WO2024232425A1 - PRODUCT INHIBITED FROM DECREASING IN CONTENT OF PROSTAGLANDIN F2α DERIVATIVE - Google Patents

Abstract

The present invention addresses the problem of providing: a container for storing an aqueous chemical preparation containing a prostaglandin F2α derivative that is easily adsorbed on containers; and a product including the aqueous chemical preparation and the container.　The problem is solved by storing an aqueous chemical preparation containing a prostaglandin F2α derivative in a thermoplastic-resin container that includes a specific polycycloolefin.

Description

A product that prevents the content of prostaglandin F2α derivatives from decreasing

The present invention relates to a product in which an aqueous liquid preparation containing a prostaglandin F2α (PGF2α) derivative is stored in a thermoplastic resin container containing a specific cyclic polyolefin, thereby preventing a decrease in the content of the prostaglandin F2α derivative.

PGF2α derivatives are used to treat glaucoma and ocular hypertension. However, PGF2α derivatives can easily adsorb to eye drop containers used to store aqueous preparations, and this adsorption undesirably reduces the content of the PGF2α derivative. There is a demand for a method to effectively inhibit the adsorption of such PGF2α derivatives to storage containers.

Patent Document 1 describes how polyethylene glycol monostearate is blended with eye drops containing latanoprost, a PGF2α derivative, to suppress the adsorption of latanoprost to a storage container. Furthermore, Patent Document 2 describes an eye drop in which an aqueous liquid preparation containing a prostaglandin derivative having a fluorine atom is stored in a container sterilized with ethylene oxide gas to suppress the decrease in content. However, it is not known that the decrease in the content of the PGF2α derivative can be suppressed by storing an aqueous liquid preparation containing a PGF2α derivative in a thermoplastic resin container containing a specific cyclic polyolefin.

JP 2009-040749 A JP 2011-063625 A

The present invention aims to provide a product in which the aqueous liquid preparation containing a PGF2α derivative is stored in a thermoplastic resin container containing a specific cyclic polyolefin, thereby preventing a decrease in the content of the PGF2α derivative.

As a result of intensive research to solve the above problems, the present inventors have found that by storing an aqueous liquid preparation containing a PGF2α derivative in a thermoplastic resin container containing a specific cyclic polyolefin, it is possible to suppress the adsorption of the PGF2α derivative to the container under various conditions (e.g., under storage conditions at 40°C or 60°C, etc.). It has also been found that the container can effectively suppress the decrease in the content of the PGF2α derivative.
Based on the above findings, the present inventors have further conducted research and have completed the present invention.

The present invention relates to the following [1a], [5a], [11a] and [1] to [11].
[1a] A product in which an aqueous liquid preparation containing a prostaglandin F2α derivative is stored in a thermoplastic resin container containing a cyclic polyolefin.
[1] A product in which an aqueous liquid preparation containing a prostaglandin F2α derivative is stored in a thermoplastic resin container containing a cyclic polyolefin, thereby suppressing a decrease in the content of the prostaglandin F2α derivative.
[2] The product described in [1a] or [1], wherein the prostaglandin F2α derivative is one or more selected from the group consisting of tafluprost, latanoprost, isopropyl unoprostone, travoprost, and bimatoprost.
[3] The product described in [1a], [1] or [2], wherein the prostaglandin F2α derivative is tafluprost.
[4] The product according to any one of [1a] and [1] to [3], wherein the thermoplastic resin container is a polymer composition containing 72% by weight or more of a cyclic polyolefin having a hydrogenated aromatic vinyl polymer block unit, which is a hydrogenated product of a polymer block consisting of an aromatic vinyl monomer unit, and a hydrogenated conjugated diene polymer block unit, which is a hydrogenated product of a polymer block consisting of a conjugated diene monomer unit.
[5a] The product according to [4], wherein the polymer composition contains 2% by weight or more and 25% by weight or less of a hydrogenated C9 petroleum resin.
[5] The product according to [4], wherein the polymer composition contains 2% by weight or more and 25% by weight or less of an alicyclic saturated hydrocarbon polymer.
[6] The article of claim [4], [5a] or [5], wherein the polymer composition comprises from 2% by weight to 25% by weight of a styrene-based block copolymer.
[7] The hydrogenated aromatic vinyl polymer block unit constituting the cyclic polyolefin is a hydrogenated polystyrene block unit which is a hydrogenated product of a polystyrene block unit composed of a styrene monomer unit, and
The product according to any one of [1a], [5a], and [1] to [6], wherein the hydrogenated conjugated diene polymer block unit constituting the cyclic polyolefin is a hydrogenated butadiene polymer block unit which is a hydrogenated product of a butadiene polymer block consisting of butadiene monomer units.
[8] The product according to any one of [1a], [5a], and [1] to [7], wherein the product is an eye drop.
[9] The product according to any one of [1a], [5a] and [1] to [8], wherein the aqueous liquid formulation contains a surfactant.
[10] A method for suppressing a decrease in the content of a prostaglandin F2α derivative in an aqueous liquid preparation by storing the aqueous liquid preparation containing the prostaglandin F2α derivative in a thermoplastic resin container containing a cyclic polyolefin.
[11a] A thermoplastic resin container for storing an aqueous liquid preparation containing a prostaglandin F2α derivative, comprising a cyclic polyolefin and a hydrogenated C9 petroleum resin and/or a styrene block copolymer.
[11] A thermoplastic resin container for storing an aqueous liquid preparation containing a prostaglandin F2α derivative, comprising a cyclic polyolefin and an alicyclic saturated hydrocarbon polymer and/or a styrene-based block copolymer.

