Water-based composition

Abstract

A technology is provided for suppressing a decrease in the content of tafluprost in an aqueous composition caused by covering at least a portion of a container made of a predetermined resin with a label having a specific material. [Solution] An aqueous composition containing tafluprost is provided, which is contained in a resin container that contains polyethylene but does not contain a cyclic olefin polymer, and at least a portion of the container is covered with a polyester label.

Description

[Technical Field]

[0001] The present invention relates to aqueous compositions that are useful primarily in the ophthalmic field. [Background technology]

[0002] Tafluprost inhibits prostaglandin F 2α Tafluprost is a derivative of tafluprost and is used as an active ingredient in drugs for treating glaucoma and ocular hypertension. Tafluprost tends to be easily adsorbed to the resin container of an eye drop. In response to this, for example, Patent Document 1 describes a unit-dose aqueous eye drop solution filled in a polyethylene resin container, which contains 0.0015% w / v tafluprost, 0.075-0.1% w / v polysorbate 80, 0.01-0.1% w / v edetate disodium, and, as necessary, a buffer, pH adjuster, and isotonicity agent commonly used in eye drops, but does not contain a preservative. It is suggested that this aqueous eye drop solution inhibits adsorption of tafluprost to the resin container, which is essentially made of polyethylene.

[0003] On the other hand, most eye drop containers are distributed, stored, etc. in a packaged state with a label indicating the brand name, composition, volume, storage method, etc., from the viewpoint of identification. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Patent No. 6148317 Summary of the Invention [Problem to be solved by the invention]

[0005] The present inventors have discovered that when an aqueous composition containing tafluprost is contained in a container made of a specified resin and at least a portion of the container is covered with a label made of a specific material, a problem arises in that the content of tafluprost in the aqueous composition decreases.

[0006] The present invention aims to provide a technology for suppressing a decrease in the content of tafluprost in an aqueous composition caused by covering at least a portion of a container made of a specified resin with a label having a specific material. [Means for solving the problem]

[0007] As a result of intensive research to solve the above problems, the inventors have found that by storing an aqueous composition containing tafluprost in a resin container that contains polyethylene but does not contain a cyclic olefin polymer, and covering this container with a polyester label, it is possible to suppress the decrease in the tafluprost content caused by the label material.

[0008] That is, the present invention relates to the following. [1] An aqueous composition containing tafluprost, the aqueous composition is contained in a resin container containing polyethylene but not containing a cyclic olefin polymer; The aqueous composition, wherein at least a portion of the container is covered with a polyester label. [2] The aqueous composition according to [1], wherein the aqueous composition is in contact with polyethylene of the container. [3] The aqueous composition according to [1] or [2], wherein the polyester contains polyethylene terephthalate. [4] The aqueous composition according to any one of [1] to [3], wherein the container is a multi-dose container. [5] The aqueous composition according to any one of [1] to [4], wherein the content of tafluprost in the aqueous composition is 0.001 to 0.002 w / v % or more. [6] The container is a container in which at least a portion of the container allows the aqueous composition to be visible from the outside of the container, The aqueous composition according to any one of [1] to [5], wherein at least 15% or more of the total surface area of ​​the portion of the container where the aqueous composition is visible from the outside of the container is covered with a label. [7] The aqueous composition according to any one of [1] to [6], wherein the content of tafluprost in the aqueous composition after storage at 60°C for 3 weeks is 86% or more compared to when the container is not covered with a label. [8] The content of tafluprost in the aqueous composition after storage at 60°C for 1 week is 84% ​​or more of that at the start of storage, and / or The aqueous composition according to any one of [1] to [7], wherein the content of tafluprost in the aqueous composition after storage at 60°C for 2 weeks is 78% or more of that at the start of storage. [9] The aqueous composition according to any one of [1] to [8], further comprising one or more selected from timolol, carteolol, bunazosin, apraclonidine, dorzolamide, brinzolamide, ripasudil, omidenepagisopropyl, and salts thereof.

[10] The aqueous composition according to any one of [1] to [9], further comprising one or more selected from the group consisting of a solubilizer, a buffer, a tonicity adjusting agent, a preservative, and a pH adjuster. [Effects of the Invention]

[0009] According to the present invention, the decrease in the content of tafluprost in an aqueous composition under predetermined conditions is suppressed. [Brief explanation of the drawings]

[0010] [Figure 1] FIG. 1 shows the results of stability study 5. [Figure 2] FIG. 2 shows the results of stability study 6. [Figure 3] FIG. 3 shows the results of stability study 7. DETAILED DESCRIPTION OF THE INVENTION

[0011] The present invention will be described in detail below. The features of the present invention described below can be combined in any combination.

[0012] In the present invention, when "Y consisting of X" or "Y consisting only of X" or the like (X and Y represent any element, the same applies hereinafter), it means that Y does not contain any element other than X. In contrast, when "Y containing (including) X" or "Y having X" or the like is used, it means that Y may contain an element other than X. Furthermore, when "Y substantially consisting of X" is used, it means that Y may contain an element other than X, as long as the effect of the present invention is not impaired. In addition, in the present invention, "consisting of", "consisting only of" and "containing (including)", "having", etc. can be used interchangeably as appropriate.

