paramethoxycinnamate,
2,4,6-tris[4-(2-ethylhexyloxycarbonyl)anilino]1,3,
5-triazine, phenylbenzimidazole sulfonic acid, 2-(4-diethylamino-
2-hydroxybenzoyl)-hexyl benzoate, dimethoxybenzylidene dioxoimidazolidine propionate 2-ethylhexyl, particularly preferably zinc oxide, titanium oxide, tinuvin (R) 328, tinuvin (R) 384-2, tinuvin ( R) 400, Tinuvin (R) 400-2, Tinuvin (R) 900, Tinuvin (R) 928, Tinuvin (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 blocker is added to the material constituting the package, the ratio of the added ultraviolet blocker is, for example, 0.05 to 5.0% by weight with respect to the total amount of the material.
, preferably 0.1 to 3.0% by weight. A package coated with an ultraviolet blocker is
For example, it can be produced by applying a coating paint containing an ultraviolet absorber to a molded package or a synthetic resin sheet. Here, as the coating paint, radical polymerization acrylic type (e.g., polyester polyacrylate, urethane polyacrylate, epoxy polyacrylate, polyether polyacrylate, side chain acryloyl type acrylic resin, etc.), thiolene type (e.g., polythiol acrylic type oligomer, polythiol spiroacetal type, etc.), unsaturated polyester, cationic polymerization type epoxy resin, or the like can be used. Moreover, the material constituting the package may be spread into a film, and the film may be formed by bonding and laminating a sheet.

The package according to the present embodiment may be a material (package) to which a coloring agent is added or coated. Inorganic pigments, lake pigments, organic pigments and the like can be used as colorants.

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

As described above, a package that blocks light with a wavelength of 280 to 320 nm can suppress photodegradation of olopatadine. Therefore, the present invention further provides an aqueous pharmaceutical preparation containing at least one selected from the group consisting of olopatadine and salts thereof, at a wavelength of 280-320.
Provided is at least one method for inhibiting photodegradation selected from the group consisting of olopatadine and salts thereof, comprising the step of housing in a package that blocks nm light rays. Further, the present invention comprises the step of housing an aqueous pharmaceutical preparation containing at least one selected from the group consisting of olopatadine and salts thereof in a package that blocks light with a wavelength of 310 to 320 nm. At least one method for inhibiting photodegradation selected from the group consisting of

In the above method, the type of olopatadine or its salt to be used, the content ratio in the aqueous pharmaceutical preparation, other ingredients blended in the aqueous pharmaceutical preparation, the form of the aqueous pharmaceutical preparation, the wavelength of 280 to 320 nm
The same aspects as those described in detail with respect to the aqueous pharmaceutical preparation in the package can be applied to the package or the like that blocks light such as the above.

The present invention also provides a method for improving drainage of an aqueous pharmaceutical preparation containing at least one selected from the group consisting of olopatadine and salts thereof, wherein the aqueous pharmaceutical preparation is made of a styrene resin or a polyester resin. to provide a method comprising the step of housing in a package that is (A
) By using a package whose material is the above type as a container for containing the aqueous pharmaceutical preparation containing the ingredients, the wettability between the aqueous pharmaceutical preparation and the package is reduced, and the liquid draining during use is improved, Liquid residue in the container of the aqueous pharmaceutical formulation can be reduced. Excellent liquid drainage is particularly useful in ophthalmic compositions, especially eye drops, in which the amount used at one time is small. The details of the styrene-based resin or polyester-based resin are the same as those described in detail with respect to the packaged aqueous pharmaceutical preparation. Moreover, in the above method, by increasing the content of the component (A), it is possible to further improve the drainage during use.

The aqueous pharmaceutical formulation according to the present embodiment can be used as a formulation for pharmaceuticals, quasi-drugs, and the like, and can be used, for example, as an ophthalmic pharmaceutical formulation or an otolaryngological pharmaceutical formulation. Ophthalmic pharmaceutical preparations include, for example, eye drops (also referred to as eye drops or eye drops. Eye drops include eye drops that can be applied to the eye while wearing contact lenses.), artificial tears, and eye washes (eye wash solutions). In addition, eye washes include eye washes that can be washed while wearing contact lenses.), ophthalmic compositions such as eye ointments; care compositions [contact lens disinfectants, contact lens preservatives, contact lens cleaning agents, contact lens cleaning preservatives], etc.). The above contact lens composition can be applied to all contact lenses including hard contact lenses and soft contact lenses. Otorhinolaryngological pharmaceutical preparations include, for example, nasal drops, nasal washes, and the like.