According to the present invention, it is possible to suppress the adsorption of the PGF2α derivative to the container over time. Furthermore, it is possible to effectively suppress the decrease in the content of the PGF2α derivative.

[Aqueous liquid preparation containing PGF2α derivative]
The prostaglandin F2α derivative (PGF2α) of the present invention may be an aqueous solution, preferably an aqueous solution for medical use, more preferably an aqueous solution for ophthalmic use, and more preferably an eye drop PGF2α derivative.The PGF2α derivative of the present invention is characterized by being easily adsorbed to container.Preferred examples of such PGF2α derivative include those suitable for ophthalmic use, such as tafluprost, latanoprost, isopropyl unoprostone, travoprost, and bimatoprost.
Their chemical structural formulas are as shown in Table 1 below, and they have a common chemical structure.

The PGF2α derivative of the present invention preferably has a molecular weight in the range of about 350 to 550, more preferably about 400 to 520, but is not limited thereto. An example of a preferred molecular formula of the PGF2α derivative of the present invention is, for example, CxHyOz (x: 20 to 30, y: 30 to 40, z: 4 to 6), which may further have a fluorine atom or a nitrogen atom in the molecule. Preferably, it is a compound having 1 to 6 fluorine atoms in the molecule, more preferably 2 to 3 fluorine atoms in the molecule, and preferably, it may further have 1 to 2 nitrogen atoms or sulfur atoms in the molecule, but is not limited thereto.

In the product of the present invention, the amount of the PGF2α derivative is 0.0001 w/v% to 0.2 w/v% of the total aqueous liquid. It is preferably 0.001 w/v% or more, and more preferably 0.0015 w/v% or more, but is not limited to these amounts.

The eye drops containing the PGF2α derivative of the present invention are usually used for the treatment of glaucoma and ocular hypertension, but are not limited thereto. "Treatment" means alleviating or curing a symptom or disease and/or its associated symptoms. Glaucoma is an eye disease characterized by progressive optic nerve damage, and is considered to be one of the main causes of blindness. Ocular hypertension is a disease in which abnormal intraocular pressure increases, but no abnormality or damage occurs in the optic nerve.
Furthermore, the PGF2α derivative of the present invention may be used in combination with known β-blockers such as timolol maleate, carteolol hydrochloride, brimonidine tartrate, and ripasudil hydrochloride hydrate, α2 agonists, or Rho kinase inhibitors, or combinations thereof.

[Thermoplastic resin container containing specific cyclic polyolefin]
In the present invention, a thermoplastic resin container containing a specific cyclic polyolefin (hereinafter also referred to as SB) is used to store an aqueous liquid preparation, preferably an eye drop. It is preferably used for the main body of an ophthalmic or eye drop container, a medicine bottle ampule, or a vial, a cap or nozzle used therefor, or an ophthalmic test tube, a blood collection tube, a specimen container, a prefilled syringe, a syringe, etc. The container may be a multi-dose eye drop container capable of storing an aqueous liquid preparation containing the above-mentioned active ingredient (PGF2α derivative). The "multi-dose eye drop container" is a storage container that can restore a sealed state to a degree that allows it to be carried even after opening so that eye drops can be used repeatedly from the same container multiple times for a period of repeated use, for example, several days to several months (preferably several days to about one month). The internal volume of the container is preferably 1 mL to 20 mL, more preferably about 1 mL to 8 mL, but is not limited thereto. The shape of the container is not particularly limited, and the shape of a storage container used for ordinary eye drops can be used. The container may be a light-shielding container. The container may be sterilized. Examples of such sterilization methods include, but are not limited to, electron beam (EB) sterilization, ethylene oxide gas (EOG) sterilization, hydrogen peroxide (H ₂ O ₂ ) gas sterilization, gamma ray sterilization, etc. Preferably, the container of the present invention is made of a material suitable for suppressing the adsorption of the PGF2α derivative to the container, and another preferred feature is that the container is made of a material suitable for suppressing the decrease in the content of the PGF2α derivative, but is not limited to these.

The thermoplastic resin container described above is a composition that contains a specific cyclic polyolefin (A) (hereinafter, sometimes referred to as "component (A)"), and may also contain an alicyclic saturated hydrocarbon polymer (B) (hereinafter, sometimes referred to as "component (B)") and a styrene-based block copolymer (C) (hereinafter, sometimes referred to as "component (C)").

<Cyclic Polyolefin (A) (Component (A))>
The cyclic polyolefin (A) of the present invention is a hydrogenated block copolymer having a hydrogenated aromatic vinyl polymer block unit which is a hydrogenated product of a polymer block consisting of at least one aromatic vinyl monomer unit, and a hydrogenated conjugated diene polymer block unit which is a hydrogenated product of a polymer block consisting of at least one conjugated diene monomer unit.
The hydrogenated block copolymer has at least two of the hydrogenated aromatic vinyl polymer block units and at least one of the hydrogenated conjugated diene polymer block units.
The term "block" refers to a copolymeric polymeric segment that exhibits microphase separation from structurally or compositionally distinct polymeric segments of the copolymer. Thus, for example, "having at least two block units" refers to having at least two copolymeric polymeric segments that exhibit microphase separation from structurally or compositionally distinct polymeric segments in the hydrogenated block copolymer.
The aromatic vinyl monomer serving as a raw material for the aromatic vinyl monomer unit is a monomer represented by the following general formula (1).

