Aqueous pharmaceutical preparation in package

Abstract

An object of the present invention is to provide an aqueous pharmaceutical preparation capable of suppressing degradation of olopatadine by light.SOLUTION: An aqueous pharmaceutical preparation contained in a packaging body, comprising: a packaging body which blocks light rays having wavelengths of 280 to 320nm; and an aqueous pharmaceutical preparation which is contained in the packaging body and contains at least one selected from the group consisting of olopatadine and salts thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a packaged liquid medical formulation. [Background technology]

[0002] Olopatadine has antihistamine activity as well as antiallergic activity, and is effective against allergic or is used in an aqueous composition as a therapeutic agent for inflammatory disorders (Patent Document 1).

[0003] On the other hand, olopatadine is an excipient and disintegrant that are frequently used in the manufacture of pharmaceutical preparations for oral administration. It is known that additives such as binders and lubricants cause degradation over time during storage ( Patent Document 2), and formulation designs aimed at stabilizing olopatadine are being studied (Patent Document 3). .

[0004] In Patent Document 4, a solid preparation containing olopatadine is not allowed to contain crystalline cellulose. A method for improving the stability of olopatadine formulations by reducing the amount of olopatadine in the formulation has been reported. [Prior art documents] [Patent documents]

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

[0006] The present invention aims to provide an aqueous medical formulation that can suppress the decomposition of olopatadine caused by light. The present invention also provides a method for inhibiting the decomposition of olopatadine by light. The purpose is to: [Means for solving the problem]

[0007] As a result of extensive research into solving the above problems, the inventors of the present invention have found that light having a wavelength of 280 to 320 nm We found that blocking light can suppress the decomposition of olopatadine. The invention was completed through further investigation based on these findings. .

[0008] That is, the present invention provides a package that blocks light having a wavelength of 280 to 320 nm, and a A pharmaceutical composition containing at least one selected from the group consisting of olopatadine and salts thereof. and an aqueous medical formulation containing the same.

[0009] The above-mentioned packaged liquid medical formulation can suppress the decomposition of olopatadine by light. This can be done.

[0010] The packaging has an average light transmittance of 25% or less in the wavelength range of 280 to 320 nm. It is preferable that the average light transmittance in the wavelength region within the above range is 25% or less. This makes it possible to more efficiently and reliably inhibit the decomposition of olopatadine.

[0011] The present invention also provides a package that blocks light having a wavelength of 310 to 320 nm, and a an aqueous solution containing at least one selected from the group consisting of olopatadine and salts thereof; The present invention provides a liquid medical formulation packaged in a package, which comprises a pharmaceutical formulation. can inhibit decomposition of olopatadine by light.

[0012] The liquid medical formulation in the package has an average wavelength of 310 to 320 nm. It is preferable that the transmittance is 25% or less. The average light transmittance in the wavelength range above is 25%. or less, the decomposition of olopatadine can be suppressed efficiently and reliably. .

[0013] The maximum light transmittance of the package at wavelengths of 400 to 700 nm is preferably 60% or more. The maximum light transmittance of 400 to 700 nm is 60% or more, so that the inside of the package The part can be easily seen.

[0014] The above-mentioned packaged liquid medical preparations may be used as eye drops, eyewashes, injections, topical skin preparations, nasal drops or It can be a composition for contact lenses.

[0015] The material of the packaging body is preferably a polyester resin. More preferably, the material is polyethylene terephthalate.

[0016] The present invention also provides a method for treating a rheumatoid arthritis, comprising administering to a patient a therapeutically effective amount of at least one compound selected from the group consisting of olopatadine and salts thereof. A method for suppressing decomposition by light, comprising the steps of: and placing the agent in a package that blocks light with a wavelength of 280 to 320 nm. The method of the present invention can inhibit photodecomposition of olopatadine.

[0017] The present invention also provides a pharmaceutical composition comprising at least one selected from the group consisting of olopatadine and salts thereof. A method for improving drainage of an aqueous medical formulation containing a polyethylene glycol compound, The method further includes the step of packaging the product in a steric or styrene-based resin package. By using the above-mentioned type of material for the packaging body, the wettability between the aqueous medical formulation and the packaging body is reduced, This can improve the drainage during use and / or storage. [Effects of the Invention]

[0018] According to the present invention, the photodecomposition of olopatadine caused by light exposure is significantly suppressed. This makes it possible to improve the storage stability of the liquid medical formulation containing olopatadine. [Brief explanation of the drawings]

[0019] [Figure 1] 1 is a graph showing the coloring degree in Test Example 4. DETAILED DESCRIPTION OF THE INVENTION

[0020] The present invention will be described in detail below. In the present specification, an aqueous pharmaceutical formulation (or an aqueous pharmaceutical composition) ) means that the formulation (or composition) contains at least 5% by mass, preferably 20% by mass or more of water. More preferably, the content is 50% by mass or more, particularly preferably 90% by mass or more, and most preferably 95% by mass or more. It means that it contains the above.

[0021] In this specification, the abbreviation "POE" stands for polyoxyethylene, and the abbreviation "POP" stands for polio. and propylene, respectively.

[0022] The liquid medical formulation in a package according to one embodiment of the present invention is irradiated with light having a wavelength of 280 to 320 nm. a package that blocks the passage of air; and a compound selected from the group consisting of olopatadine and salts thereof contained in the package. An aqueous medical formulation containing at least one selected from the group consisting of: The liquid medical formulation containing component (A) is irradiated with light at a wavelength of 280 to 320 nm. By storing the liquid pharmaceutical formulation in a light-blocking package, It is possible to suppress photodecomposition and also to suppress coloring or discoloration and precipitation of the aqueous medical formulation. This can be done.

[0023] Olopatadine, whose chemical name is (Z)-11-(3-dimethylaminopropylidene)-6, It is a known compound, 11-dihydrodibenzo[b,e]-oxepin-2-acetic acid. Lopatadine may be synthesized by known methods or is available as a commercially available product.

[0024] Salts of olopatadine are pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. Such salts are not particularly limited, and examples thereof include salts with inorganic acids (e.g., salts Acid salts, bromates, sulfates, phosphates, sodium orthophosphate, potassium hydrogen sulfate etc.), salts with organic acids (e.g., acetate, glycolate, lactate, pyruvate, malonate, etc.), Salt, succinate, glutarate, fumarate, malate, tartrate, citrate, Corbate, maleate, hydroxymaleate, benzoate, hydroxybenzoate Examples include benzoates, phenylacetates, cinnamates, salicylates, and 2-phenoxybenzoates. It can be obtained.

[0025] These olopatadine and / or salts thereof may be used alone or in combination of two or more. may be used in any combination. From the viewpoint of the effect of suppressing the onset of steroid use, component (A) is preferably olopatadine or a salt thereof with an inorganic acid. is preferred, and olopatadine hydrochloride is more preferred.

[0026] The content of the component (A) in the liquid medical formulation according to this embodiment is not particularly limited, and The type of ingredients, the shape of the container in which the liquid medical formulation is stored, the purpose of the liquid medical formulation, and the formulation form. The content of component (A) is set appropriately depending on the method of use, etc. For example, in the present embodiment, The total content of component (A) is 0.002 to 1 w / w based on the total amount of the liquid medical formulation. % w / v, and more preferably 0.005 to 0.8 w / v%, It is more preferable that the content is 0.005 to 0.5 w / v%, and more preferably 0.01 to 0.22 w / v%. It is even more preferable that the concentration is 0.01 to 0.2 w / v%, and it is particularly preferable that the concentration is 0. The most preferred range is 0.2 to 0.11 w / v%. From the viewpoint of the effect of suppressing photodecomposition of the component (A), it is preferable to set the content of the component (A) within the above range. It is preferable that:

[0027] In addition to the component (A), the liquid medical formulation according to this embodiment contains a compound that imparts photostability to olopatadine. By incorporating a compound that provides this, decomposition of component (A) by light can be more significantly suppressed. This makes it possible to

[0028] Compounds that impart photostability to olopatadine include (B) bromfenac and its salts, Berberine and its salts, allantoins, and zinc and zinc compounds are selected from the group consisting of zinc compounds and berberine and its salts. At least one selected from the above can be exemplified.

[0029] Bromfenac is also known as 2-amino-3-(4-bromobenzoyl)phenylacetic acid. These compounds are known compounds and may be synthesized by known methods or may be commercially available. can.

[0030] Salts of bromfenac include those that are pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. There are no particular limitations on the salts, as long as they are suitable for the purpose. Examples of such salts include organic acid salts (e.g., monocalcium salts, Carboxylate [acetate, trifluoroacetate, butyrate, palmitate, stearate, etc. ], polycarboxylic acid salts [fumarates, maleates, succinates, malonates, etc.], Dicarboxylic acid salts [lactate, tartrate, citrate, etc.], organic sulfonates [methanesulfonates phosphates, toluenesulfonates, tosylates, etc.), inorganic acid salts (e.g., hydrochlorides, sulfates, etc.) salts with organic bases (e.g., methylamine, thiamin ... Triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripeptide salts with organic amines such as lysine and picoline), salts with inorganic bases (e.g., ammonium salts) Alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.) Examples of suitable salts include various salts such as salts with metals such as ammonium, aluminum, etc.