The above-mentioned aqueous pharmaceutical formulations may be injections, suppositories, oral drugs, formulations for inhalation, etc., or may be topically applied aqueous pharmaceutical formulations that are likely to be exposed to light when applied to patients. In addition, it is an aqueous pharmaceutical preparation that is applied not only to the skin but also to sensitive mucous membranes (ocular mucosa such as cornea and conjunctiva, gums, tongue, lips, oral mucosa, nasal mucosa, pharyngeal mucosa, etc.). good too.
For example, examples of the above-mentioned aqueous pharmaceutical formulations include skin external preparations (epidermal ointments, dermal creams, dermal liquid preparations, etc.), eye drops (eye drops), eye washes (eye wash), eye ointments, and contact lens-wearing solutions. , contact lens agents (cleaning solution, storage solution, antiseptic solution, multi-purpose solution, etc.), nasal drops (nasal drops), nasal cleaning solutions, oropharyngeal drugs, mouthwashes, ear drops, etc. As used herein, contact lenses include all types of contact lenses such as hard contact lenses (including oxygen-permeable hard contact lenses) and soft contact lenses. Among these, preferably eye drops (eye drops), eye wash (eye wash)
, injections, external skin preparations, nasal drops and contact lens preparations.

In particular, when the package is a package with visibility, it is possible to inspect the presence or absence of foreign substances by observing the pharmaceutical preparation in the container with the naked eye from the outside. In view of the effect of the present invention that the insoluble foreign matter inspection method for injections can be suitably performed, preferred pharmaceutical formulations include, for example, eye drops, eye washes, injections, and the like. In addition, a formulation containing multiple doses is preferable because the user can visually check the remaining amount of the formulation after each use. Specific examples of formulations containing multiple doses include eye drops, eye washes, external skin preparations, nasal drops, and contact lens preparations.
When the package is a package having visibility, eye drops and eye washes are particularly preferred for the above reasons.

EXAMPLES The present invention will be described in detail below based on examples, but the present invention is not limited to these.

[Test Example 1-1: Photodegradation inhibition confirmation test of olopatadine]
An aqueous pharmaceutical formulation containing olopatadine (eye drops) was prepared according to Formulation Example 1 shown in Table 1, and
5 mL each was placed in various containers shown in , and sealed. The ratio of each component in the formulation examples in Table 1 is based on the total amount of the aqueous pharmaceutical preparation, and the unit is w/v%. As the container, a colorless or colored container made of polyethylene terephthalate (PET), a container made of polyethylene naphthalate (PEN),
Polycarbonate (PC) container, polyethylene (PE) container, polypropylene (PP
) or a glass container was used. A photostability tester (“Light-Tron LT-120 D3CJ
Model", manufactured by Nagano Science Co., Ltd.), a D65 fluorescent lamp is used as a light source, and 5,000 lx light is continuously irradiated for 120 hours at a room temperature of 25 ° C. The cumulative irradiation amount is 600,000 lx h.
of light. Thereafter, the concentration of olopatadine in each aqueous pharmaceutical formulation was analyzed by high performance liquid chromatography to quantify the residual concentration of olopatadine. From the measured residual concentration of olopatadine, the residual rate (%) relative to the concentration of olopatadine before light irradiation was calculated. Table 2 shows the results.

In order to evaluate the light transmittance of the container used in the test, a part of each container was cut out and used as a sample with a microplate reader ("SH-9000", manufactured by Corona Denki 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 of the container at a predetermined wavelength and the maximum transmittance at a wavelength of 400 to 700 nm were obtained. note that,
If there was a label or the like on the part to be measured that interfered with the measurement, the measurement was performed after removing it.

The internal visibility of the container used in the test was evaluated based on the following evaluation criteria. The evaluation was carried out by observing with the naked eye using a white light source at a brightness of 3000 to 5000 lx.
Table 2 shows the results.
<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 seen △ The amount of aqueous pharmaceutical preparation inside can be seen, but foreign matter is difficult to see × Inside The amount of aqueous pharmaceutical preparation and foreign matter cannot be visually recognized

Of the various containers used in the test, those with a maximum light transmittance of 60% or more at a wavelength of 400 to 700 nm were sufficiently transparent, allowing the aqueous pharmaceutical preparation contained inside to be visually recognized from the outside. .