In general formula (1), R is hydrogen or an alkyl group.
The alkyl group may be an alkyl group which is mono- or poly-substituted with a functional group such as a halo group (halogen), a nitro group, an amino group, a hydroxyl group, a cyano group, a carbonyl group, or a carboxyl group, and the number of carbon atoms of the alkyl group is preferably 1 to 6.
Of these, R is preferably hydrogen.

In general formula (1), Ar is a phenyl group, a halophenyl group, an alkylphenyl group, an alkylhalophenyl group, a naphthyl group, a pyridinyl group, or an anthracenyl group. Of these, Ar is preferably a phenyl group or an alkylphenyl group, and more preferably a phenyl group.

Examples of the aromatic vinyl monomer include styrene, α-methylstyrene, vinyltoluene (including all isomers, preferably p-vinyltoluene), ethylstyrene, propylstyrene, butylstyrene, vinylbiphenyl, vinylnaphthalene, vinylanthracene (including all isomers), and mixtures thereof, with styrene being preferred.

The conjugated diene monomer serving as the raw material for the conjugated diene monomer unit may be any monomer having two conjugated double bonds.
Conjugated diene monomers include, for example, 1,3-butadiene, 2-methyl-1,3-butadiene (isoprene), 2-methyl-1,3-pentadiene and the like, and mixtures thereof, with 1,3-butadiene being preferred.

The polybutadiene, a polymer of 1,3-butadiene, can contain either a 1,2 configuration that upon hydrogenation gives the equivalent of a 1-butene repeat unit, or a 1,4 configuration that upon hydrogenation gives the equivalent of an ethylene repeat unit.

A preferred example of the hydrogenated aromatic vinyl polymer block unit is a block unit made of hydrogenated polystyrene, which is a hydrogenated product of a polystyrene block unit made of styrene monomer units. A preferred example of the hydrogenated conjugated diene polymer block unit is a block unit made of hydrogenated polybutadiene, which is a hydrogenated product of a butadiene polymer block made of butadiene monomer units.
A preferred embodiment of the hydrogenated block copolymer is a hydrogenated triblock or pentablock copolymer of styrene and butadiene, which preferably does not contain any other functional groups or structural modifiers.

The content of the hydrogenated aromatic vinyl polymer block unit is 30 to 80 mol %, preferably 40 to 75 mol %, based on the cyclic polyolefin (A).
When the ratio of the hydrogenated aromatic vinyl polymer block unit is equal to or more than the above-mentioned lower limit, the rigidity does not decrease, and when it is equal to or less than the above-mentioned upper limit, the toughness is improved and the brittleness does not worsen.

The content of the hydrogenated conjugated diene polymer block unit is from 20 to 70 mol %, preferably from 25 to 60 mol %, based on the cyclic polyolefin (A).
When the ratio of the hydrogenated conjugated diene polymer block units is equal to or greater than the above-mentioned lower limit, the toughness is improved and the brittleness is not deteriorated, whereas when the ratio is equal to or less than the above-mentioned upper limit, the rigidity is not decreased.

In the present invention, the "cyclic" in cyclic polyolefin refers to an alicyclic structure that is generated by hydrogenating the aromatic ring contained in the hydrogenated aromatic vinyl polymer block unit.

Hydrogenated block copolymers are produced by hydrogenation of block copolymers including triblock, multiblock, tapered block, and star block copolymers such as SBS, SBSBS, SIS, SISIS, and SISBS (where S is polystyrene, B is polybutadiene, and I is polyisoprene).

The hydrogenated block copolymer contains a segment of aromatic vinyl polymer at each end. Therefore, the hydrogenated block copolymer has at least two hydrogenated aromatic vinyl polymer block units. And, between these two hydrogenated aromatic vinyl polymer block units, there is at least one hydrogenated conjugated diene polymer block unit.

The block copolymers that make up the hydrogenated block before hydrogenation may contain additional blocks, which may be attached at any position along the block polymer backbone. Thus, linear blocks include, for example, SBS, SBSB, SBSBS, and SBSBSB. The copolymers may be branched, with the polymer chains attached at any position along the backbone of the copolymer.

The lower limit of the weight average molecular weight (Mw) of the hydrogenated block copolymer is preferably 30,000 or more, more preferably 40,000 or more, even more preferably 45,000 or more, and particularly preferably 50,000 or more. The upper limit of Mw is preferably 120,000 or less, more preferably 100,000 or less, even more preferably 95,000 or less, particularly preferably 90,000 or less, extremely preferably 85,000 or less, and most preferably 80,000 or less.
When Mw is equal to or greater than the above-mentioned lower limit, the mechanical strength does not decrease, and when Mw is equal to or less than the above-mentioned upper limit, the moldability does not deteriorate.
Here, the Mw of the cyclic polyolefin (A) is determined by gel permeation chromatography (GPC) under the same measurement conditions as those for the styrene-based block copolymer (C) described below.