[0031] These bromfenac and its salts may be used singly or in combination of two or more. Bromfenac or its salts may be used in combination with any of their solvates ( For example, hydrates) are also included. Examples of solvate forms include hemihydrates. Examples of hydroxybenzoates include, but are not limited to, bromfenac, monohydrate, hemihydrate, and the like. and / or its salts, which are intended to inhibit the photodecomposition of olopatadine in aqueous pharmaceutical formulations. From this viewpoint, bromfenac, its salt with an inorganic base, or a solvate thereof is preferred, More preferred is romfenac or an alkali metal salt thereof, or a solvate thereof. Mufenac sodium or its hydrate is more preferred, and bromfenac sodium 3 The dihydrate is particularly preferred.

[0032] Berberine is a known compound having a benzylisoquinoline skeleton and can be synthesized by known methods. They may be synthesized or commercially available.

[0033] Berberine salts include those that are pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. There are no particular limitations on the salts, as long as they are in the above range. Examples of such salts include berberine chloride, sulfate, etc. Examples include berberine and berberine tannate.

[0034] These berberines and their salts may be used alone or in combination of two or more. Berberine or its salts may be used in combination. The photodegradation of olopatadine in aqueous pharmaceutical formulations is further suppressed. From the viewpoint of controlling the effects of berberine and / or its salts, berberine sulfate or berberine chloride is preferred. Berberine is preferred, and berberine sulfate is more preferred.

[0035] Allantoin is a known compound also known as 5-ureidohydantoin. The allantoin compounds include allantoin or its salts, or allantoin derivatives or their derivatives. Salt is one example.

[0036] Allantoins are medicinally, pharmacologically (pharmaceutical) or physiologically acceptable. There are no particular limitations on the allantoins as long as they are of a suitable type. Allantoin dihydroxyaluminum, allantoin chlorohydroxyaluminum, Allantoin Glycyrrhetin, Allantoin Acetyl-DL-Methionine, Allantoin Examples include DL-pantothenyl alcohol and allantoin polygalacturonic acid.

[0037] These allantoins may be used alone or in any combination of two or more. It may be used in combination with other agents to further suppress the photodecomposition of olopatadine in aqueous pharmaceutical formulations. From this perspective, allantoin derivatives include allantoin, allantoin dihydroxyacetone, Aluminum or allantoin chlorohydroxyaluminum is preferred, and allantoin is more preferred.

[0038] Zinc or zinc compounds are elements or compounds containing at least one zinc atom. Lead, inorganic zinc salts, organic zinc salts, and hydrates of these may be used in any form. It is possible.

[0039] Zinc or zinc compounds include zinc, zinc chloride, zinc sulfate, zinc lactate, zinc nitrate, and glutamic acid. Zinc conate, zinc citrate, zinc 2-oxoglutarate, zinc oxide, zinc phosphate, aluminum Zinc phosphate, zinc fluoride, zinc iodide, zinc hydroxide, zinc carbonate, zinc chromate, zinc benzoate Lead, zinc acetate, zinc paraaminobenzoate, zinc paradimethylaminobenzoate, parapheno Zinc diolsulfonate, zinc paramethoxycinnamate, 2-mercaptopyridine-N-oxide Zinc, zinc picrate, zinc aspartate, zinc naphthenate, zinc salicylate, pheno Zinc diol sulfonate, zinc sebacate, zinc sodium tripolyphosphate, sodium stearate Lead, zinc caprate, zinc laurate, zinc myristate, zinc palmitate, olein Zinc acid, zinc polyphosphonate, zinc chondroitin sulfate, zinc undecylenate, ascorbic acid Zinc bicarbonate, zinc pyrithione, hinokitiol zinc, zinc dipicolinate, zinc glycerin chlorate complex, bishistidine zinc complex, zinc-3,4-dihydroxybenzoate complex, and and hydrates thereof.

[0040] These zinc and zinc compounds may be used alone or in any combination of two or more. Zinc or zinc compounds may be used in the form of their solvates (e.g., hydrates). The solvate form includes, for example, a heptahydrate. However, the present invention is not limited to these. From this viewpoint, zinc and / or zinc compounds include zinc chloride, zinc sulfate, zinc lactate, , zinc gluconate, zinc citrate, or hydrates thereof are preferred, and zinc chloride and zinc sulfate are also preferred. , zinc lactate, or a hydrate thereof is more preferred, and zinc sulfate, zinc lactate, or a hydrate thereof is more preferred. Zinc sulfate heptahydrate is more preferred, and zinc sulfate heptahydrate is particularly preferred.

[0041] The content of the component (B) in the liquid medical formulation according to this embodiment is not particularly limited, and The type of component, the type and content of the (A) component used in combination, the purpose of the liquid medical preparation, the formulation form, The content of component (B) is set appropriately depending on the method of use, etc. For example, in this embodiment, The total content of component (B) is 0.0001 to 5 wt. / v%, more preferably 0.0002 to 3 w / v%, and It is more preferably 0.0005 to 1 w / v%, and more preferably 0.001 to 0.5 w / v%. It is particularly preferred that

[0042] The content of bromfenac and / or a salt thereof in the aqueous pharmaceutical composition according to this embodiment may be, for example, The total content of bromfenac and / or its salts is 0.000 based on the total amount of the drug formulation. It is preferably 5 to 1 w / v%, and more preferably 0.001 to 0.5 w / v%. The concentration is preferably 0.005 to 0.2 w / v %, and more preferably 0.005 to 0.2 w / v %.

[0043] The content of berberine and / or a salt thereof in the aqueous medicine according to this embodiment can be, for example, Based on the total amount of the preparation, the total content of berberine and / or its salts is 0.0001 to 0. It is preferably 1 w / v%, and more preferably 0.0005 to 0.05 w / v%. The concentration is preferably 0.001 to 0.025 w / v %, and more preferably 0.001 to 0.025 w / v %.

[0044] The content of allantoins may be, for example, based on the total amount of the liquid medical formulation according to this embodiment. As a guideline, the total content of allantoins is preferably 0.001 to 1 w / v%. 0.005 to 0.5 w / v% is more preferable, and 0.01 to 0.3 w / v% is more preferable. It is more preferable that there is.

[0045] The content of zinc and / or zinc compounds in the liquid medical formulation according to this embodiment can be, for example, The total content of zinc and / or zinc compounds is 0.0001 to 1 w / v based on the total amount of %, more preferably 0.0002 to 0.7 w / v%, and 0 It is more preferably 0.001 to 0.5 w / v%, and more preferably 0.01 to 0.25 w / v%. It is even more preferred that

[0046] From the viewpoint of further suppressing the photodegradation of olopatadine in the aqueous pharmaceutical formulation, (B It is preferable that the content of the component (a) is within the above range.

[0047] In addition, the content of component (B) relative to component (A) in the liquid medical formulation according to this embodiment is The ratio is not particularly limited, and depends on the types of component (A) and component (B), the purpose of the liquid medical preparation, and the formulation. The content ratio of component (B) to component (A) is set appropriately depending on the form, method of use, etc. For example, the total content of component (A) contained in the liquid medical formulation according to this embodiment is 1 mass %. The total content of the (B) component is preferably 0.0005 to 2000 parts by mass relative to the total amount of the (B) component. It is preferably 0.002 to 500 parts by mass, more preferably 0.005 to 100 parts by mass. It is more preferable that the content is 0.01 to 50 parts by mass, and particularly preferable that the content is 0.01 to 50 parts by mass.

[0048] From the viewpoint of further suppressing the photodecomposition of olopatadine in the aqueous pharmaceutical formulation, It is preferable that the content ratio of component (B) to component (A) be within the above range.

[0049] The content ratio of bromfenac and / or its salts to component (A) is, for example, Bromine per 1 part by mass of the total content of component (A) contained in the liquid medical formulation according to the embodiment The total content of phenac and / or a salt thereof is preferably 0.0005 to 500 parts by mass. It is preferable that the amount is 0.002 to 100 parts by mass, and more preferably 0.01 to 20 parts by mass. It is more preferable that the amount is 0.05 to 10 parts by mass, and particularly preferable that the amount is 0.05 to 10 parts by mass.

[0050] The content ratio of berberine and / or its salts to component (A) is, for example, Berberine per part by mass of the total content of component (A) contained in the liquid medical formulation and / or its salt is preferably 0.0001 to 50 parts by mass in total, and 0. It is more preferably 0.005 to 10 parts by mass, and even more preferably 0.002 to 5 parts by mass. It is particularly preferable that the amount is 0.01 to 1 part by mass.

[0051] The content ratio of allantoins relative to the component (A) can be, for example, The total content of allantoins per part by mass of the total content of ingredient (A) contained in the active pharmaceutical preparation The amount is preferably 0.001 to 500 parts by mass, more preferably 0.005 to 100 parts by mass. It is more preferable that the amount is 0.02 to 50 parts by mass, and further more preferable that the amount is 0.1 to 15 Parts by weight are particularly preferred.

[0052] The content ratio of zinc and / or zinc compound to component (A) is, for example, Zinc and / or The total content of zinc compounds is preferably 0.0001 to 500 parts by mass, and 0.0 It is more preferable that the content is 0.005 to 100 parts by mass, and it is preferable that the content is 0.001 to 50 parts by mass. It is more preferably 0.002 to 50 parts by mass, and even more preferably 0.1 to 10 parts by mass. Particularly preferred is a part by weight.