The residual rate of olopatadine after light irradiation showed a remarkably high value for the olopatadine-containing aqueous pharmaceutical preparation housed in a container shielded from light with a wavelength of 280 to 320 nm. Wavelength 280-3
It was confirmed that even within the range of 20 nm, the lower the light transmittance, especially in the wavelength regions 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. This can also be confirmed, for example, by comparing the coefficient of determination ^R2 for the olopatadine residual rate of the average light transmittance in each wavelength range shown in Table 2 above. It was also confirmed that in a container in which light with a wavelength of 280 to 320 nm is blocked as well as light with a wavelength of 340 to 350 nm is blocked, the decomposition of olopatadine is further suppressed and is maintained stably. rice field.

From the above results, it was clarified that light rays of 280 to 320 nm are involved in the decomposition of olopatadine due to light exposure, and that blocking light in the above wavelength range can suppress the decomposition of olopatadine due to light exposure. confirmed. Furthermore, it was confirmed that when 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, good visibility of the interior can be ensured.

[Test Example 1-2: Photodegradation inhibition confirmation test of olopatadine]
Olopatadine-containing aqueous pharmaceutical preparations (eye drops) were prepared according to Formulation Examples 2 and 3 shown in Table 3, and Example 6-1-1 shown in Table 2 (colorless polyethylene terephthalate (PET) container)
and Example 7-1-1 (container made of polycarbonate (PC)), each containing 5 mL, and sealed tightly. The ratio of each component in the formulation examples in Table 3 is based on the total amount of the aqueous pharmaceutical formulation, and the unit is w/v %. The obtained aqueous pharmaceutical preparations containing olopatadine in various containers were subjected to light irradiation and post-exposure quantification of olopatadine residual concentration in the same manner as in Test Example 1-1 above, and the residual ratio ( %) was calculated. Table 4
shown in Formulation Examples 2 and 3, in which the pH was changed from Formulation Example 1, also showed a significantly high olopatadine residual rate after light irradiation by using the container of the example.

[Test Example 2 Photodegradation inhibition confirmation test of olopatadine]
Olopatadine-containing aqueous solution containing 0.11 w/v% olopatadine hydrochloride, benzalkonium chloride, anhydrous sodium monohydrogen phosphate, a pH adjuster and a tonicity agent, and having a pH of 7.0 and an osmotic pressure ratio of 0.9 to 1.1 Pharmaceutical formulation (Patanol ophthalmic solution 0.1% Manufacturing and sales agency: Alcon Japan Co., Ltd.)
, this 5 mL was housed in the same type of container as used in Example 6-1-1 and Comparative Example 3-1 shown in Table 2 and sealed, respectively Example 6-2 and Comparative Example 3- 2.

A photostability tester (“Light-Tron LT-120 D3CJ type”, manufactured by Nagano Scientific Co., Ltd.) was applied to the aqueous pharmaceutical preparations containing olopatadine in various containers thus obtained.
using a D65 fluorescent lamp as a light source at a room temperature of 25°C and 120
By continuously irradiating for a period of time, the light was exposed to an accumulated irradiation amount of 600,000 lx·h. Thereafter, the concentration of olopatadine in each aqueous pharmaceutical formulation was analyzed by high performance liquid chromatography to quantify the residual concentration of olopatadine. From the measured residual concentration of olopatadine, the residual rate (%) relative to the concentration of olopatadine before light irradiation was calculated.

Table 5 shows the results of the residual rate of olopatadine after light irradiation. Even when the compositions of the aqueous pharmaceutical preparations are different, in the olopatadine-containing aqueous pharmaceutical preparations housed in a container shielded from light with a wavelength of 280 to 320 nm, the residual rate of olopatadine after light irradiation was reduced in the same manner as in Test Example 1-1. Remarkably high values were shown.

[Test Example 3 Olopatadine Photodegradation Suppression Confirmation Test]
Aqueous pharmaceutical formulations were prepared according to the formulation examples shown in Table 6 below, and the degradation of olopatadine or its salts against light was evaluated. Specific experimental procedures and results are shown below. The ratio of each component in the formulation examples in Table 6 is based on the total amount of the aqueous pharmaceutical preparation, and the unit is w/v %.