[0013] When referring to a salt of a compound in the present invention, the salt may be an acidic or basic salt. Examples of acidic salts include, but are not limited to, mineral acid salts such as hydrochloride, hydrobromide, nitric acid, and sulfuric acid; organic carboxylic acid salts such as formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, gluconic acid, succinic acid, malic acid, tartaric acid, aspartic acid, trichloroacetic acid, and trifluoroacetic acid; and sulfonic acid salts such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, and naphthalenesulfonic acid. Examples of basic salts include, but are not limited to, alkali metal salts such as sodium and potassium; alkaline earth metal salts such as calcium and magnesium; ammonium salts; and salts of nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine.

[0014] In the present invention, when referring to a solvate of a compound or a salt thereof, it means a molecule containing solvent molecules in a certain stoichiometric ratio in the crystal. The solvate may contain any solvent molecules such as water or alcohol, and may be, for example, a hydrate containing water molecules. The number of solvent molecules in the solvate is not particularly limited, and for example, the solvate may be a dihydrate containing two water molecules. The solvate also includes an anhydrate (anhydrous product) obtained by removing water molecules from a hydrate.

[0015] [Aqueous composition] One embodiment of the present invention relates to an aqueous composition. In the present invention, an aqueous composition refers to a composition containing water. The water content in the aqueous composition may be, for example, 80% or more, 90% or more, 95% or more, or more. The water may be purified water, sterile purified water, water for injection, etc.

[0016] (active ingredient) The aqueous composition of the present invention contains tafluprost as an active ingredient, which is a compound represented by the chemical formula: 1-Methylethyl(5Z)-7-{(1R,2R,3R,5S)-2-[(1E)3,3-difluoro-4-phenoxy-1-butenyl]3,5-dihydroxycyclopentyl}-5-heptenoate.

[0017] The content of tafluprost in the aqueous composition may be, for example, 0.0001 w / v% or more, 0.001 w / v% or more, or 0.0015 w / v% or more, or may be, for example, 0.01 w / v% or less, 0.005 w / v% or less, 0.003 w / v% or less, or 0.002 w / v% or less. The above-mentioned upper and lower limit values ​​may be arbitrarily combined to represent a range of the tafluprost content. In one embodiment, the content of tafluprost in the aqueous composition is 0.001 to 0.002 w / v%.

[0018] (Other ingredients) The aqueous composition of the present invention may further contain other ingredients in addition to the active ingredient.The other ingredients include a solubilizer, a buffer, an isotonicity agent, a preservative, a pH adjuster, a stabilizer, a thickener, etc.In addition, the aqueous composition of the present invention may further contain one or more active ingredients other than tafluprost.

[0019] Examples of solubilizers include polyoxyethylene hydrogenated castor oil derivatives, polyoxyethylene glycol monostearate, polysorbates, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid esters, and tyloxapol, but are not particularly limited as long as they are commonly used in the pharmaceutical (preferably ophthalmic) field. The aqueous composition of the present invention may contain two or more solubilizers. In one embodiment, the solubilizer is a polyoxyethylene hydrogenated castor oil derivative such as polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, or polyoxyethylene hydrogenated castor oil 80. In another embodiment, the solubilizer is a polysorbate such as polysorbate 20, polysorbate 60, polysorbate 65, or polysorbate 80.

[0020] The content of the solubilizer (the total content when there are two or more solubilizers) may be within a range that achieves the desired solubilizing effect, and may be, for example, 0.001 w / v% or more, 0.005 w / v% or more, 0.01 w / v% or more, or 0.05 w / v% or more in the aqueous composition, or may be, for example, 1.0 w / v% or less, 0.5 w / v% or less, or 0.1 w / v% or less. The range of the solubilizer content may be expressed by any combination of the above-mentioned upper and lower limit values.

[0021] Examples of buffering agents include phosphoric acid, acetic acid, epsilon-aminocaproic acid, boric acid, tartaric acid, salts thereof, and solvates thereof, but are not particularly limited as long as they are commonly used in the pharmaceutical (preferably ophthalmic) field. The aqueous composition of the present invention may contain two or more buffering agents. In one embodiment, the buffering agent is one or more selected from phosphoric acid, salts thereof, and solvates thereof, and in a specific embodiment, is sodium dihydrogen phosphate hydrate.

[0022] The content of the buffering agent (the total content when two or more buffering agents are used) may be within a range that provides the desired buffering effect, and may be, for example, 0.01 w / v% or more, 0.05 w / v% or more, or 0.1 w / v% or more in the aqueous composition, or may be, for example, 5.0 w / v% or less, 1.0 w / v% or less, or 0.5 w / v% or less. The range of the buffering agent content may be expressed by combining any of the above upper and lower limit values.