[0053] From the viewpoint of further suppressing the photodecomposition of olopatadine in the aqueous pharmaceutical formulation, It is preferable that the content ratio of each component (B) relative to component (A) is within the above range.

[0054] In order to more significantly exhibit the effects of the present invention, the liquid medical formulation according to this embodiment further contains terpene. The liquid medical formulation according to this embodiment preferably contains a terpenoid. The compound may be used without restriction, provided that it is medicamentarily, pharmacologically (pharmaceutical) or physiologically acceptable. Examples of terpenoids used in the liquid medical formulation according to this embodiment include, but are not limited to: Menthol, Menthone, Camphor, Borneol, Geraniol, Cineole, Citronellol ol, carvone, anethole, eugenol, limonene, linalool, linalyl acetate, These derivatives can be used. These compounds are available in any of the d-, l- and dl-forms. In addition, in the liquid medical formulation according to this embodiment, the terpenoid may be Alternatively, essential oils containing the above compounds may be used. Potash oil, bergamot oil, peppermint oil, cool mint oil, spearmint oil, peppermint oil , fennel oil, cinnamon oil, rose oil, camphor oil, etc.

[0055] These terpenoids may be used alone or in any combination of two or more. From the viewpoint of inhibiting the photodecomposition of olopatadine, it is possible to use terpenoids and As the menthol, menthol, menthone, camphor, borneol, and geraniol are preferred. Menthol, camphor, and borneol are more preferred, and menthol and camphor are even more preferred. Menthol such as l-menthol and dl-menthol is even more preferred.

[0056] The content of terpenoid in the liquid medical formulation according to this embodiment is not particularly limited. the type and content of the (A) component and the (B) component, the use of the liquid medical preparation, the formulation form, The content of terpenoids is appropriately set depending on the method of use, etc. For example, in the present embodiment, The total content of terpenoids is 0.0001 to 0.2 based on the total amount of the liquid pharmaceutical preparation. w / v % is preferable, and 0.0005 to 0.1 w / v % is more preferable. It is more preferable that the content is 0.001 to 0.08 w / v%. When using essential oils containing terpenoids, the terpenoids in the essential oils contained in the aqueous pharmaceutical preparation must be From the viewpoint of suppressing photodegradation of olopatadine, Therefore, the content of the terpenoid can be set within the above range.

[0057] The liquid medical formulation according to this embodiment may further contain a buffering agent. The pH of the aqueous pharmaceutical preparation can be adjusted. Buffers are used for pharmaceutical, pharmacological (pharmaceutical) or There are no particular limitations on the buffering agent as long as it is physiologically acceptable. , borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, Tris buffer agents, aspartic acid, aspartate salts, epsilon-aminocaproic acid, etc. These buffers may be used alone or in any combination of two or more. The borate buffer may be boric acid, an alkali metal borate, or an alkali metal borate. Examples of phosphate buffers include phosphoric acid, or phosphate salts of potassium earth metals. Examples of the carbonate buffer include alkali metal salts and phosphates such as alkaline earth metal phosphates. Examples of the carbonate include carbonic acid, and carbonates such as alkali metal carbonates and alkaline earth metal carbonates. The citrate buffer may be citric acid, an alkali metal citrate, or an alkali citrate. Examples of the tris buffer include trishydroxymethylaminomethyl. In addition, boric acid buffers and phosphate buffers include phosphate buffers. A hydrate of a borate or a phosphate may be used. Boric acid or its salts (sodium borate, potassium tetraborate, potassium metaborate) ammonium borate, borax, etc.); phosphoric acid or its salts (phosphate buffers) Disodium phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate , dipotassium phosphate, monobasic calcium phosphate, dibasic calcium phosphate, etc.); carbonate buffer As an agent, carbonic acid or its salts (sodium bicarbonate, sodium carbonate, ammonium carbonate, Potassium carbonate, calcium carbonate, potassium bicarbonate, magnesium carbonate, etc.); citric acid buffer As a buffer, citric acid or its salts (sodium citrate, potassium citrate, calcium citrate) calcium, sodium dihydrogen citrate, disodium citrate, etc.); acetate buffers, Acetic acid or its salts (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.) ); Aspartic acid or its salts (sodium aspartate, magnesium aspartate) Examples of buffers include boric acid buffer, potassium aspartate, etc. Preferred are phosphate buffers, Tris buffers, and borate buffers (e.g., boric acid and borax). combinations), phosphate buffers (e.g., disodium hydrogen phosphate and sodium dihydrogen phosphate) combinations thereof) are particularly preferred, with borate buffer being most preferred.

[0058] When a buffering agent is added to the liquid medical formulation according to this embodiment, the content of the buffering agent depends on the type of the buffering agent. The type and content of other ingredients, the purpose of the liquid medical preparation, the formulation form, the method of use, etc. The content of the buffering agent is set appropriately depending on the liquid medical formulation according to this embodiment, for example. The total content of the buffer is preferably 0.01 to 15 w / v% based on the total amount of the solution. It is preferable that the content is 0.05 to 10 w / v%, and more preferable that the content is 0.1 to 7.5 w / v%. It is more preferable that the concentration is 0.5 to 5 w / v%, and particularly preferable that the concentration is 0.5 to 2.5 Most preferably, it is w / v %.

[0059] The pH of the liquid medical formulation according to this embodiment is determined based on medicinal, pharmacological (pharmaceutical) or There are no particular limitations on the pH of the liquid medical formulation as long as it is within a physiologically acceptable range. For example, it is preferably 4.0 to 9.5, and more preferably 5.0 to 9.0. It is more preferable that the ratio is 5.5 to 8.5, and particularly preferably 6.5 to 8.0. The pH is preferably 6.8 to 7.8, and most preferably 6.8 to 7.8. The pH may be 6.0 to 8.0.

[0060] The osmotic pressure of the liquid medical formulation according to this embodiment is within the range acceptable to the living body. The osmotic pressure ratio of the liquid pharmaceutical preparation is, for example, 0.5 to 5.0. It is preferable that the ratio is 0.6 to 3.0, and more preferably 0.7 to 2.0. It is more preferable that the osmotic pressure is 0.9 to 1.55, and particularly preferable that the osmotic pressure is 0.9 to 1.55. This can be done by methods known in the art using inorganic salts, polyhydric alcohols, sugar alcohols, sugars, etc. The osmotic pressure ratio is 286 mOsm (0.9 s) based on the 16th edition of the Japanese Pharmacopoeia. The osmotic pressure is the ratio of the osmotic pressure of the sample to that of a w / v% sodium chloride solution. Measure the osmotic pressure ratio by referring to the osmotic pressure measurement method (freezing point depression method) described in the Pharmacopoeia. The standard solution (0.9 w / v% sodium chloride aqueous solution) was prepared by the Japan Pharmacopoeia After drying the standard reagent at 500-650°C for 40-50 minutes, Cool in the refrigerator, weigh out 0.900 g accurately, dissolve in purified water and make exactly 100 mL. Or prepare it with a commercially available standard solution for measuring osmolality ratio (0.9 w / v% sodium chloride aqueous solution). It can be used.

[0061] The viscosity of the liquid medical formulation according to this embodiment may be within a range acceptable to the living body. 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 Preferably, the viscosity is 0.05 to 100 mPa·s, more preferably 0.1 It is more preferably up to 10 mPa·s.

[0062] In addition, the liquid medical formulation according to this embodiment may contain other ingredients in addition to the above ingredients, as long as the effects of the present invention are not impaired. In addition, various pharmacologically active ingredients or physiologically active ingredients may be combined and contained in appropriate amounts. There are no particular restrictions on the type of ingredients, and for example, (Supervised by the Japan Society of Regulatory Science) Examples of ingredients that can be used in ophthalmic drugs include the following: Ingredients include:

[0063] Antihistamines or antiallergic agents: for example, ketotifen, iproheptin, diphenhydramine, phenhydramine, chlorpheniramine maleate, pemirolast potassium, cromoglycate sodium, tranilast, etc.

[0064] Decongestants: e.g., tetrahydrozoline, naphazoline, epinephrine, ephedrine methylephedrine, etc.

[0065] Ocular muscle regulating drugs: for example, cholinesterases with an active center similar to that of acetylcholine enzyme inhibitors, specifically neostigmine methylsulfate, tropicamide, and atroxenic sulfate Ping et al.

[0066] Bactericides: e.g., acrinol, cetylpyridinium, benzalkonium, benzethonium um, chlorhexidine, polyhexamethylene biguanide, etc.

[0067] Vitamins: e.g., flavin adenine dinucleotide sodium, cyanocobalamin , Retinol Acetate, Retinol Palmitate, Pyridoxine Hydrochloride, Panthenol, Pantothenic Acid calcium carbonate, tocopheryl acetate, etc.

[0068] Amino acids: e.g., potassium aspartate, magnesium aspartate, aspartic acid, Magnesium and potassium lauryl phosphate (mixture of equal parts), aminoethylsulfonic acid, etc.

[0069] Anti-inflammatory agents: for example, glycyrrhetinic acid, glycyrrhizic acid, methyl salicylate, salicylic acid Acid glycol, azulene sulfonic acid, tranexamic acid, epsilon-aminocaproic acid, Lysozyme, licorice, pranoprofen, etc.