First, each aqueous pharmaceutical formulation shown in Table 6 was prepared by a conventional method. Each aqueous pharmaceutical formulation was then 10
5 mL each was filled in a mL-capacity transparent glass vial (the same kind as the glass (colorless) container used in Comparative Example 3-1 shown in Table 2) or a 13-mL-capacity PET container. Table 7 shows the average light transmittance and maximum light transmittance of the PET container at a given wavelength. Photostability tester (“Ligh
t-Tron LT-120 D3CJ type", manufactured by Nagano Science Co., Ltd.), D65
Using a lamp as a light source, 5000 lx light is continuously irradiated at room temperature for 120 hours, and after exposing the aqueous pharmaceutical preparation to light with an accumulated irradiation dose of 600,000 lx hr, olopatadine is treated in the same manner as in Test Example 1-1. The residual concentration was quantified, and the photostability improvement rate of olopatadine was calculated according to the following formulas (I) and (II). Table 6 shows the results.
Residual rate (%) = (Olopatadine hydrochloride content after light irradiation)/(Olopatadine hydrochloride content before light irradiation) x 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, Comparative Examples 4-6 containing olopatadine and filled in glass vials
Compared to , in an aqueous pharmaceutical preparation filled in a PET container (transparent) and containing olopatadine, bromfenac sodium and berberine sulfate, the residual rate of olopatadine was improved, and the photostability of olopatadine in the aqueous pharmaceutical preparation was improved. It was confirmed that the performance was improved.

[Test Example 4: Olopatadine Coloration and Precipitation Suppression Confirmation Test]
As in Test Example 1-1, Formulation Example 1 in Table 1 is placed in the container in Table 2 (select a representative container) for 5 m
Each L was accommodated and sealed. Examples 1-1, 5-1, 6-1-1, Comparative Examples 1-1, 2-1,
Examples 1-4, 5-4, 6-4 and Comparative Examples 1-4, 2-4, 3-4 were filled in the containers used in 3-1.

Aqueous pharmaceutical formulations containing olopatadine in various containers obtained in this way were subjected to 765 W/
By irradiating with m ² for 19 hours, the light was exposed to light with an accumulated irradiation amount of 52,000 kJ/m ² . 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 using a microplate reader (“SH-9000” manufactured by Corona Denki Co., Ltd.). After that, the value obtained by subtracting the absorbance of the sample before light irradiation from the absorbance of the sample after light irradiation was calculated as the degree of coloration. The results are shown in FIG.

The color of the sample after light irradiation and the presence or absence of precipitation were visually examined, evaluated according to the following criteria, and a property score was obtained. Table 8 shows the results.
<Evaluation Criteria>
◎ Colorless, no precipitation ○ Slightly yellow, no precipitation △ Pale yellow, no precipitation × Dark yellow, no precipitation × × Dark yellow, precipitation

Regarding the color tone of the olopatadine-containing aqueous pharmaceutical preparation after light irradiation, when it was housed in a container shielded from light with a wavelength of 280 to 320 nm, there was no coloration at all, or only a slight yellow coloration. On the other hand, in the comparative example where the container was not shielded from light with a wavelength of 280 to 320 nm, the aqueous pharmaceutical preparation was observed to be colored in dark yellow and deposited.

In addition to blocking light with a wavelength of 280 to 320 nm,
It was confirmed that coloration was further suppressed in the aqueous pharmaceutical preparation housed in a container that also shielded the light of m. On the other hand, even if the light transmittance at a wavelength of 260 to 270 nm is low, the wavelength of 2
In an olopatadine-containing aqueous pharmaceutical formulation housed in a container with high light transmittance of 80 to 320 nm,
It was confirmed that the coloring and precipitation of the formulation due to light irradiation could not be suppressed.

Based on the above results, the coloration of olopatadine-containing aqueous formulations due to exposure to light has a wavelength of 280 to 3
It was found that light of 20 nm was involved, and it was confirmed that blocking the light in the above wavelength range could suppress the coloring and precipitation of the olopatadine-containing preparation due to light exposure.

[Test Example 5: Confirmation test of inhibition of photodegradation of olopatadine]
Olopatadine-containing aqueous pharmaceutical preparations (eye drops) were prepared according to Formulation Examples 4 and 5 shown in Table 9, and Example 6-1-1 shown in Table 2 (colorless polyethylene terephthalate (PET) container)
and Example 7-1-1 (container made of polycarbonate (PC)), each containing 5 mL, and sealed tightly. The ratio of each component in the formulation examples in Table 9 is based on the total amount of the aqueous pharmaceutical formulation, and the unit is w/v%. Formulation Examples 4 and 5 correspond to Formulation Examples 2 and 3, respectively, with a predetermined amount of menthol added thereto. The obtained aqueous pharmaceutical preparations containing olopatadine in various containers were subjected to light irradiation and post-exposure quantification of olopatadine residual concentration in the same manner as in Test Example 1-1 above, and the residual ratio ( %) was calculated.