[0023] Examples of isotonicity agents include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, glycerin, concentrated glycerin, propylene glycol, polyethylene glycol, glucose, sorbitol, mannitol, trehalose, maltose, sucrose, butylene glycol, etc., but are not particularly limited as long as they are commonly used in the pharmaceutical (preferably ophthalmic) field. The aqueous composition of the present invention may contain two or more isotonicity agents. In one embodiment, the isotonicity agent is one or more selected from sodium chloride and propylene glycol. In another embodiment, the isotonicity agent is one or more selected from glycerin and concentrated glycerin.

[0024] The content of the isotonicity agent (the total content when two or more isotonicity agents are used) may be within a range that achieves the desired isotonicity effect, and may be, for example, 0.1 w / v% or more, 0.5 w / v% or more, 1.0 w / v% or more, or 1.5 w / v% or more in the aqueous composition, or may be, for example, 5.0 w / v% or less, or 3.0 w / v% or less. The range of the isotonicity agent content may be expressed by combining any of the above upper and lower limit values.

[0025] Examples of preservatives include biguanide compounds, quaternary ammonium salts, benzoic acid and its salts, parahydroxybenzoic acid esters, chlorobutanol, sorbic acid and its salts, dehydroacetic acid and its salts, benzyl alcohol, parachlormetaxylenol, chlorocresol, phenethyl alcohol, thimerosal, polydronium chloride, zinc chloride, and chlorite, but are not particularly limited as long as they are commonly used in the pharmaceutical (preferably ophthalmic) field. The aqueous composition of the present invention may contain two or more preservatives. In one embodiment, the preservative is one or more biguanide compounds selected from polyhexanide hydrochloride, chlorhexidine gluconate, and the like. In another embodiment, the preservative is one or more quaternary ammonium salts selected from benzethonium chloride, benzalkonium chloride, methylbenzethonium chloride, polydronium chloride, and the like.

[0026] The content of the preservative (the total content when two or more preservatives are used) may be within a range that provides the desired preservative effect (bacteriostatic or bactericidal effect) (e.g., conforms to the preservative effectiveness test specified in the Japanese Pharmacopoeia (18th Edition)), and may be, for example, 0.000001 w / v% or more, 0.000005 w / v% or more, or 0.00001 w / v% or more in the aqueous composition, or may be, for example, 0.01 w / v% or less, 0.005 w / v% or less, or 0.001 w / v% or less. The range of the preservative content may be expressed by arbitrarily combining the respective upper and lower limits described above.

[0027] Examples of pH adjusters include hydrochloric acid, citric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, etc., but are not particularly limited as long as they are commonly used in the field of pharmaceuticals (preferably ophthalmic agents). The pH adjuster may be one or more types, as long as it can adjust the pH of the aqueous composition of the present invention to the desired range, and the content thereof is not particularly limited.

[0028] Examples of stabilizers include ascorbic acid, tocopherol, dibutylhydroxytoluene, edetic acid or its salts and solvates thereof, povidone, sulfite, monoethanolamine, cyclodextrin, dextran, taurine, etc., but are not particularly limited as long as they are commonly used in the pharmaceutical (preferably ophthalmic) field. The aqueous composition of the present invention may contain two or more stabilizers. In one embodiment, the stabilizer is edetic acid or its salts, such as edetic acid, monosodium edetate, disodium edetate (also known as sodium edetate), trisodium edetate, or tetrasodium edetate, as well as solvates thereof.

[0029] Examples of thickeners include carboxyvinyl polymer, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, xanthan gum, sodium chondroitin sulfate, sodium hyaluronate, hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose, etc., but are not particularly limited as long as they are commonly used in the pharmaceutical (preferably ophthalmic) field.The aqueous composition of the present invention may contain two or more thickeners.

[0030] The active ingredient other than tafluprost may be, for example, any ingredient having an intraocular pressure-reducing effect. Non-limiting examples include compounds having β-receptor blocking activity such as timolol and carteolol; compounds having α-receptor blocking activity such as bunazosin hydrochloride; compounds having α-receptor agonist activity such as apraclonidine; compounds having carbonic anhydrase inhibitory activity such as dorzolamide hydrochloride and brinzolamide; compounds having Rho kinase inhibitory activity such as ripasudil hydrochloride; and compounds having EP2 receptor agonist activity such as omidenepagisopropyl. In some embodiments, the active ingredient other than tafluprost is one or more selected from timolol and its salts.

[0031] The content of the active ingredient other than tafluprost may be within a range in which its efficacy and safety are recognized. For example, when the active ingredient other than tafluprost is one or more selected from timolol and its salts, the content may be, for example, 0.1 w / v% or more, 0.25 w / v% or more, or 0.5 w / v% or more, as timolol in the aqueous composition, and may be, for example, 1.5 w / v% or less, or 1.0 w / v% or less. The above-mentioned upper and lower limit values ​​may be arbitrarily combined to represent the range of the content of one or more selected from timolol and its salts.