[0070] Others: e.g., sodium hyaluronate, sulfamethoxazole, indomethacin , ibuprofen, ibuprofen piconol, bufexamac, butyl flufenamate , bendazac, piroxicam, ketoprofen, felbinac, purple root, horse chestnut Ki, and salts thereof, etc.

[0071] In addition, the liquid medical formulation according to this embodiment may contain any of the following substances as long as the effects of the invention are not impaired. Depending on the intended use and formulation, various additives are selected appropriately according to the usual method, and one or more The above may be used in combination in an appropriate amount. Examples include the various additives listed in the 2007 Pharmaceutical Additives Standard (edited by the Japan Pharmaceutical Additives Association). The following additives are listed as ingredients:

[0072] Carrier: For example, an aqueous carrier such as water or aqueous ethanol. Sugars: for example, glucose, cyclodextrin, etc. Sugar alcohols: For example, xylitol, sorbitol, mannitol, etc. These are D It may be any of the L-, L- and DL-isomers.

[0073] Preservatives, disinfectants or antibacterial agents: e.g., alkyldiaminoethylglycine hydrochloride, benzoic acid Sodium, ethanol, benzalkonium chloride, benzethonium chloride, chlorogluconate Hexidine, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate Sodium, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propranolol propyl, butyl parahydroxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzoyl diethyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide, etc.), Glowkill (product name manufactured by Rhodia), etc.

[0074] Stabilizers: e.g. trometamol, sodium formaldehyde sulfoxylate ( ingalite), tocopherol, sodium pyrosulfite, monoethanolamine, monosodium Aluminum tearate, glycerin monostearate, dibutylhydroxytoluene, etc. .

[0075] Surfactants: For example, POE(20) sorbitan monolaurate (Polysorbate 20 ), POE(20) sorbitan monopalmitate (polysorbate 40), monostearyl POE(20) Sorbitan (Polysorbate 60), POE(20) Tristearate ) Sorbitan (Polysorbate 65), POE (20) Sorbitan Monooleate (Poly POE sorbitan fatty acid esters such as sorbate 80; POE (40) hydrogenated castor oil ( Polyoxyethylene hydrogenated castor oil 40), POE(60) hydrogenated castor oil (polyoxyethylene POE hydrogenated castor oil such as POE hydrogenated castor oil 60; POE castor oil 10, POE castor oil POE castor oil such as 35; POE alkyl ether such as POE(9) 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; Non-ionic surfactants such as polyethylene glycol monostearate, e.g., polyoxyl 40 stearate Acetone surfactant (in the compounds exemplified above, the numbers in parentheses indicate the number of moles added). , alkyldiaminoethylglycine or a salt thereof (e.g., hydrochloride, etc.), and other amphoteric surfactants. cationic surfactants such as benzalkonium chloride and benzethonium chloride, alkyl benzoates, Diphenylsulfonate, alkyl sulfate, polyoxyethylene alkyl sulfate, α-sulfo fatty acid Anionic surfactants such as fatty acid ester salts and α-olefin sulfonic acid.

[0076] Thickeners: for example, polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone Don (K25, K30, K90, etc.), carboxyvinyl polymer, polyoxyethylene Polyoxypropylene block copolymer (BASF Wyandotte Copro ration, Pluronic, Tetronic, etc.), cellulose derivatives (methylcellulose , ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, Hydroxypropyl methylcellulose [2208, 2906, 2910, etc.], carboxymethyl ethyl cellulose, carboxyethyl cellulose, 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, algin sodium carbonate, glucose, sorbitol, etc.

[0077] Isotonicity agents: e.g., disodium hydrogen phosphate, sodium dihydrogen phosphate, dihydrogen phosphate Potassium, sodium bisulfite, sodium sulfite, potassium chloride, calcium chloride, Sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium bicarbonate , sodium carbonate, sodium thiosulfate, magnesium sulfate, glycerin, propylene glycol, polyethylene glycol, glucose, mannitol, sorbitol, etc.

[0078] Chelating agents: e.g., ethylenediaminediacetic acid (EDDA), ethylenediaminetriacetic acid , ethylenediaminetetraacetic acid (edetic acid, EDTA), N-(2-hydroxyethyl)ethyl diaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), and the like.

[0079] The liquid medical formulation according to this embodiment contains the above-mentioned component (A), and optionally component (B), and other components. The formulation is prepared by adding the ingredients to a carrier to a desired concentration. In the case of pharmaceutical preparations, the ingredients are dissolved or suspended in purified water and adjusted to the desired pH and osmotic pressure. It can be prepared by sterilizing it by filtration or other methods. The drug is first mixed with surfactants and other solubilizing ingredients and then further refined. Purified water may be added to dissolve or suspend the compound.

[0080] (packaging) The container for storing the liquid medical formulation will be described below. The packaging blocks light rays of 20 nm.

[0081] The above-mentioned package mainly refers to a package (primary package) that directly contains the above-mentioned liquid medical formulation. However, the primary package containing the liquid medical formulation may be further contained, and the liquid medical formulation may be stored in a double or multiple containers. The packaging body (secondary packaging body) for packaging the above is also included. The packaging body may comprise only a packaging body portion, a lid portion and / or an extraction spout portion.

[0082] In the case of a liquid pharmaceutical product in a package with a secondary package, the primary package and the secondary package At least one of the above packaging materials may block the light. From the viewpoint of suppressing the decomposition of olopatadine in the package not only during use but also during storage. Therefore, it is desirable that the primary packaging body is one that blocks the above-mentioned light rays.

[0083] The form of the package is not particularly limited as long as it can accommodate the liquid medical formulation. Select appropriately depending on the form and use of the liquid medicinal preparation to be contained, whether it is a primary or secondary package, etc. Examples of the form of the package include a tube-shaped container, a bottle-shaped container, etc. Examples of the secondary packaging include a pillowcase and a packaging bag.

[0084] For pharmaceutical preparations such as eye drops, eyewashes, and injections, foreign matter confirmation tests are required as part of quality control under the Pharmaceutical Affairs Law. It is stipulated (in the Japanese Pharmacopoeia) that the container of a pharmaceutical preparation must be a transparent package (container) that allows the inside to be observed. In addition, it is necessary for users to check the remaining amount. It is desirable for the packaging (container) to be transparent enough that the contents can be observed with the naked eye. Therefore, from the perspective of foreign matter confirmation tests in quality control, the packaging must be such that the inside can be observed with the naked eye. It is preferable that the packaging has a degree of internal visibility (transparency). In particular, packaging that has foreign matter confirmation tests in quality control is required under the Pharmaceutical Affairs Law (Japanese Pharmacopoeia). On the other hand, from the viewpoint of checking the remaining amount, All types of liquid pharmaceutical preparations are packaged in transparent packaging that allows for internal visibility. It is preferable that

[0085] Specifically, packaging that allows for internal visibility (transparency) is a material that can transmit light with wavelengths of 400 to 700 nm. The maximum light transmittance in the visible light range (hereinafter referred to as "maximum light transmittance") is 60% or more, Preferably, the content is 70% or more, more preferably 80% or more, and particularly preferably 90% or more. In the present invention, the light transmittance is measured by the method described in the examples. The maximum transmittance in the visible light region of wavelength 400 to 700 nm is, for example, The light transmittance is measured every 10 nm between wavelengths of 400 and 700 nm, and from each of the obtained light transmittances can be requested.

[0086] In this embodiment, when the packaging body is a visible packaging body, at least the packaging body If the above-mentioned internal visibility (transparency) is ensured in a part of the packaging, the drug product inside the packaging can be seen. Therefore, the visibility (transparency) of the inside of the package is not necessarily on the entire surface of the package. For example, if the liquid pharmaceutical formulation is an eye drop or an injection, In this case, the provisions of the General Provisions for Preparations of Eye Drops in the Japanese Pharmacopoeia and the Insoluble Foreign Matter Testing Method for Injections are implemented. From the viewpoint of application, it is preferable that the area of ​​the container (package) is at least 20% or more, preferably 50% or more, more preferably 70% or more, even more preferably 80% or more, and particularly preferably It is sufficient that the transparent portion occupies 90% or more. Also, for example, at the distribution stage, The packaging used in this embodiment has a label on the surface of the packaging to display the ingredients and product name. The purpose is to prevent the visibility (transparency) of the inside of the package from being impaired by the application of a bell. However, in the packaging, the part that allows the user to see the inside (transparency) of the packaging is It is desirable that the amount of the drug product inside the package be secured so that it can be confirmed. If the drug product is packaged in two or more layers, all the layers must have the transparency described above. It is preferable that:

[0087] In the present invention, blocking light rays with wavelengths of 280 to 320 nm means, for example, blocking light rays with wavelengths of 280 The average light transmittance over the entire range of 320 nm (hereinafter referred to as "average light transmittance") is 25% or more. Here, the light transmittance in the wavelength range of 280 to 320 nm is As in the case of the maximum light transmittance in the visible light region of 00 to 700 nm, The average light transmittance in the wavelength range of 280 to 320 nm can be measured by the method For example, the light transmittance is measured every 10 nm between 280 and 320 nm, and the obtained light transmittance is It can be obtained by calculating the average value of these.