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

[Test Example 6: Confirmation test for improvement of liquid shortage]
Aqueous pharmaceutical formulations containing olopatadine were prepared according to Formulation Examples 6, 7 and 8 shown in Table 11.
Aqueous pharmaceutical preparations were prepared in the same manner as in Formulation Examples 6, 7 and 8, except that neither olopatadine hydrochloride nor l-menthol was contained, and designated Comparative Formulation Examples 6', 7' and 8', respectively. The aqueous pharmaceutical formulations of Formulation Example 8 and Comparative Formulation Example 8' were stored at 70°C in 10 mL capacity glass vials.
and stored for 5 days was used in the following tests.

Using a contact angle meter DM-501 (manufactured by Kyowa Interface Science Co., Ltd.), measure the advancing contact angle, which is the contact angle when the solid-liquid interface moves, according to the measurement procedure of the expansion/contraction method of the same measurement device. did.
Specifically, each container material shown in Table 12 was placed on the stage of the contact angle meter, and the test liquid was set in the dispenser so that the combination of the formulation example and container material shown in Table 13 was obtained. A droplet of 1 μL of the test solution was dropped on the surface of the material of the container to form a hemispherical droplet. Next, the tip of the liquid ejection part of the dispenser was quickly brought into contact with the upper hemisphere. In that state, the test liquid was discharged at a speed of 2 μm.
The ink was discharged continuously at L/sec, and the shape of the droplet was photographed 15 times every 0.1 sec from the side. Comparative formulation examples corresponding to each formulation example were also continuously measured at the same room temperature using the same container material, and photographed in the same manner.

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 on the side containing the test liquid among the angles formed by the tangent line drawn to the test liquid from the contact point P of the container material surface, the test liquid and air, and the tangent line drawn to the surface of the container material. means
As the droplet spreads by ejecting the test liquid, the contact angle behaves to change and then to be almost constant. The average value of the left and right contact angles was calculated for each image, and the average values of the left and right contact angles were arranged in the order in which the images were taken. Select 5 consecutive values with a standard deviation of 2.5° at the beginning
The initial contact angle that became below was taken as the advancing contact angle in this test. Photographing of the droplet shape and calculation of the advancing contact angle were performed three times for each test liquid, and the average value of the three advancing contact angles was taken as the advancing contact angle between the test liquid and the material of the container. The advancing contact angle was calculated in the same manner when the advancing contact angle did not change in the process of droplet expansion.

Using the following formula (1), the increasing rate of the advancing contact angle of each formulation example from the advancing contact angle of the corresponding comparative formulation example was calculated when the same kind of container material was used. The results are shown in Table 13.
Increasing rate of advancing contact angle (%)
= {(advancing contact angle of each prescription example/advancing contact angle of comparative prescription example) -1} × 100 (1)

As shown in Table 13, when polyethylene (PE) was used as the material, the advancing contact angle of the aqueous pharmaceutical formulation containing component (A) was lower than when component (A) was not contained. On the other hand, when the container material of polyethylene terephthalate (PET) or polystyrene (PS) is used, quite unexpectedly, the advancing contact angle of the aqueous pharmaceutical preparation containing component (A) is was significantly higher compared to It was confirmed that the aqueous pharmaceutical formulation containing component (A) has remarkably low wettability when the liquid flows with respect to PET and PS container materials. That is, when an aqueous pharmaceutical preparation containing component (A) is contained in a container made of PET or PS, particularly PET, the drainage of the aqueous pharmaceutical preparation is improved when the aqueous pharmaceutical preparation is used, and the container or the like is wetted. It has been shown to have the beneficial effect of suppressing the remainder. Moreover, in Formulation Example 7, in which the concentration of component (A) in the aqueous pharmaceutical preparation was high, the increasing rate of the advancing contact angle was even higher than when component (A) was not contained.

(Formulation example)
Formulation Examples are given below. Each example was prepared so that the osmotic pressure ratio was between 0.5 and 2.0. Formulation Examples 9 to 23 were filled in the same container (PET + UV blocker, colorless) as in Example 1-1, Formulation Examples 1 to 15, and Formulation Examples 9 to 23 were filled in the same container as in Example 2-1 ( PET+
Formulation Examples 16 to 30 filled in UV blocking agent + coloring agent, brown), Formulation Examples 31 to 45 filled in Formulation Examples 9 to 23 in the same type of container (PEN, colorless) as in Example 5-1 , Formulation Example 9
Formulation Examples 46-
60.