The hydrogenation level of the hydrogenated block copolymer is preferably 90% or more of hydrogenated vinyl aromatic polymer block units and 95% or more of hydrogenated conjugated diene polymer block units; more preferably 95% or more of hydrogenated vinyl aromatic polymer block units and 99% or more of hydrogenated conjugated diene polymer block units; even more preferably 98% or more of hydrogenated vinyl aromatic polymer block units and 99.5% or more of hydrogenated conjugated diene polymer block units; particularly preferably 99.5% or more of hydrogenated vinyl aromatic polymer block units and 99.5% or more of hydrogenated conjugated diene polymer block units.
The hydrogenation level of the hydrogenated aromatic vinyl polymer block unit refers to the proportion of the aromatic vinyl polymer block unit saturated by hydrogenation, and the hydrogenation level of the hydrogenated conjugated diene polymer block unit refers to the proportion of the conjugated diene polymer block unit saturated by hydrogenation. Such a high level of hydrogenation is preferred for heat resistance and transparency.
The hydrogenation level of component (A) is determined using proton NMR.

The melt flow rate (MFR) of the component (A) of the present invention is preferably 0.1 g/10 min or more, more preferably 0.2 g/10 min or more, from the viewpoint of the molding method and the appearance of the molded product, and is preferably 200 g/10 min or less, more preferably 100 g/10 min or less, and even more preferably 50 g/10 min or less, from the viewpoint of material strength.
The MFR was measured in accordance with ISO R1133 at a measurement temperature of 230° C. and a measurement load of 2.16 kg.

The component (A) of the present invention may use one type alone, or two or more types differing in monomer unit composition, physical properties, etc. may be used in combination.
As the component (A) of the present invention, commercially available products can be used, specifically, ZELAS (registered trademark) manufactured by Mitsubishi Chemical Corporation.

<Alicyclic saturated hydrocarbon polymer (B) (component (B))>
The alicyclic saturated hydrocarbon polymer (B) (component (B)) is a saturated hydrocarbon having a main chain made of hydrocarbon and an alicyclic structure, and specific examples thereof include hydrogenated petroleum resins obtained by hydrogenating aromatic petroleum resins, resins obtained by hydrogenating petroleum resins containing aromatic compounds, and resins obtained by hydrogenating alicyclic hydrocarbon resins having unsaturated bonds. This hydrogenation converts the aromatic rings into alicyclic saturated structures.
This alicyclic saturated hydrocarbon polymer (B) has good compatibility with the above cyclic polyolefin (A), and can suppress evaporation and improve flexibility.

The (B) component of the present invention may, for example, be hydrogenated terpene resins (Clearon (registered trademark) P, M, K series manufactured by Yasuhara Chemical Co., Ltd.), hydrogenated rosin and hydrogenated rosin ester resins (Foral (registered trademark) AX, Foral 105 manufactured by Rika Finetech Co., Ltd., Pencel (registered trademark) A manufactured by Arakawa Chemical Industries, Ltd., Ester Gum (registered trademark) H manufactured by Arakawa Chemical Industries, Ltd., Super Ester (registered trademark) A series manufactured by Arakawa Chemical Industries, Ltd.), disproportionated rosin and disproportionated rosin ester resins (Pine Crystal (registered trademark) series manufactured by Arakawa Chemical Industries, Ltd.), and C5 petroleum resins obtained by copolymerizing C5 fractions such as pentene, isoprene, piperine, and 1,3-pentadiene produced by the thermal decomposition of petroleum naphtha. Hydrogenated dicyclopentadiene resins (Escoretz (registered trademark) 5300, 5400 series manufactured by Donex Co., Ltd., Eastotac (registered trademark) H series manufactured by Eastman Chemical Japan Co., Ltd.), partially hydrogenated aromatic modified dicyclopentadiene resins (Escoretz (registered trademark) 5600 series manufactured by Tonex Co., Ltd.), resins obtained by copolymerizing C9 fractions such as indene, vinyl toluene, α- or β-methylstyrene produced by thermal cracking of petroleum naphtha, and hydrogenated C9 petroleum resins (Arcon (registered trademark) P and M series manufactured by Arakawa Chemical Industries Co., Ltd.), and resins obtained by hydrogenating the copolymerized petroleum resins of the above-mentioned C5 fraction and C9 fraction (Imerve (registered trademark) series manufactured by Idemitsu Kosan Co., Ltd.). These alicyclic saturated hydrocarbon polymers may be used alone or in a mixture of two or more types.

The softening point of component (B) of the present invention, as measured by JIS K6823 (ring and ball method), is preferably 100°C or higher, more preferably 115°C or higher, and particularly preferably 125°C or higher, while it is preferably 180°C or lower, more preferably 175°C or lower, even more preferably 170°C or lower, and particularly preferably 165°C or lower. If the softening point is equal to or higher than the lower limit mentioned above, there is a tendency for the suppression of transpiration to be further improved. On the other hand, if the softening point is equal to or lower than the upper limit mentioned above, there is a tendency for the moldability to be good.