[0088] From the viewpoint of more effectively suppressing the decomposition of olopatadine by light, 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, and even more particularly preferably 2 % or less, and most preferably 1% or less.

[0089] (A) A liquid pharmaceutical formulation containing the component (A) is provided with an even more excellent photodecomposition inhibitory effect. In order to prevent this, it is desirable that the packaging be able to block light with a wavelength of 300 to 320 nm. That is, the average light transmittance at wavelengths of 300 to 320 nm (average light transmittance) is preferred. or 35% or less, more preferably 30% or less, even more preferably 20% or less, even more preferably Preferably it is 10% or less, particularly preferably 5% or less, further particularly preferably 2% or less, most preferably A package in which the average wavelength of 300 to 320 nm is 1% or less is more preferable. The measurement method for average light transmittance is the same as that for average light transmittance of 280 to 320 nm. is.

[0090] (A) To provide an aqueous pharmaceutical preparation containing the component (A) with a particularly excellent photodecomposition inhibitory effect. To achieve this, it is desirable that the packaging be able to block light with a wavelength of 310 to 320 nm. That is, the average light transmittance at wavelengths of 310 to 320 nm (average light transmittance) is preferred. Preferably, the ratio is 45% or less, more preferably 40% or less, even more preferably 25% or less, and even more preferably or 20% or less, particularly preferably 10% or less, further particularly preferably 5% or less, and even more preferably A package with a density of 2% or less is particularly preferred, and 1% or less is most preferred. The method for measuring the average light transmittance at wavelengths of 310 to 320 nm is as follows: The method for measuring the average light transmittance of m is the same as that for m.

[0091] In this way, the packaged article is irradiated with light having a wavelength of 280 to 320 nm (preferably 300 to 320 nm, and more preferably Preferably, the light in the wavelength range of 310 to 320 nm is blocked, and the light in the wavelength range is transmitted into the container. By preventing this, it is possible to suppress photodecomposition of olopatadine inside the package. become.

[0092] The liquid medical formulation in a package according to another embodiment of the present invention is irradiated with light having a wavelength of 310 to 320 nm. a packaging body that blocks radiation; and an aqueous medical formulation that contains component (A) and is contained in the packaging body. The liquid medical formulation containing the component (A) is subjected to irradiation with light having a wavelength of 310 to 320 nm. By storing the olopatadine in a light-blocking package, the light-blocking effect of the aqueous pharmaceutical formulation can be reduced. Decomposition can be suppressed, and coloring or discoloration and precipitation of the aqueous pharmaceutical preparation can be suppressed. The type of olopatadine or a salt thereof used in this embodiment, The content ratio of the liquid medicine, other ingredients contained in the liquid medicine, the form of the liquid medicine, packaging, etc. In this case, the same aspects as those detailed above can be applied, except for the wavelength of the light that the packaging blocks. This can be done.

[0093] (A) To provide an aqueous pharmaceutical preparation containing the component (A) with a particularly excellent photodecomposition inhibitory effect. In order to achieve this, the packaging must block light with wavelengths of 280 to 320 nm and 310 to 320 nm. It is desirable that the filter should block light with wavelengths of 280 to 320 nm. Blocking all light with wavelengths of 280 to 320 nm and blocking all light with wavelengths of 310 to 320 nm means blocking all light with wavelengths of 280 to 320 nm. The average light transmittance of the range is, for example, 25% or less, 20% or less, 10% or less, 5% or less, 2% or less , 1% or less, and the average light transmittance over 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, 1% or less It means it's below.

[0094] (A) In aqueous pharmaceutical preparations containing component (A), particularly, more excellent inhibition of photodecomposition of olopatadine In order to achieve this effect, the package must be irradiated with light having a wavelength of 280 to 320 nm (preferably 300 to 32 In addition to being able to block light of wavelengths of 300 nm, and more preferably 310 to 320 nm, It is preferable that the envelope can also block light rays with a wavelength of 340 nm to 350 nm. The coating has a wavelength of 280 to 320 nm (preferably 300 to 320 nm, more preferably 310 In addition to being able to block light rays of wavelengths from 340 to 350 nm, The average (average light transmittance) is preferably 40% or less, more preferably 30% or less, and even more preferably Preferably, the content is 10% or less, more preferably 5% or less, and most preferably 1% or less. Here, the method for measuring the average light transmittance at wavelengths of 340 to 350 nm is as follows: The method is the same as that for measuring the average light transmittance from 280 to 320 nm.

[0095] As mentioned above, there is no particular limitation on the means for blocking light with wavelengths of 280 to 320 nm. However, for example, if the material constituting the packaging contains a substance that blocks light with a wavelength of 280 to 320 nm, or coating the packaging with a substance that blocks light with a wavelength of 280 to 320 nm. A film containing a substance that blocks light with a wavelength of 280 to 320 nm is attached to the packaging. These methods can be applied singly or in combination of two or more. Specifically, the method for attaching the film to the container is to use a method using a wavelength of 280 to 320 nm. A heat-shrinkable film (shrink film) that blocks light is placed over the package, and then heated. For example, the film can be tightly attached to the packaging material by using a light source. Regarding the means for blocking other light such as 100 nm, the wavelength to be blocked in the above method is also set as the target. The method is the same as above except that the wavelength is changed to correspond to the wavelength of the light.

[0096] The packaging material used in this embodiment is not limited, and may be made of glass, plastic, or the like. The material may be any of plastic, cellulose, pulp, rubber, etc. From the viewpoint of outstanding effectiveness, squeezability and durability, plastic packaging is preferred.

[0097] The resin used in the plastic packaging body used in this embodiment is a thermoplastic resin. Resins are preferred, for example, olefin resins (polyethylene, polypropylene, etc.), polyethylene, ster resin, polyphenylene ether resin, polycarbonate resin, polysulfone Resin, polyamide resin, rigid vinyl chloride resin, styrene resin (polystyrene (PS ), acrylonitrile-styrene copolymer (AS resin), etc. The resin is polyethylene, polypropylene, polyester resin or polycarbonate resin. The resin is preferably a polyester resin, which is a resin that significantly exhibits the effects of the present invention. The resin is preferably a polyester resin or a polycarbonate resin. be.

[0098] Polyester resins include dicarboxylic acid components (phthalic acid, terephthalic acid, naphthalene A component containing an aromatic dicarboxylic acid component such as benzodicarboxylic acid and a diol component is used. The resulting resin can be used. Specifically, aromatic polyester resins, for example, polyal Polyethylene terephthalate (PET), Polybutylene terephthalate Poly(C2-4 alkylene terephthalate) such as poly(PBT) Phthalates (polyethylene naphthalate (PEN), polybutylene naphthalate, etc.) C2-4 alkylene naphthalate, etc.), polycycloalkylene terephthalate (poly( 1,4-cyclohexylene dimethylene terephthalate (PCT), etc.), polyarylate Bisphenols (bisphenol A, etc.) and phthalates (phthalic acid, terephthalic acid ] and a resin composed of)) homopolyester. The polyester resin contains the homopolyester unit as the main component (for example, 50% by weight or more). Copolyesters such as PET and PCT copolymers, and copolymers of the above homopolyesters (such as copolymers of PET and PCT) Polycarbonate resins include, for example, bisphenols (bispheno It is an aromatic polycarbonate based on ethylene glycol-A, etc.

[0099] In this embodiment, the plastic packaging has strength, light transmission, and gas or water vapor barrier properties. Polymer alloys (polymer blends, etc.) are not used unless they have a negative effect on the properties (breathability) of the material. A preferred polymer alloy is a polymer blend of multiple synthetic resins ( For example, polymer blends of PET and PEN are included. In the case of an alloy, it contains the above polyester resin as the main component (for example, 50% or more). The resin constituting the packaging body has good squeezability and can withstand repeated pressure. It is preferable that the packaging material can be made durable against the impact.

[0100] The material of the packaging body is polyester resin, which is preferable because it exhibits the remarkable effect of the present invention. is preferably a polyalkylene terephthalate or a polyalkylene naphthalate, More preferably, polyethylene terephthalate (PET) and polybutylene terephthalate ( The packaging material is either PBT or polyethylene naphthalate (PEN). The polyester may be a homopolyester or a copolyester, It may also be a polymer alloy containing an ester.

[0101] In addition, from the viewpoint of preventing the liquid from draining out of the liquid medical formulation, the packaging material is polyester. It is preferably a resin or a styrene-based resin, and more preferably PET or PS. It is more preferable that the packaging material is PET. This reduces the wettability of the liquid medical formulation containing component (A) with the packaging, and the liquid medical formulation is easily absorbed during use and / or storage. Alternatively, it is possible to improve the drainage of liquid during storage, and prevent the liquid from remaining in the container of the liquid medical formulation.

[0102] The packaging body according to this embodiment may be made of a material to which an ultraviolet blocking agent is added. The packaging may be coated with an ultraviolet blocking agent. For example, the packaging may be made of glass or synthetic resin. Packaging materials made by adding UV blocking agents to plastics, etc., and processing synthetic resins into sheets. From UV blocking agent coated and then molded packaging, glass or synthetic resin etc. Examples include a package that is molded into the final package shape and then coated with an ultraviolet blocking agent. In addition, sheet-shaped synthetic resins that have been added or coated with ultraviolet blocking agents are used as packaging after molding. It may be shrink-wrapped on the body.