[0032] (pH) The pH of the aqueous composition of the present invention is not particularly limited as long as the effects of the present invention are not impaired, and may be, for example, 4 or more, 4.5 or more, 5 or more, 5.5 or more, or 6 or more, or may be, for example, 8 or less, 7.5 or less, or 7 or less. The above-mentioned upper and lower limit values ​​may be appropriately combined to represent a pH range.

[0033] (osmotic pressure ratio) The osmotic pressure ratio of the aqueous composition of the present invention is not particularly limited as long as the effects of the present invention are not impaired, and may be, for example, 0.8 or more, 0.85 or more, 0.9 or more, 0.95 or more, or 1.0 or more, or may be, for example, 1.3 or less, 1.25 or less, 1.2 or less, 1.15 or less, or 1.1 or less. The above-mentioned upper and lower limit values ​​may be appropriately combined to represent a range of the osmotic pressure ratio.

[0034] (Other characteristics, etc.) The properties of the aqueous composition of the present invention other than those described above are not particularly limited as long as the effects of the present invention are not impaired. For example, the aqueous composition of the present invention may have a clarity acceptable for use as an eye drop. Furthermore, for example, the amount of gas (e.g., oxygen) dissolved in the aqueous composition of the present invention is not particularly limited as long as the effects of the present invention are not impaired, and may be, for example, 0 to 50 ppm, 1 to 40 ppm, 1 to 30 ppm, 1 to 20 ppm, 1 to 15 ppm, or 1 to 10 ppm.

[0035] (Preparation method) The aqueous composition of the present invention can be prepared by any method. For example, the composition of the present invention can be prepared by dissolving each component in water and then adjusting the pH. The preparation may include a filtration sterilization step. The filtration sterilization step may include, for example, passing the aqueous composition through a filter. The order in which each component is dissolved or mixed, or the order in which each preparation step, such as dissolution, pH adjustment, and sterilization, is performed, is not particularly limited.

[0036] [Containment Unit] The aqueous composition of the present invention is contained in a container made of a predetermined resin. The container may be any container capable of containing the aqueous composition, and its shape and size are not particularly limited. The container may be, for example, an eye dropper. The phrase "the aqueous composition is contained in a container" means that the aqueous composition is present inside the container.

[0037] The capacity of the container is not particularly limited and may be, for example, 1 mL or more, 2 mL or more, 2.5 mL or more, 3 mL or more, or 5 mL or more, or may be, for example, 10 mL or less, preferably 7.5 mL or less, and more preferably 5 mL or less. The above-mentioned upper and lower limit values ​​may be appropriately combined to represent the range of the container capacity.

[0038] The resin forming the container may be made of a single layer or may be made of multiple layers.

[0039] (resin) The container of the present invention is made of a resin containing polyethylene. The polyethylene may be, for example, low-density polyethylene, linear low-density polyethylene, medium-density polyethylene, high-density polyethylene, etc., and the type is not particularly limited. When the container is made of multiple resin layers, the container only needs to have at least one layer made of a resin containing polyethylene. In this case, it is preferable that the layer that comes into contact with the aqueous composition is a layer made of a resin containing polyethylene. In other words, it is preferable that the aqueous composition comes into contact with the polyethylene of the container.

[0040] Resins that can be contained include, for example, one or more of the following resin materials commonly used in so-called plastic containers for eye drops: polyolefin resins such as polypropylene; polycarbonate resins; polyester resins such as polyethylene terephthalate and polybutylene terephthalate; polyphenylene ether resins; polyarylate resins such as bisphenol A / terephthalic acid condensate and bisphenol A / isophthalic acid condensate; polyvinyl chloride resins; polystyrene resins; acrylic resins, etc. Note that cyclic olefin polymers can be excluded from the polyolefin resins.

[0041] In one embodiment, the resin does not contain a cyclic olefin polymer. In another embodiment, the resin consists essentially of polyethylene and does not contain a cyclic olefin polymer. "A resin consists essentially of polyethylene" means that the content of resin materials other than polyethylene in the resin is, for example, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less in the resin. Note that a cyclic olefin copolymer may be included.

[0042] In one embodiment, the resin comprises polyethylene.

[0043] (Other ingredients) The container may contain materials other than resin as long as the effects of the present invention are not impaired. Examples of such materials include ultraviolet absorbers such as 2-(2H-benzotriazol-2-yl)-p-cresol and 2-(2H-benzotriazol-2-yl)-4,6-bis(1-methyl-1-phenylethyl)phenol, ultraviolet scattering agents such as titanium oxide and zinc oxide, and colorants such as inorganic pigments, organic pigments, and dyes.

[0044] (characteristics, form, etc.) The container may be, for example, airtight (a state in which solid foreign matter cannot be introduced and the contents cannot be lost under normal handling, transportation or storage conditions), airtight (a state in which solid or liquid foreign matter cannot be introduced and the contents cannot be lost, efflorescence, deliquescence or evaporation under normal handling, transportation or storage conditions), or sealed (a state in which gas cannot be introduced under normal handling, transportation or storage conditions). The shape of the container is not particularly limited, and it can be manufactured taking into consideration the properties and thickness of the resin used.