Claims (12)

a package that blocks light with a wavelength of 280 to 320 nm;
an aqueous pharmaceutical formulation containing at least one selected from the group consisting of olopatadine and salts thereof, contained in the package;
The content of olopatadine or a salt thereof in the aqueous pharmaceutical preparation is 0.002 w/v% to 1 w/v%,
A packaged aqueous pharmaceutical formulation, wherein the packaging body is made of a polyester resin or a styrene resin, and the packaging body directly accommodates the aqueous pharmaceutical formulation (wherein the aqueous pharmaceutical formulation contains pranoprofen and at least one selected from the group consisting of salts thereof). The packaged aqueous pharmaceutical preparation according to claim 1, wherein the package has an average light transmittance of 25% or less in a wavelength range of 280 to 320 nm. a package that blocks light with a wavelength of 310 to 320 nm;
an aqueous pharmaceutical formulation containing at least one selected from the group consisting of olopatadine and salts thereof, contained in the package;
The content of olopatadine or a salt thereof in the aqueous pharmaceutical preparation is 0.002 w/v% to 1 w/v%,
A packaged aqueous pharmaceutical formulation, wherein the packaging body is made of a polyester resin or a styrene resin, and the packaging body directly accommodates the aqueous pharmaceutical formulation (wherein the aqueous pharmaceutical formulation contains pranoprofen and at least one selected from the group consisting of salts thereof). The packaged aqueous pharmaceutical preparation according to claim 3, wherein the package has an average light transmittance of 25% or less in a wavelength range of 310 to 320 nm. The packaged aqueous pharmaceutical preparation according to any one of claims 1 to 4, wherein the package has a maximum light transmittance of 60% or more at a wavelength of 400 to 700 nm. The packaged aqueous pharmaceutical preparation according to any one of claims 1 to 5, wherein the package has an average light transmittance of 30% or less in a wavelength range of 340 to 350 nm. The packaged aqueous pharmaceutical preparation according to any one of claims 1 to 6, which is an eye drop, eye wash, injection, external skin preparation, nose drop or contact lens composition. The packaged aqueous pharmaceutical preparation according to any one of claims 1 to 7, wherein the packaging material is polyethylene terephthalate or polystyrene. The aqueous pharmaceutical formulation according to any one of claims 1 to 8, further comprising one or more selected from bromfenac and its salts, berberine and its salts, allantoins, zinc and zinc compounds, buffers and menthol. Aqueous pharmaceutical preparation in a package as described. A method for inhibiting photodegradation of at least one selected from the group consisting of olopatadine and salts thereof, wherein an aqueous pharmaceutical preparation containing at least one selected from the group consisting of olopatadine and salts thereof is treated at a wavelength of a step of housing in a package that blocks light of 280 to 320 nm, wherein the content of olopatadine or a salt thereof in the aqueous pharmaceutical preparation is 0.002 w/v% to 1 w/v%, and the material of the package is a polyester-based resin or a styrene-based resin, and the package directly contains the aqueous pharmaceutical preparation (provided that the aqueous pharmaceutical preparation is at least selected from the group consisting of pranoprofen and its salts except those containing one species). A method for enhancing the storage stability of an aqueous pharmaceutical formulation containing at least one selected from the group consisting of olopatadine and salts thereof, wherein the aqueous pharmaceutical formulation is housed in a package that blocks light with a wavelength of 280 to 320 nm. wherein the content of olopatadine or a salt thereof in the aqueous pharmaceutical preparation is 0.002 w/v% to 1 w/v%, the material of the package is polyester resin or styrene resin, and A method in which the packaging body directly accommodates the aqueous pharmaceutical preparation (excluding those in which the aqueous pharmaceutical preparation contains at least one selected from the group consisting of pranoprofen and salts thereof). A method for improving drainage of an aqueous pharmaceutical preparation containing at least one selected from the group consisting of olopatadine and salts thereof, wherein the aqueous pharmaceutical preparation is housed in a package that blocks light with a wavelength of 280 to 320 nm. wherein the content of olopatadine or a salt thereof in the aqueous pharmaceutical preparation is 0.002 w/v% to 1 w/v%, the material of the package is polyester resin or styrene resin, and A method in which the packaging body directly accommodates the aqueous pharmaceutical preparation (excluding those in which the aqueous pharmaceutical preparation contains at least one selected from the group consisting of pranoprofen and salts thereof).

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