<Styrene-Based Block Copolymer (C) (Component (C))>
The styrene-based block copolymer (C) (component (C)) of the present invention is a hydrogenated styrene-based copolymer.
The styrene copolymer of the present invention is produced by hydrogenating a styrene copolymer such as polystyrene, a styrene/α-methylstyrene copolymer, a styrene/vinylnaphthalene copolymer, etc. Among these, hydrogenated polystyrene, which is a hydrogenated product of polystyrene, is preferred.

The lower limit of the weight average molecular weight (Mw) of the component (C) of the present invention is preferably 100,000 or more. The upper limit of Mw is preferably 400,000 or less, more preferably 300,000 or less, and even more preferably 200,000 or less.
When Mw is equal to or greater than the above-mentioned lower limit, the mechanical strength does not decrease, and when Mw is equal to or less than the above-mentioned upper limit, the moldability does not deteriorate.

Here, the Mw of the styrene-based block copolymer (C) is a polystyrene-equivalent value measured by GPC under the following conditions.
・Equipment: Tosoh Corporation "GPC HLC-832GPC/HT"
Column: Showa Denko K.K. "AD806M/S" x 3 (The columns were calibrated using Tosoh Corporation's monodisperse polystyrene (A500, A2500, F1, F2, F4, F10, F20, F40, F288, each 0.5 mg/mL solution), and the elution volume and the logarithm of the molecular weight were approximated by a cubic equation.)
Detector: MIRAN "1A Infrared Spectrophotometer" (measurement wavelength: 3.42 μm)
Solvent: o-dichlorobenzene Temperature: 135°C
・Flow rate: 1.0mL/min ・Injection volume: 200μL
・Concentration: 20mg/10mL

The hydrogenation level of component (C) of the present invention is preferably 90% or more, more preferably 95% or more, and even more preferably 97% or more.
The hydrogenation level of the hydrogenated aromatic vinyl polymer refers to the proportion of the aromatic vinyl polymer that is saturated by hydrogenation. Such a high level of hydrogenation is preferred for heat resistance and transparency.
The hydrogenation level of the styrenic block copolymer (C) is determined using proton NMR.

The MFR of the component (C) of the present invention is preferably 0.1 g/10 min or more, more preferably 0.2 g/10 min or more, from the viewpoint of the molding method and the appearance of the molded product, and is preferably 200 g/10 min or less, more preferably 100 g/10 min or less, and even more preferably 50 g/10 min or less, from the viewpoint of material strength.
The MFR was measured in accordance with ISO R1133 at a measurement temperature of 230° C. and a measurement load of 2.16 kg.

The component (C) of the present invention may be used alone or in combination with two or more types differing in the composition of the monomer units, physical properties, etc.

<Polymer Composition>
The liquid container of the present invention contains a polymer composition containing the component (A) described above, and may further contain a component (B) and/or a component (C).
The content of the component (A) is preferably 72 parts by weight or more, and more preferably 75 parts by weight or more, based on 100 parts by weight of the polymer composition.
The upper limit of the content of the component (A) may be 100 parts by weight, but when other components such as the component (B) and the component (C) are added, the upper limit is preferably 95 parts by weight.

When the (B) component is contained, the content of this (B) component is preferably 2 parts by weight or more, more preferably 5 parts by weight or more, and even more preferably 7 parts by weight or more, per 100 parts by weight of the polymer composition. Furthermore, when the (B) component is contained, the upper limit of the content of this (B) component is preferably 25 parts by weight or less, more preferably 20 parts by weight or less, per 100 parts by weight of the polymer composition. By keeping the content within the above range, it is possible to improve squeezability (flexibility) and suppression of transpiration.

When the (C) component is contained, the content of this (C) component is preferably 2 parts by weight or more, and more preferably 5 parts by weight or more, per 100 parts by weight of the polymer composition. Furthermore, when the (C) component is contained, the upper limit of the content of this (C) component is preferably 25 parts by weight or less, and more preferably 20 parts by weight or less, per 100 parts by weight of the polymer composition. By keeping the content within the above range, it is possible to improve squeezability (flexibility) and suppression of transpiration.

From the viewpoint of improving squeezability (flexibility) and suppression of transpiration, the polymer composition preferably contains components (A), (B), and (C), and the content ratio (weight ratio) of these components is preferably within the range of component (A)/component (B)/component (C)=72-95/2-25/2-25, more preferably 75-85/5-20/5-15.

<Other ingredients>
The polymer composition of the present invention may contain, as other components, compounding agents that are commonly used in resin compositions, within the range that does not impair the effects of the present invention.
Examples of such additives include heat stabilizers, ultraviolet absorbers, light stabilizers, antioxidants, antistatic agents, crystal nucleating agents, rust inhibitors, inorganic fillers, foaming agents, and pigments.
Among these, it is preferable to contain an antioxidant, particularly a phenol-based, sulfur-based or phosphorus-based antioxidant, and the antioxidant is preferably contained in an amount of 0.01 to 2 parts by weight per 100 parts by weight of the polymer composition.

Furthermore, resin components and elastomer components other than the components (A), (B) and (C) may be contained within the scope of the invention without impairing the effects thereof.
Examples of such resin components include polyethylene resins, polypropylene resins, ethylene/α-olefin copolymer resins, propylene/α-olefin copolymer resins, ethylene/vinyl acetate copolymer resins, ethylene/acrylic acid ester copolymer resins, ethylene/(meth)acrylic acid copolymer resins, polystyrene-based resins, polyvinyl chloride-based resins, polyester-based resins, polyamide-based resins, ethylene/vinyl alcohol copolymers, acrylic resins, and petroleum resins.