[0045] In one embodiment, at least a portion of the container is transparent. "Transparent" may mean, for example, being transparent or translucent. In the present invention, "transparent" or "translucent" means that the transmittance of visible light at wavelengths of 380 nm to 780 nm is, for example, 10% or more, 20% or more, 30% or more, 40% or more, or 50% or more. In one embodiment, at least a portion of the container is transparent enough to allow the aqueous composition to be visible from the outside of the container (the side not in contact with the aqueous composition). In a specific embodiment, the container is transparent enough to allow visual inspection of insoluble foreign matter.

[0046] In one embodiment, the container is a multi-dose container. A multi-dose container refers to a packaging form intended for repeated use, in which the cap or the like can be freely opened and resealed. In contrast, a packaging form intended for use up in one opening is called a unit-dose container or the like. The capacity of a multi-dose container is not particularly limited and may be, for example, 1 mL or more, 2 mL or more, 2.5 mL or more, 3 mL or more, or 5 mL or more, or may be, for example, 10 mL or less, preferably 7.5 mL or less, and more preferably 5 mL or less. The above-mentioned upper and lower limit values ​​may be appropriately combined to represent the range of the capacity of the multi-dose container.

[0047] When the container is an eye drop container, the container may be composed of multiple parts that eye drop containers generally have, such as a cap, an inner stopper, a bottle (bottle, main body), and a filter. The cap, inner stopper, bottle (bottle, main body), and filter may each contain a different material, but it is preferable that at least the bottle (bottle, main body) contains the resin described above. In a more preferred embodiment, the cap, inner stopper, and bottle (bottle, main body) contain the resin described above.

[0048] When the eye drop container has a filter, the pore size of the filter may be, for example, 5 μm or less, preferably 0.1 to 2.5 μm, and more preferably 0.1 to 1.0 μm. The material of the filter does not need to be the same as the material of the cap, inner stopper, and bottle (bottle, main body), and may be, for example, one or more selected from polyethersulfone, polyvinylidene fluoride, polycarbonate, polytetrafluoroethylene, mixed cellulose esters, and polyamide.

[0049] When the container is an eye drop container and at least a portion of the container is transparent, it is preferable that at least a portion of the bottle (main body) of the eye drop container is transparent. In one embodiment, the container is an eye drop container and 80% or more, or 90% or more of the total surface area of ​​the bottle (main body) of the eye drop container is transparent.

[0050] The container may be sterilized. The sterilization may be, for example, gas sterilization, and examples of gases used in gas sterilization include ethylene oxide gas, hydrogen peroxide gas, and mixed gases of these with carbon dioxide, etc. The sterilization may also be radiation sterilization, including gamma ray irradiation and electron beam irradiation.

[0051] (label) At least a portion of the container of the present invention is covered with a polyester label. "At least a portion of the container is covered with a label" means that at least a portion of the outer surface of the container (the surface not in contact with the aqueous composition) is covered with the label.

[0052] The label may be made of a single layer of polyester or may be made of multiple layers. When the label is multi-layered, the label may have a layer containing an adhesive (adhesive layer) in addition to the polyester layer.

[0053] The polyester may be, for example, polyethylene terephthalate (PET), polyethylene naphthalate (PEN), polybutylene terephthalate (PBT), polybutylene naphthalate (PBN), etc. In one embodiment, the polyester comprises polyethylene terephthalate (PET).

[0054] In addition to polyester, the label may further contain one or more materials commonly used as film substrates for labels, such as polyamides such as nylon and aramid; polyarylates such as bisphenol A / terephthalic acid condensates and bisphenol A / isophthalic acid condensates; polycarbonate; polyolefins such as polypropylene and polyethylene; and polyvinyl chloride, as long as the effects of the present invention are not impaired. In one embodiment, the label does not contain biaxially oriented polystyrene (OPS). In another embodiment, the label does not contain polystyrene.

[0055] When the label has an adhesive layer, the adhesive layer may contain, for example, an acrylic adhesive such as butyl acrylate, amyl acrylate, hexyl acrylate, cyclohexyl acrylate, phenyl acrylate, methoxyethyl acrylate, ethoxyethyl acrylate, diethylaminoethyl acrylate, 2-hydroxyethyl acrylate, or 2-aminoethyl acrylate.

[0056] The label may be a shrink label, a shrink tack label, a tack label, etc., and its form is not particularly limited. A shrink label is a label that has heat shrinkability and shrinks when heat is applied, allowing the container to be shrink-wrapped. A shrink tack label is a label that has a tack (adhesive) surface and shrinks when heat is applied after application, conforming to the shape of the container. A tack label is a label that has a tack (adhesive) surface and can be applied with pressure to wrap the container. In one embodiment, the label is a shrink label.

[0057] The surface area of ​​the portion of the container that is covered by the label may be, for example, 10% or more, 15% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or more, of the total surface area of ​​the container.