[0103] UV blocking agents include zinc oxide, titanium oxide, triazole compounds, and benzoates. compounds, substituted acrylonitrile compounds, cyanoacrylate compounds, triazine compounds Compounds, oxalic acid anilide compounds, nickel complex compounds, trade name Tinuvin (registered trademark) ) 328, Tinuvin(R) 384-2, Tinuvin(R) 400, Tinuvin(R) 400- 2. Benzophenone such as Tinuvin(R) 900, Tinuvin(R) 928, and Tinuvin(R) 1130 Triazole compounds; methyl diisopropylcinnamate, cinoxate, di-para-methoxy Glyceryl cinnamate, mono-2-ethylhexanoate, isopropyl paramethoxycinnamate Diisopropyl cinnamate mixture, 2-ethylhexyl paramethoxycinnamate, Cinnamic acid-based ultraviolet absorbers such as benzyl cinnamate; oxybenzone, hydroxymethoxybenzo Benzophenone sulfonic acid, sodium hydroxymethoxybenzophenone sulfonate, dihydroxybenzophenone Dihydroxydimethoxybenzophenone, dihydroxydimethoxybenzophenone disulfone Benzophenone, sodium carbonate, dihydroxybenzophenone, tetrahydroxybenzophenone, etc. Zofenone-based ultraviolet absorbers; para-aminobenzoic acid, ethyl para-aminobenzoate, para-aminobenzoic acid Glyceryl parabenzoate, amyl paradimethylaminobenzoate, paradimethylaminobenzoin 2-Ethylhexyl benzoate, 4-[N,N-di(2-hydroxypropyl)amino]benzoic acid Ethyl benzoate ester ultraviolet absorbers; ethylene glycol salicylate, salicylic acid Octyl Salicylate, Dipropylene Glycol Salicylate, Phenyl Salicylate, Homo Salicylate Salicylic acid-based UV absorbers such as menthyl and methyl salicylate, guaiazulene, dimethicone 2-Ethylhexyl Benzylidene Dioxoimidazolidinepropionate, 2,4,6- Tris[4-(2-ethylhexyloxycarbonyl)anilino]1,3,5-triazine Benzene, parahydroxyanisole, 2-(2-hydroxy-5-methylphenyl)benzoxazole Triazole, 4-tert-butyl-4'-methoxydibenzoylmethane, phenylbenzene Zimidazole sulfonic acid, 2-(4-diethylamino-2-hydroxybenzoyl)- Hexyl benzoate, etc. Riboflavin, anthraquinone pigments (1- Amino-4-methylanthraquinone, 1,4-diaminoanthraquinone, anthraquinone Phthalocyanine pigments (e.g., phthalocyanine yellow), phthalocyanine blue (CIPigme nt Blue15; CI74160; Blue No. 404), Phthalocyanine Green ( Examples include CI Pigment Green7).

[0104] The UV blocking agent is preferably zinc oxide, titanium oxide, Tinuvin® 328, Nuvin(R) 384-2, Tinuvin(R) 400, Tinuvin(R) 400-2, Tinuvin (R)900, Tinuvin(R)928, Tinuvin(R)1130, paramethoxycinnamic acid 2-Ethylhexyl, Glyceryl Di-para-Methoxycinnamate Mono-2-ethylhexanoate, 2,4,6-tris[4-(2-ethylhexyloxycarbonyl)anilino]1,3, 5-Triazine, phenylbenzimidazole sulfonic acid, 2-(4-diethylamino- 2-Hydroxybenzoyl)-Hexyl Benzoate, Dimethoxybenzylidene Dioxoimide 2-ethylhexyl dazolidinepropionate is particularly preferred, and zinc oxide and zinc oxide are particularly preferred. Titanium, Tinuvin(R)328, Tinuvin(R)384-2, Tinuvin(R)400, Nuvin(R) 400-2, Tinuvin(R) 900, Tinuvin(R) 928, Tinuvin(R) ) 1130. Zinc oxide and titanium oxide are further compounded with silica, silicon, zinc silicate, etc. It may be coated.

[0105] In the packaging body according to this embodiment, when an ultraviolet blocking agent is added to the material constituting the packaging body, In this case, the proportion of the ultraviolet blocking agent to be added is, for example, 0.05 to 5.0% by weight based on the total amount of the material. The content of the ultraviolet blocking agent is preferably 0.1 to 3.0% by weight. For example, a coating paint containing an ultraviolet absorber is applied to a molded package or synthetic resin sheet. Here, the coating paint can be applied to a radiator or the like. Acrylic type of cal-polymerization system (e.g., polyester polyacrylate, urethane polyacrylate) acrylate, epoxy polyacrylate, polyether polyacrylate, side chain acryloyl acrylic resins, etc.), thiol-ene type (e.g., polythiol acrylic oligomers, poly Lithiol spiroacetal type, etc.), unsaturated polyester or cationic polymerization epoxy Resin or the like can be used. In addition, the material constituting the packaging body is spread into a film shape, and this It may also be formed from a sheet of adhesively laminated film.

[0106] The packaging material according to this embodiment is a material (packaging material) to which a coloring agent is added or coated. As the colorant, inorganic pigments, lake pigments, organic pigments, etc. can be used. .

[0107] The liquid medical formulation of the present invention has excellent photostability and can be packaged in a form for multiple administrations. It is useful as a multi-dose eye drop that is packaged and used continuously by the user, but It can also be formulated as a single-dose eye drop.

[0108] As described above, the packaging that blocks light with wavelengths of 280 to 320 nm is Therefore, the present invention further provides a method for preventing the decomposition of olopatadine and its salts. and a liquid medical formulation containing at least one selected from the group consisting of: A method for producing a compound comprising the steps of: The present invention also provides at least one method for inhibiting photodecomposition selected from the following: The liquid medical formulation contains at least one selected from the group consisting of phenanthrene and its salts. A method for manufacturing a pharmaceutical composition comprising the steps of: The present invention provides a method for inhibiting photodecomposition by using at least one compound selected from the group consisting of salts thereof.

[0109] In the above method, the type of olopatadine or its salt to be used, the content in the liquid pharmaceutical formulation In this case, other ingredients contained in the aqueous medicinal preparation, the form of the aqueous medicinal preparation, and wavelength 280 to 320 nm Regarding the package that blocks light such as the above, The same aspects as those described above can be applied.

[0110] The present invention also provides a pharmaceutical composition comprising at least one selected from the group consisting of olopatadine and salts thereof. A method for improving drainage of an aqueous medical formulation comprising: The method further includes a step of packaging the resin in a package made of a resin-based or polyester-based resin. The packaging material is of the above type and is used as a container for storing an aqueous medical formulation containing the ingredient This reduces the wettability between the liquid pharmaceutical formulation and the packaging, improving drainage during use. This reduces the amount of liquid remaining in the container. is particularly useful in ophthalmic compositions, particularly eye drops, which require a small amount of administration per time. For details of the styrene-based resin or polyester-based resin, see the above-mentioned packaged liquid medical preparation. In the above method, the content of component (A) can be increased. This can further improve the liquid drainage during use.

[0111] The liquid medical formulation according to this embodiment can be used as a formulation for pharmaceuticals, quasi-drugs, etc. For example, it can be used as an ophthalmic pharmaceutical preparation or an otolaryngological pharmaceutical preparation. For example, eye drops (also called eye drops or eye drops. Eye drops include contact lenses. This includes eye drops that can be applied during use.), artificial tears, eyewash (also called eyewash or eyewash medicine. In addition, eyewashes include eyewashes that can be used to wash the eyes while wearing contact lenses, and eye ointments, etc. Compositions for medical use; compositions for contact lenses (contact lens wetting solution, contact lens case) Contact lens disinfectant, contact lens preservative, contact lens preservative Cleaning agents, cleaning and preservative agents for contact lenses, etc.) are also included. The composition for use can be used for all types of contact lenses, including hard and soft contact lenses. The otorhinolaryngological pharmaceutical preparations include, for example, nasal drops, nasal washes, etc. can be.

[0112] The liquid medical formulation may be an injection, a suppository, an oral drug, an inhalation formulation, or the like. The liquid pharmaceutical preparation may be a topically applied liquid pharmaceutical preparation that is easily exposed to light when applied to a patient. Not only for skin application, but also for sensitive mucous membranes (cornea, conjunctiva, etc., mucous membranes of the eyes, gums, tongue, mouth) The liquid pharmaceutical preparation may be applied to the lips, oral mucosa, nasal mucosa, pharyngeal mucosa, etc. For example, examples of the aqueous medical preparation include topical skin preparations (ointments for skin, creams for skin, Skin liquids, etc.), eye drops, eyewash, eye ointments, contact lens wear solutions, contact lens solutions (cleaning solutions, storage solutions, disinfectants, multi-purpose solutions, etc.) These include nasal sprays (nose drops), nasal washes, oropharyngeal medicines, mouthwashes, and ear drops. In this specification, the term "contact lens" refers to a hard contact lens (oxygen permeable hard contact lens). All types of contact lenses, including hard contact lenses, soft contact lenses, etc. Among these, eye drops (eye drops), eye washes (eye washes), etc. are preferred. Examples of the pharmaceutical compositions include injections, topical skin preparations, nasal drops, and contact lens preparations.