Examples of the elastomer component include olefin-based elastomers, styrene-based elastomers, polyester-based elastomers, urethane-based elastomers, acrylic-based elastomers, and nylon-based elastomers.

The other components may be added to component (A), component (B), or component (C) by a kneading method commonly used for melt kneading thermoplastic resins, or may be dissolved in an organic solvent together with component (A), component (B), or component (C) and mixed.

<Method of producing polymer composition>
The polymer composition of the present invention can be produced by kneading the component (A), and, if necessary, the component (B) and the component (C), and the other components described above, in a conventional manner using a conventional extruder, Banbury mixer, roll, Brabender Plastograph, kneader-Brabender, or the like.
Among these production methods, it is preferable to use an extruder, in particular a twin-screw extruder.
When the polymer composition of the present invention is produced by kneading in an extruder or the like, it is melt-kneaded in a heated state usually at 220 to 320°C, preferably 250 to 300°C.

[Products, methods of the present invention, etc.]
In the present invention, the "product" preferably refers to a state in which an aqueous liquid preparation containing a PGF2α derivative is stored in a thermoplastic resin container containing a specific cyclic polyolefin.
The present invention also includes a method for suppressing a decrease in the content of a PGF2α derivative in an aqueous liquid preparation by storing the aqueous liquid preparation containing the PGF2α derivative in a thermoplastic resin container containing a specific cyclic polyolefin.
Furthermore, the present invention also includes a thermoplastic resin container for storing an aqueous liquid preparation containing a PGF2α derivative, the container comprising a specific polymer composition containing a specific cyclic polyolefin.

[Other components in the aqueous liquid]
The aqueous liquid preparation of the present invention may contain a surfactant, preferably a nonionic surfactant. For example, it may contain polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, etc. Specifically, nonionic surfactants such as polyoxyethylene sorbitan fatty acid esters such as polysorbate 60, polysorbate 65, polysorbate 80, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (200) polyoxypropylene (70) glycol, polyoxyl 40 stearate, polyethylene glycol monostearate, etc. may be mentioned, but are not limited thereto. The surfactant may be used alone or in any combination of two or more.

The aqueous liquid preparation of the present invention may contain a pH adjuster. For example, it may contain pH adjusters such as hydrochloric acid, acetic acid, sulfuric acid, polyphosphoric acid, propionic acid, oxalic acid, gluconic acid, malic acid, succinic acid, fumaric acid, lactic acid, tartaric acid, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, monoethanolamine, triethanolamine, and diisopropanolamine. The pH adjusters may be used alone or in any combination of two or more.

The aqueous liquid preparation of the present invention may contain a buffering agent. Examples of the buffering agent include, but are not limited to, boric acid, borax, potassium tetraborate, potassium metaborate, ammonium borate, and other borates or hydrates thereof; phosphates or hydrates thereof such as disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, and other phosphates; carbonates or hydrates thereof such as sodium bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, and magnesium carbonate; citrates or hydrates thereof such as sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, and disodium citrate; and acetates such as ammonium acetate, potassium acetate, calcium acetate, and sodium acetate. The buffering agent may be used alone or in any combination of two or more.

The aqueous liquid preparation of the present invention may contain an isotonicity agent. Examples include, but are not limited to, sodium bisulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, sodium thiosulfate, magnesium sulfate, glycerin, concentrated glycerin, propylene glycol, macrogol 400, macrogol 4000, macrogol 6000, D-mannitol, etc. The isotonicity agent may be used alone or in any combination of two or more kinds.

The aqueous liquid preparation of the present invention may contain a chelating agent or a stabilizer. Examples include, but are not limited to, ethylenediaminediacetic acid, ethylenediaminetriacetic acid, ethylenediaminetetraacetic acid (EDTA, edetic acid), salts thereof, and salt hydrates, sodium hydrogen sulfite, glycerin monostearate, cyclodextrin, monoethanolamine, etc. The chelating agent or stabilizer may be used alone or in any combination of two or more kinds.

The aqueous liquid preparation of the present invention may contain a preservative, a bactericide, or an antibacterial agent. Examples include, but are not limited to, zinc chloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, sorbic acid, potassium sorbate, sodium sorbate, chlorobutanol, sodium dehydroacetate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, and propyl parahydroxybenzoate. The preservative, bactericide, or antibacterial agent may be used alone or in any combination of two or more.

The aqueous liquid preparation of the present invention may further contain a sodium salt and/or a potassium salt. For example, a sodium salt and a potassium salt are used. Examples of the sodium salt include sodium chloride, disodium monohydrogen phosphate, monosodium dihydrogen phosphate, sodium sulfate, sodium bicarbonate, sodium carbonate, sodium citrate, and sodium hydroxide. Sodium chloride, sodium monohydrogen phosphate, and sodium dihydrogen phosphate are preferable, and sodium chloride is more preferable.
Examples of potassium salts include potassium chloride, dipotassium monohydrogen phosphate, monopotassium dihydrogen phosphate, potassium acetate, etc. Potassium chloride, dipotassium monohydrogen phosphate, monopotassium dihydrogen phosphate are preferred, and potassium chloride is more preferred. One or more types of sodium salts and/or potassium salts can be used.