[0058] In the present invention, the term "label coverage" refers to the ratio of the surface area of ​​the portion of the container covered with the label to the surface area of ​​the container covered with the label. The label coverage rate is, for example, the ratio of the surface area of ​​the bottle (bottle, body) covered with the label to the surface area of ​​the bottle (top, sides, and bottom in the case of multi-dose containers). However, it does not include the part of the bottle (bottle, body) covered by the cap that is not directly covered with the label.

[0059] When the container is an eye drop container, it is preferable that at least a portion of the bottle (main body) of the eye drop container is covered with the label. In this case, the coverage of the label on the bottle (main body) may be, for example, 10% or more, 15% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 85% or more, 90% or more, or more.

[0060] When at least a portion of the container allows the aqueous composition to be seen from the outside of the container, the coverage of the label on the container may be, for example, 15% or more of the total surface area of ​​the portion of the container where the aqueous composition is visible from the outside of the container, preferably at least 30% or more, and more preferably 40% or more, 50% or more, 60% or more, or more.

[0061] [Prevention of decrease in tafluprost content] According to one embodiment of the present invention, the decrease in the content of tafluprost in the aqueous composition is suppressed.The content of tafluprost in the aqueous composition can be evaluated by any suitable method.For example, as shown in this example, the method may include measuring the peak area derived from tafluprost in the aqueous composition using high performance liquid chromatography.In this method, if the decrease in the peak area after storage under predetermined conditions, for example, relative to the peak area at a certain time point, is smaller than that of any control, it can be evaluated that the decrease in the content of tafluprost in the aqueous composition is suppressed.

[0062] One embodiment of the present invention relates to a method for suppressing a decrease in the content of tafluprost in an aqueous composition, the method comprising: storing the aqueous composition containing tafluprost in a resin container containing polyethylene but not containing a cyclic olefin polymer, and covering at least a portion of the container with a polyester label. In this method, a container at least a portion of which is covered with a polyester label may be used.

[0063] Another embodiment of the present invention relates to a method for suppressing a decrease in the content of tafluprost in an aqueous composition, comprising covering at least a portion of a container made of a resin containing polyethylene but not a cyclic olefin polymer, in which the aqueous composition containing tafluprost is contained, with a polyester label.

[0064] According to some embodiments of the present invention, the content of tafluprost in the aqueous composition after 3 weeks of storage at 60°C is 86% or more, preferably 90% or more, more preferably 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more, particularly preferably 99.2% or more, relative to when the container is not coated with a label. As shown in this example, this value can be calculated as the tafluprost ratio (%) by the following formula based on the results of measuring the peak area derived from tafluprost in the aqueous composition by high performance liquid chromatography. Tafluprost ratio (%) = Peak area when the container is coated with a label / Peak area when the container is not coated with a label × 100 (%)

[0065] According to some embodiments of the present invention, the content of tafluprost in the aqueous composition after storage at 60°C for one week is 84% ​​or more, preferably 85% or more, relative to the content at the start of storage, and / or the content of tafluprost in the aqueous composition after storage at 60°C for two weeks is 78% or more, preferably 80% or more, more preferably 81% or more, or 82% or more, relative to the content at the start of storage. According to some embodiments of the present invention, the content of tafluprost in the aqueous composition after storage at 60°C for three weeks is 68% or more, preferably 70% or more, more preferably 75% or more, and even more preferably 80% or more, or 81% or more, relative to the content at the start of storage. As shown in the present Examples, this value can be calculated as the tafluprost ratio (%) by measuring the peak area derived from tafluprost in the aqueous composition by high performance liquid chromatography and using the results to calculate the tafluprost ratio (%) using the following formula: Tafluprost ratio (%) = tafluprost peak area at a given time point during storage / tafluprost peak area at the start of storage × 100 (%) [Example]

[0066] The present invention will be specifically described below with reference to examples. Note that the following examples are merely examples of specific implementations of the present invention and are not intended to limit the scope of the present invention in any way.

[0067] Example 1 <Preparation of aqueous composition> Tafluprost (1.5 mg), polyoxyethylene hydrogenated castor oil 40 (appropriate amount), sodium dihydrogen phosphate hydrate (appropriate amount), propylene glycol, sodium chloride (adjusted to an osmotic pressure ratio of 1), and 20% polyhexanide hydrochloride solution (adjusted to comply with the preservative effectiveness test of the Japanese Pharmacopoeia (18th revision)) were dissolved in purified water, and the pH was adjusted to 6 using sodium hydroxide or hydrochloric acid (appropriate amount) as needed. Purified water was added to make the total volume 100 mL, and the solution was filtered to prepare an aqueous composition. It was confirmed that the ocular tissue penetration of this solution was equivalent to that of Tapros® ophthalmic solution 0.0015% (Santen Pharmaceuticals).

[0068] <Manufacturing unlabeled products> 3 mL of the obtained aqueous composition was placed in a polyethylene resin container (a multi-dose container in which the entire top surface of the bottle (main body) is covered with a cap) to produce an unlabeled product. The aqueous composition contained in the container was visible from the outside of the container.