[0113] In particular, when the packaging is a visible packaging, the pharmaceutical preparation in the container can be seen from the outside with the naked eye. It is possible to inspect the presence or absence of foreign matter by observation, and it complies with the provisions of the General Provisions for Preparation of Eye Drops in the Japanese Pharmacopoeia and In view of the effect of the present invention that the method for testing insoluble foreign matter in injections can be suitably carried out, Examples of pharmaceutical preparations include eye drops, eye washes, injections, etc. A formulation containing a single dose is preferred because it allows the user to visually check the amount of formulation remaining after each use. Specific examples of formulations containing multiple doses include eye drops, eye washes, topical skin preparations, and nasal drops. and contact lens preparations. When the package is a visible package, eye drops and eye washes are particularly suitable for the above reasons. preferable. [Example]

[0114] The present invention will be described in detail below based on examples, but the present invention is not limited to these. It is not something that can be done.

[0115] [Test Example 1-1: Photodecomposition inhibition confirmation test for olopatadine] An olopatadine-containing aqueous pharmaceutical formulation (eye drops) was prepared according to Formulation Example 1 shown in Table 1, and the results shown in Table 2 were The proportions of each ingredient in the formulation examples in Table 1 were calculated based on the aqueous pharmaceutical The unit is w / v% based on the total amount of the drug formulation. polyethylene terephthalate (PET) containers, polyethylene naphthalate (PEN) containers, Polycarbonate (PC) containers, polyethylene (PE) containers, polypropylene (PP The containers containing olopatadine were made of either a metal or glass. For aqueous pharmaceutical formulations, a photostability tester (Light-Tron LT-120 D3CJ) was used. A D65 fluorescent lamp was used as the light source, and the temperature was kept at 25°C. By continuously irradiating the lamp with 5,000 lx for 120 hours, the cumulative irradiation amount was 600,000 lx·h. The concentration of olopatadine in each liquid pharmaceutical formulation was then measured by high performance liquid chromatography. The remaining concentration of olopatadine was quantified by analysis using a fluororesin. The residual rate (%) of olopatadine relative to the concentration before light irradiation was calculated from the above data. The results are shown in Table 2. .

[0116] To evaluate the light transmittance of the containers used in the test, a portion of each container was cut out and examined. The system was a microplate reader (SH-9000, manufactured by Corona Electric Co., Ltd.). The light transmittance is measured in 10 nm increments in the wavelength range of 200 to 700 nm, and the specified wavelength of the container is The average light transmittance and the maximum transmittance in the wavelength range of 400 to 700 nm were determined. When there was a label or the like on the measurement area that interfered with the measurement, the measurement was carried out after removing it.

[0117] The visibility inside the containers used in the test was evaluated based on the following evaluation criteria. The test was carried out using a white light source at a brightness of 3000 to 5000 lx and was observed with the naked eye. The results are shown in Table 2. <Evaluation criteria> ◎ The amount of liquid pharmaceutical preparation inside and any foreign matter can be clearly seen ○ The amount of liquid pharmaceutical preparation inside and any foreign matter can be visually confirmed △ The amount of liquid medical preparation inside can be visually confirmed, but foreign matter is difficult to see. × The amount of aqueous pharmaceutical preparation inside and foreign matter cannot be visually confirmed

[0118] [Table 1]

[0119] [Table 2]

[0120] Among the various containers used in the test, the maximum light transmittance of 400 to 700 nm wavelength was 60% or more. The container has sufficient transparency so that the aqueous medical formulation contained inside can be seen from the outside. It was.

[0121] The residual rate of olopatadine after light irradiation was measured in a container that blocked light with wavelengths of 280 to 320 nm. The aqueous pharmaceutical formulation containing olopatadine contained in the container showed a significantly higher value. Even within the 20 nm range, especially the wavelength regions of 300 to 320 nm and 310 to 320 nm The lower the light transmittance in the region, the more the decomposition of olopatadine is suppressed, and the more stable olopatadine becomes in the container. It was confirmed that the wavelength ranges shown in Table 2 above were maintained. Coefficient of determination R for olopatadine residual rate of mean light transmittance of the area 2 By comparing It can also be seen that light with wavelengths of 280 to 320 nm is blocked. In addition, in a container that blocks light of 340 to 350 nm, the It was confirmed that decomposition was suppressed and the substance was stably maintained.

[0122] From the above results, it is believed that light of 280 to 320 nm is essential for the decomposition of olopatadine by exposure to light. It has been revealed that Olopata is involved in this process, and by blocking light in the above wavelength range, Furthermore, it was confirmed that the decomposition of olopatadine due to exposure to light can be suppressed. If the maximum light transmittance of the container containing the pharmaceutical preparation at wavelengths of 400 to 700 nm is 60% or more, It was confirmed that good visibility inside the vehicle could be ensured.

[0123] [Test Example 1-2: Photodecomposition inhibition confirmation test for olopatadine] Olopatadine-containing aqueous pharmaceutical formulations (eye drops) were prepared according to Formulation Examples 2 and 3 shown in Table 3. , Example 6-1-1 (colorless polyethylene terephthalate (PET) container) shown in Table 2 and in the same kind of container as that used in Example 7-1-1 (polycarbonate (PC) container). The proportion of each ingredient in the formulation examples in Table 3 is based on the total amount of the liquid pharmaceutical formulation. The unit is w / v%. The remaining concentration of olopatadine after light irradiation and exposure was measured in the same manner as in Test Example 1-1. Quantitation was performed, and the residual rate (%) relative to the olopatadine concentration before light irradiation was calculated. The results are shown in Table 4. The container of the example was also used for formulation examples 2 and 3, which have pH values ​​changed from formulation example 1. As a result, the residual rate of olopatadine after light irradiation was significantly high.

[0124] [Table 3]

[0125] [Table 4]

[0126] [Test Example 2: Confirmation test for inhibition of photodecomposition of olopatadine] Olopatadine hydrochloride 0.11 w / v%, benzalkonium chloride, anhydrous sodium monohydrogen phosphate The solution contains a cereal, a pH adjuster, and an isotonicity agent, and has a pH of 7.0 and an osmotic pressure ratio of 0.9 to 1.1. Patadin-containing aqueous pharmaceutical preparation (Patanol ophthalmic solution 0.1%, manufactured and sold by Alcon Japan) 5 mL of this was added to the same solution as that used in Example 6-1-1 and Comparative Example 3-1 shown in Table 2. The mixture was placed in a container and sealed, and designated as Example 6-2 and Comparative Example 3-2, respectively.

[0127] The thus obtained aqueous pharmaceutical formulations containing olopatadine in various containers were subjected to a photostability test. Equipment (Light-Tron LT-120 D3CJ type, manufactured by Nagano Scientific Co., Ltd.) Using a D65 fluorescent lamp as the light source, the light was irradiated with 5,000 lx at 120°C under a room temperature of 25°C. The samples were exposed to light with a cumulative irradiation dose of 600,000 lx·h by continuously irradiating them for 10 hours. The concentration of olopatadine in the sexually transmitted disease drug was analyzed by high performance liquid chromatography. The remaining concentration of olopatadine was quantified. From the measured remaining concentration of olopatadine, the The residual rate (%) relative to the concentration was calculated.

[0128] The results of the residual rate of olopatadine after light irradiation are shown in Table 5. When the composition of the liquid pharmaceutical formulation was different, Even in this case, the product containing olopatadine is stored in a container that blocks light with wavelengths of 280 to 320 nm. In the liquid pharmaceutical formulation, the residual rate of olopatadine after light irradiation was significantly high, as in Test Example 1-1. The values ​​were high.

[0129] [Table 5]

[0130] [Test Example 3: Confirmation test for inhibition of photodecomposition of olopatadine] An aqueous pharmaceutical formulation was prepared according to the formulation example shown in Table 6 below, and olopatadine or its derivatives were used to treat the photosensitivity of the liquid. The specific experimental procedures and results are shown below. The proportion of each ingredient in the examples is based on the total volume of the liquid pharmaceutical preparation, and the unit is w / v%.

[0131] [Table 6]

[0132] First, each liquid medical formulation shown in Table 6 was prepared by a conventional method. mL capacity transparent glass vial (similar to the glass (colorless) container used in Comparative Example 3-1 shown in Table 2) The same type) or 13 mL PET containers were filled with 5 mL each. The average light transmittance and maximum light transmittance at various lengths are shown in Table 7. Using the t-Tron LT-120 D3CJ type (manufactured by Nagano Scientific Co., Ltd.), Using a lamp as a light source, the liquid medicine was irradiated with 5000lx light for 120 hours continuously at room temperature. After exposing the agent to light with an accumulated irradiation dose of 600,000 lx·hr, the The remaining concentration of olopatadine was quantified, and the photostabilization of olopatadine was calculated according to the following formulas (I) and (II). The qualitative improvement rate was calculated, and the results are shown in Table 6. Residual rate (%) = (Olopatadine hydrochloride content after light irradiation) / (Olopatadine hydrochloride content before light irradiation) (I) × 100 (I) Photostability improvement rate (%) = {(residual rate of each Example or Comparative Example / residual rate of Comparative Example 4) - 1} ×100 (II)

[0133] [Table 7]

[0134] As shown in Table 6, Comparative Examples 4 to 6 each contained olopatadine and were filled in a glass vial. In comparison, it is packed in a PET container (transparent) and contains bromfenac together with olopatadine. In aqueous pharmaceutical preparations containing thorium and berberine sulfate, the residual rate of olopatadine It was confirmed that the photostability of olopatadine in the aqueous pharmaceutical formulation was improved.