In addition to the above-mentioned components, the aqueous liquid preparation of the present invention may contain bases such as water, other active ingredients, and other additives (carriers, solubilizers, antioxidants, solvents, solubilizers, suspending agents, flavorings, fragrances, refreshing agents, sugars, sugar alcohols, thickening agents), etc., within the range that does not impair the effects of the present invention. The amount of these optional ingredients to be added may be normal amounts, within the range that does not impair the effects of the present invention.
The water used as a base in the preparation of the eye drops is not particularly limited as long as it is usable for ophthalmic preparations, and for example, purified water can be used. The order of mixing the components, the mixing method, etc. are not particularly limited, and each component may be dissolved in water by a known preparation method.

The PGF2α derivative used in the present invention may be, for example, a commercially available product, or a synthetic product.

[Suppression of adsorption of PGF2α derivative to container, suppression of decrease in content of PGF2α derivative]
In the present invention, the method for quantifying the PGF2α derivative in the aqueous liquid preparation can be, for example, using high performance liquid chromatography (HPLC) to measure the content, but is not limited to this method.The method for calculating the content, as described in the examples below, can be calculated as a percentage based on the content of the PGF2α derivative in the aqueous liquid preparation before storage in a container, and the content after storage in a container at 40°C or 60°C for a certain period of time.
In addition, in the present invention, the PGF2α derivative being easily adsorbed to a container preferably means that the content of the PGF2α derivative is significantly reduced when an aqueous liquid preparation containing the PGF2α derivative is stored in a container, and for example, when the aqueous liquid preparation containing the PGF2α derivative is 0.0015 w/v%, the content of the PGF2α derivative is reduced by 5% or more, more preferably 10% or more after storage in a polyolefin container, such as a polyethylene (PE) or polypropylene (PP) container, preferably at 40°C for 6 weeks, more preferably at 60°C for 1 week, but is not limited to this.

The aqueous liquid preparation of the present invention preferably has an osmotic pressure ratio of 0.9 to 1.1. More preferably, it is 1.0 to 1.1. The osmotic pressure can be measured by the method described in the Japanese Pharmacopoeia (18th revision) 2.47 Osmotic Pressure Measurement Method (Osmolarity Measurement Method), or it may be measured by a method known in the art.

The aqueous liquid preparation of the present invention preferably has a pH of about 5.0 to 8.0. More preferably, it is about 5.5 to 7.0, and even more preferably, it is about 5.7 to 6.3. The osmotic pressure ratio and pH can be adjusted by methods known in the art using the above-mentioned or known pH adjusters, isotonicity agents, salts, etc.

The preferred subjects for administration of the product or aqueous liquid of the present invention are individuals (animals) that have or are at risk of developing the above-mentioned symptoms of glaucoma or ocular hypertension, and preferably individuals that have the above-mentioned glaucoma or ocular hypertension. Preferred individuals are mammals such as humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, and monkeys, and particularly preferred are humans, but are not limited to these.

The dosage and frequency of administration of the product or aqueous liquid of the present invention can be appropriately selected depending on the symptoms of the patient. Generally, about one drop is administered to the eye of an adult about once a day.

The present invention will be explained in more detail below with reference to examples, comparative examples, test examples, etc., but the present invention is not limited to the following examples as long as it does not deviate from the gist of the invention. The values of various manufacturing conditions and evaluation results in the following examples are meant as preferred upper or lower limit values in the implementation of the present invention, and the preferred range may be a range defined by a combination of the above-mentioned upper or lower limit values and the values of the following examples or values between the examples.

[Calculation formula for PGF2α derivative content]

(Product Preparation Method)
An aqueous liquid preparation and a thermoplastic resin container were prepared by the following method to obtain the product of the present invention.

(Example 1: Production of aqueous liquid preparation used in the present invention)
The aqueous liquid preparation used in the present invention was obtained by the method described below. Appropriate amounts of sodium edetate hydrate, benzalkonium chloride, buffer, and isotonicity agent were dissolved in purified water, and a solution of tafluprost dissolved in purified water using polysorbate 80 was added. A pH adjuster was further used to produce an aqueous liquid preparation with an osmotic pressure ratio of about 1 and a pH of about 6.0.
The details of the formulation of the aqueous liquid preparation are as shown in Table 2 below.