[0069] <Production of labeled products> The resulting unlabeled product was covered with a shrinkable polyethylene terephthalate label to produce a labeled product. The label coverage of the container was 85% of the surface area of ​​the container (surface area of ​​the sides and bottom).

[0070] (Comparative Example 1) An aqueous composition prepared in the same manner as in Example 1 was placed in a polyethylene resin container (a multi-dose container in which the entire top surface of the bottle (main body) is covered with a cap) to prepare an unlabeled product. The unlabeled product was then covered with a shrink label made of biaxially oriented polystyrene to produce a labeled product.

[0071] (Stability test 1) <Test Method> The labeled and unlabeled samples were stored at 60°C (at constant humidity) for 3 weeks. The peak area of ​​tafluprost was then measured using high-performance liquid chromatography, and the tafluprost ratio of the labeled sample was calculated based on the peak area of ​​tafluprost in the unlabeled sample stored at 60°C for 3 weeks. Tafluprost ratio (%) = peak area of ​​tafluprost in labeled product (60°C for 3 weeks) / peak area of ​​tafluprost in unlabeled product (60°C for 3 weeks) × 100

[0072] <Result> As shown in Table 1, Example 1 showed a significant improvement in the tafluprost ratio compared to Comparative Example 1, and it was confirmed that a decrease in the tafluprost content caused by the label material could be suppressed.

[0073] [Table 1]

[0074] (Stability test 2) Similar results can be obtained by replacing the aqueous compositions used in Example 1 and Comparative Example 1 with Tapros (registered trademark) ophthalmic solution 0.0015% by the same evaluation method (Table 2, Example 2, Comparative Example 2). Tapros (registered trademark) ophthalmic solution 0.0015% is an aqueous ophthalmic solution containing tafluprost at a concentration of 0.0015 w / v % and further containing polysorbate 80, sodium dihydrogen phosphate hydrate, sodium edetate hydrate, concentrated glycerin, benzalkonium chloride, and a pH adjuster in predetermined content ratios.

[0075] <Result> As shown in Table 2, Example 2 exhibited a significant improvement in the tafluprost ratio compared to Comparative Example 2, and was able to suppress a decrease in the tafluprost content caused by the label material.

[0076] [Table 2]

[0077] Example 3 Tafluprost (1.5 mg), timolol maleate (683 mg) (500 mg as timolol), polyoxyethylene hydrogenated castor oil 40 (appropriate amount), sodium dihydrogen phosphate hydrate (appropriate amount), propylene glycol (adjusted to an osmotic pressure ratio of 1), and 20% polyhexanide hydrochloride solution (adjusted to comply with the preservative effectiveness test of the Japanese Pharmacopoeia (18th edition)) were dissolved in purified water, and the pH was adjusted to 7 using sodium hydroxide or hydrochloric acid (appropriate amount) as needed. Purified water was added to make the total volume 100 mL, and the solution was filtered to prepare an aqueous composition. Unlabeled and labeled products were produced in the same manner as in Example 1. It was confirmed that the ocular tissue penetration of this solution was equivalent to that of Tapcom® Combination Ophthalmic Solution (Santen Pharmaceuticals).

[0078] (Comparative Example 3) An aqueous composition prepared in the same manner as in Example 3 was placed in a polyethylene resin container (multi-dose container) and an unlabeled product was then covered with a biaxially oriented polystyrene label to produce a labeled product.

[0079] (Stability test 3) The tafluprost ratio was calculated in the same manner as in Stability Test 1.

[0080] [Table 3]

[0081] As shown in Table 3, Example 3 showed a significant improvement in the tafluprost ratio compared to Comparative Example 3, and it was confirmed that a decrease in the tafluprost content caused by the label material could be suppressed.

[0082] (Stability test 4) Similar results can be obtained by replacing the aqueous compositions used in Example 3 and Comparative Example 3 with the Tapcom (registered trademark) ophthalmic solution by evaluation in the same manner (Table 4, Example 4, Comparative Example 4). The Tapcom (registered trademark) ophthalmic solution is an aqueous ophthalmic solution containing tafluprost at a concentration of 0.0015 w / v%, timolol maleate at a concentration of 0.5 w / v% as timolol, and polysorbate 80, sodium dihydrogen phosphate hydrate, sodium edetate hydrate, concentrated glycerin, benzalkonium chloride, and a pH adjuster in predetermined content ratios.

[0083] [Table 4]

[0084] As shown in Table 4, Example 4 exhibited a significant improvement in the tafluprost ratio compared to Comparative Example 4, and was able to suppress a decrease in the tafluprost content caused by the label material.

[0085] Example 5 <Preparation of aqueous composition> An aqueous composition was prepared by dissolving tafluprost (1.5 mg), timolol maleate (683 mg) (500 mg as timolol), and polysorbate 80 (50 mg) in purified water, adjusting the pH to 7 using sodium hydroxide or hydrochloric acid (minimum amount necessary) as needed, and adding purified water to make the total volume 100 mL.