[0135] Test Example 4: Test to confirm inhibition of coloration and precipitation of olopatadine As in Test Example 1-1, Formulation Example 1 in Table 1 was poured into a container in Table 2 (a representative container was selected) for 5 ml. L each and sealed. Examples 1-1, 5-1, 6-1-1, Comparative Examples 1-1, 2-1, The contents filled in the containers used in 3-1 were used as Examples 1-4, 5-4, 6-4, and Comparative Example 1-4, respectively. The scores were 1-4, 2-4, and 3-4.

[0136] The thus obtained various container-packed aqueous pharmaceutical formulations containing olopatadine were subjected to a photostability test using a photostability tester. (Using Suntester (SUNTEST XLS+: manufactured by ATLAS)) 765W / m 2 By irradiating for 19 hours, the cumulative irradiation dose was 52,000 kJ / m 2 The light was exposed to 200 μL of each sample before and after irradiation was placed in a 96-well plate and microplate- A rate reader (SH-9000, manufactured by Corona Electric Co., Ltd.) was used to measure the intensity at 420 nm. The absorbance of the sample before light irradiation was then measured. The value obtained by subtracting the absorbance was used to calculate the coloring degree. The results are shown in Figure 1.

[0137] After light irradiation, the color of the sample and the presence or absence of precipitation were visually inspected and evaluated according to the following criteria. The core was measured and the results are shown in Table 8. <Evaluation criteria> ◎ Colorless, no precipitation ○ Slightly yellow, no precipitation △ Light yellow, no precipitation × Deep yellow, no precipitation ×× Dark yellow, precipitates present

[0138] [Table 8]

[0139] The color of the olopatadine-containing aqueous pharmaceutical formulation after light irradiation is different from that of the 280-320 nm wavelength liquid pharmaceutical formulation. If the product is stored in a sealed container, there will be no coloring or only a slight yellow coloring. On the other hand, the comparative example, which was placed in a container that did not block light with wavelengths of 280 to 320 nm, In this case, deep yellow coloration and precipitation of the liquid pharmaceutical formulation were confirmed.

[0140] In addition to blocking light with wavelengths of 280 to 320 nm, it also blocks light with wavelengths of 340 to 350 nm. In the case of aqueous pharmaceutical preparations stored in containers that also block light, coloring is further suppressed. On the other hand, even if the light transmittance at wavelengths of 260 to 270 nm is low, In the case of an olopatadine-containing aqueous pharmaceutical formulation stored in a container with high light transmittance of 80 to 320 nm, It was confirmed that coloration and precipitation of the preparation due to light irradiation could not be suppressed.

[0141] From the above results, the coloring of aqueous formulations containing olopatadine due to light exposure is caused by wavelengths of 280 to 3 It has become clear that 20 nm light is involved, and by blocking light in this wavelength range, Therefore, it was confirmed that the coloring and precipitation of olopatadine-containing preparations due to exposure to light can be suppressed. Ta.

[0142] [Test Example 5: Confirmation test for inhibition of photodecomposition of olopatadine] Olopatadine-containing aqueous pharmaceutical formulations (eye drops) were prepared according to Formulation Examples 4 and 5 shown in Table 9. , Example 6-1-1 (colorless polyethylene terephthalate (PET) container) shown in Table 2 and in the same kind of container as that used in Example 7-1-1 (polycarbonate (PC) container). The proportion of each ingredient in the formulation examples in Table 9 is based on the total amount of the liquid pharmaceutical formulation. The units are w / v%. Formulation Examples 4 and 5 are the same as Formulation Examples 2 and 3, but with the addition of menthol. The resulting liquid pharmaceutical formulations containing olopatadine in various containers correspond to those containing a predetermined amount of 1,000 mg ... The remaining olopatadine after light irradiation and exposure to light was measured in the same manner as in Test Example 1-1. The concentration was quantified, and the residual rate (%) relative to the olopatadine concentration before light irradiation was calculated.

[0143] [Table 9]

[0144] [Table 10]

[0145] In the above examples, formulation examples 4 and 5 containing menthol were used, while formulation examples 2 and 3 were used. The residual rate of olopatadine after light irradiation was even higher than that of the Example in Test Example 1-2. It has been confirmed that the addition of menthol further increases the photostability of olopatadine. It was.

[0146] [Test Example 6: Test to confirm improvement of liquid drainage] Olopatadine-containing aqueous pharmaceutical formulations were prepared according to Formulation Examples 6, 7 and 8 shown in Table 11. In addition, the same formulations as Formulation Examples 6, 7, and 8 were used except that they did not contain olopatadine hydrochloride and l-menthol. Liquid medical formulations were prepared in the same manner and designated Comparative Formulation Examples 6', 7' and 8', respectively. The liquid pharmaceutical formulations of Formulation Example 8 and Comparative Formulation Example 8' were placed in a 10 mL glass vial and heated at 70°C. The samples were stored at RT for 5 days and used in the following tests.

[0147] [Table 11]

[0148] Using a contact angle meter DM-501 (manufactured by Kyowa Interface Science Co., Ltd.), expansion / contraction of the measuring device According to the measurement procedure of the method, the advancing contact angle, which is the contact angle when the interface between a solid and a liquid moves, is measured. Ta. Specifically, each container material shown in Table 12 was placed on the stage of the contact angle meter, and the The test liquid was set in the dispenser to match the formulation and container material. A 1 μL droplet of the test solution was dropped onto the surface of the container material and allowed to settle in a hemispherical shape. The tip of the liquid discharge part of the dispenser was placed on the top. In this state, the test liquid was discharged at a speed of 2μ The droplets were continuously discharged at a rate of 1 L / sec, and the droplet shapes were photographed from the side every 0.1 seconds 15 times. The comparative formulations corresponding to the above were also measured in succession using the same container material at the same room temperature. and photographed in the same way.

[0149] Next, the left and right contact angles were calculated for each image using the analysis software FAMAS for the above measurement device. Here, the contact angle is the distance from the contact point P between the container surface, the test liquid, and air to the test liquid. This refers to the angle between the line and a tangent drawn on the surface of the container material on the side containing the test solution. As the droplet expands by ejecting the test liquid, the contact angle changes and then remains approximately constant. The average value of the left and right contact angles was calculated for each image, and the images were sorted in the order they were taken. The average values ​​of the left and right contact angles were arranged. Five consecutive values ​​were selected, and the first one with a standard deviation of 2.5° was selected. The first contact angle below this was taken as the advancing contact angle in this test. The advancing contact angle was calculated three times for each test liquid, and the average of the three advancing contact angles was used as the test liquid. The advancing contact angle between the container materials was used. The same applies to cases where the advancing contact angle does not change during the droplet expansion process. The advancing contact angle was calculated in the same manner.

[0150] The advancing contact angle of each formulation example when using the same type of container material is calculated using the following formula (1). The percentage increase in the advancing contact angle from the corresponding comparative formulation was calculated. The results are shown in Table 13. Increase rate of advancing contact angle (%) = {(advancing contact angle of each formulation example / advancing contact angle of comparative formulation example) - 1}×100···(1)

[0151] [Table 12]

[0152] [Table 13]

[0153] As shown in Table 13, when polyethylene (PE) is used as the material, (A) composition The advancing contact angle of the aqueous medicinal formulation containing component (A) is lower than that of the formulation not containing component (A). On the other hand, container materials made of polyethylene terephthalate (PET) or polystyrene (PS) When the substance was used, quite unexpectedly, the forward adhesion of the aqueous pharmaceutical preparation containing component (A) was The antennae were significantly higher than those without component (A). When liquid-based pharmaceutical formulations flow into PET and PS containers, their wettability is significantly increased. In other words, it was confirmed that the (A) composition was low in PET or PS containers, especially PET containers. When an aqueous medical formulation containing the compound is stored, the liquid may run out when the aqueous medical formulation is used. It has been shown that this has the advantageous effect of improving the wetness of the coating and suppressing residual wetness on containers, etc. In addition, in Formulation Example 7, where the concentration of component (A) in the liquid medical formulation was high, The rate of increase in the advancing contact angle was even higher compared to the case without the coating.

[0154] (Formulation example) The following are examples of formulations. Each example was prepared so that the osmotic pressure ratio was 0.5 to 2.0. Formulation Examples 9 to 23 were placed in the same type of container as in Example 1-1 (PET + UV blocking agent, colorless). The filled products were placed in the same containers (PET+) as in Example 2-1 for Formulation Examples 1 to 15 and Formulation Examples 9 to 23. UV blocking agent + coloring agent (brown) was used in Formulation Examples 16 to 30 and Formulation Examples 9 to 23. The same type of container (PEN, colorless) as in Example 5-1 was filled and used in Formulation Examples 31 to 45 and Formulation Example 9. Formulation Example 46-23 was filled in the same type of container (PET, colorless) as in Example 6-1-1. I set it at 60.

[0155] [Table 14]

[0156] [Table 15]

Claims

[Claim 1] The invention described in the specification.

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