[0086] <Manufacturing unlabeled products> 3 mL of the obtained aqueous composition was placed in a polyethylene resin container (a multi-dose container in which the entire top surface of the bottle (main body) is covered with a cap) to produce an unlabeled product. The aqueous composition contained in the container was visible from the outside of the container.

[0087] <Production of labeled products> The resulting unlabeled product was covered with a shrinkable polyethylene terephthalate label to produce a labeled product. The label coverage of the container was 85% of the surface area of ​​the container (surface area of ​​the sides and bottom).

[0088] (Comparative Example 5) An aqueous composition prepared in the same manner as in Example 5 was placed in a polypropylene resin container (a multi-dose container in which the entire top surface of the bottle (main body) is covered with a cap) to prepare an unlabeled product. A polyethylene terephthalate shrink label was then applied to the unlabeled product to produce a labeled product.

[0089] (Stability test 5) <Test Method> The labeled products of Example 5 and Comparative Example 5 were stored for 3 weeks at 60°C (at constant humidity). Thereafter, the peak area of ​​tafluprost was obtained by high performance liquid chromatography, and the tafluprost ratios at 1 week, 2 weeks, and 3 weeks were calculated based on the peak area of ​​tafluprost at the start of storage. Tafluprost ratio (%) = tafluprost peak area at each time point / tafluprost peak area at the start of storage × 100

[0090] <Result> As shown in Table 5 and FIG. 1, in Example 5, the tafluprost ratio was larger at each of the time points of 1 week, 2 weeks, and 3 weeks compared to Comparative Example 5, and it was confirmed that the decrease in the tafluprost content under high temperature conditions could be suppressed.

[0091] [Table 5]

[0092] (Stability test 6) Similar results can be obtained by replacing the aqueous composition used in Example 5 and Comparative Example 5 with the Tapcom (registered trademark) ophthalmic solution used in Stability Test 4 and evaluating the results at 1 week and 2 weeks after the start of storage in the same manner (Table 6, Figure 2, Example 6, Comparative Example 6).

[0093] <Result> As shown in Table 6 and FIG. 2, in Example 6, the tafluprost ratio was larger at each time point of 1 week and 2 weeks compared to Comparative Example 6, and it was confirmed that the decrease in the tafluprost content under high temperature conditions could be suppressed.

[0094] [Table 6]

[0095] (Stability test 7) Similar results could be obtained by replacing the aqueous composition used in Example 6 and Comparative Example 6 with the 0.0015% Tapros (registered trademark) ophthalmic solution used in Stability Test 2 and evaluating the results at 1 week and 2 weeks after the start of storage in the same manner (Table 7, Figure 3, Example 7, Comparative Example 7).

[0096] <Result> As shown in Table 7 and FIG. 3, in Example 7, the tafluprost ratio was larger at each time point of 1 week and 2 weeks compared to Comparative Example 7, and it was confirmed that the decrease in the tafluprost content under high temperature conditions could be suppressed.

[0097] [Table 7]

[0098] (Manufacturing example) The effect of suppressing the decrease in the tafluprost content in the aqueous composition can be confirmed even when the bottle (bottle, main body) used in the examples is covered with a shrink label or shrink tack label made of polyethylene terephthalate so that the label coverage on the bottle (bottle, main body) is 15%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

Claims

1. An aqueous composition containing tafluprost, the aqueous composition is contained in a resin container containing polyethylene but not containing a cyclic olefin polymer; At least a portion of the container is covered with a polyester label; The aqueous composition wherein the polyester comprises polyethylene terephthalate.

2. 10. The aqueous composition of claim 1, wherein the aqueous composition is in contact with polyethylene of the container.

3. 10. The aqueous composition of claim 1, wherein the container is a multi-dose container.

4. 2. The aqueous composition according to claim 1, wherein the content of tafluprost in the aqueous composition is 0.001 to 0.002 w / v %.

5. the container is a container in which at least a portion of the container allows the aqueous composition to be visible from the outside of the container, 2. The aqueous composition according to claim 1, wherein at least 15% of the total surface area of ​​the container where the aqueous composition is visible from the outside of the container is covered with a label.

6. 6. The aqueous composition according to claim 1, wherein the content of tafluprost in the aqueous composition after storage at 60°C for 3 weeks is 86% or more of that in a case where the container is not covered with a label.

7. The content of tafluprost in the aqueous composition after storage at 60°C for 1 week is 84% ​​or more of that at the start of storage, and / or 6. The aqueous composition according to claim 1, wherein the content of tafluprost in the aqueous composition after storage at 60° C. for 2 weeks is 78% or more of that at the start of storage.

8. 6. The aqueous composition according to claim 1, further comprising one or more selected from timolol, carteolol, bunazosin, apraclonidine, dorzolamide, brinzolamide, ripasudil, omidenepagisopropyl, and salts thereof.

9. The aqueous composition according to any one of claims 1 to 5, further comprising one or more selected from the group consisting of a solubilizer, a buffer, a tonicity adjusting agent, a preservative, and a pH adjusting agent.

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