[Physical Properties]
<Ratio of Polymer Blocks of Cyclic Polyolefin (A)>
[Measurement by Carbon NMR]
Apparatus: Bruker "AVANCE 400 Spectrometer"
Solvent: o-dichlorobenzene- _h4 /p-dichlorobenzene- _d4 mixed solvent Concentration: 0.3 g/2.5 mL
・Measurement: ^13C -NMR
・Resonance frequency: 400MHz
・Number of times accumulated: 1536
Flip angle: 45 degrees Data acquisition time: 1.5 seconds Pulse repetition time: 15 seconds Measurement temperature: 100°C
・^1H irradiation: Complete decoupling

<Hydrogenation level>
[Measurement by proton NMR]
Apparatus: JASCO Corporation "400YH spectrometer"
Solvent: deuterated chloroform Concentration: 0.045 g/1.0 mL
・Measurement: ^1H -NMR
・Resonance frequency: 400MHz
・Number of times: 8
・Measurement temperature: 18.5℃
Hydrogenation level of styrene-based block copolymer (C): integral value reduction rate of 6.8 to 7.5 ppm Hydrogenation level of hydrogenated aromatic vinyl polymer block unit of cyclic polyolefin (A): integral value reduction rate of 6.8 to 7.5 ppm Hydrogenation level of hydrogenated conjugated diene polymer block unit of cyclic polyolefin (A): integral value reduction rate of 5.7 to 6.4 ppm

(Raw materials)
(Cyclic polyolefin (A))...Mitsubishi Chemical Corporation: ZELAS Density (ASTM D792): 0.94 g/ ^cm3
MFR (230°C, 2.16 kg): 0.5 g/10 min. Hydrogenated aromatic vinyl polymer block unit: hydrogenated polystyrene with a content of 50 mol% and a hydrogenation level of 98.7%. Hydrogenated conjugated diene polymer block unit: hydrogenated polybutadiene with a content of 50 mol% and a hydrogenation level of 99.5% or more. Block structure: pentablock structure, total hydrogenation level: 99.2%.
(Alicyclic Saturated Hydrocarbon Polymer (B))
・Density (ASTM D792): 1.00g/ ^cm3
・C9 hydrogenated petroleum resin ・Softening temperature: 115℃
(Styrene-based block copolymer (C))
Hydrogenated styrene-butadiene-styrene block copolymer, aromatic vinyl polymer block unit (polystyrene block unit): 30% by weight, hydrogenation rate of butadiene: 99% or more, Mw: 90,000

(Examples 2 and 3: Production of thermoplastic resin containers containing cyclic polyolefins of the present invention)
A thermoplastic resin container containing the cyclic polyolefin (SB) of the present invention was obtained by the method described below. The internal volume of the container was 7.8 mL.

The components (A), (B), and (C) were mixed in the amounts shown in Table 3 below, and melt-kneaded in a twin-screw extruder at a temperature of 220° C. to 280° C. to obtain thermoplastic resin pellets. The obtained pellets were used to manufacture the SB container of the present invention by injection blow molding.

(Comparative Examples 1 and 2: Production of PP and PE containers)
A polypropylene (PP) container was used as Comparative Example 1, and a polyethylene (PE) container was used as Comparative Example 2. These containers were manufactured by injection blow molding. The internal volume of these containers was also 7.8 mL, similar to the SB container.
In the following Test Examples 1 and 2, the aqueous liquid preparations and thermoplastic resin containers (SB, PP, and PE) produced in the above-mentioned Examples and Comparative Examples were used.

[Test Example 1] Confirmation of the effect of reducing the content of PGF2α derivative in the aqueous liquid preparation and the effect of suppressing adsorption to the container under storage conditions at 40°C. The content of PGF2α derivative in the aqueous liquid preparation was confirmed when about 2.5mL of the aqueous liquid preparation of the present invention was stored in a thermoplastic resin container (SB, PP and PE) for 6 weeks under conditions of 40°C. The content (%) in the table was calculated as a percentage based on the content of PGF2α derivative in the aqueous liquid preparation before storage in the container, and the content after a certain period of time. The results are shown in Table 4 below (n=2).

From the contents of Table 4 above, it can be seen that the thermoplastic resin container (SB) containing the cyclic polyolefin of the present invention was able to suppress the decrease in the content of PGF2α derivative compared to the thermoplastic resin containers of the comparative examples (PP and PE).
That is, the container of the present invention was able to inhibit the PGF2α derivative in the aqueous liquid preparation from being adsorbed to the container under accelerated and long-term storage conditions.

[Test Example 2] Confirmation of the effect of reducing the content of PGF2α derivative in the aqueous liquid preparation and the effect of suppressing adsorption to the container under 60°C storage conditions. The content of PGF2α derivative in the aqueous liquid preparation was confirmed when about 2.5mL of the aqueous liquid preparation of the present invention was stored in a thermoplastic resin container (SB, PP and PE) for one week under the condition of 60°C. The content (%) in the table was calculated in the same manner as in Test Example 1. The results are shown in Table 5 below (n=2).

From the contents of Table 5 above, it can be seen that the thermoplastic resin container (SB) containing the cyclic polyolefin of the present invention was able to suppress the decrease in the content of PGF2α derivative compared to the thermoplastic resin containers of the comparative examples (PP and PE).
That is, the container of the present invention was able to inhibit the PGF2α derivative in the aqueous liquid preparation from being adsorbed onto the container under storage conditions at 60°C.

The product and container of the present invention are useful for medical aqueous liquid preparations, particularly in the field of ophthalmology and eye drops.

Claims (12)

A product in which an aqueous liquid containing a prostaglandin F2α derivative is stored in a thermoplastic resin container containing cyclic polyolefin. Aqueous liquid preparations containing prostaglandin F2α derivatives are stored in thermoplastic resin containers containing cyclic polyolefins, which prevents the content of prostaglandin F2α derivatives from decreasing. The product according to claim 1 or 2, wherein the prostaglandin F2α derivative is one or more selected from the group consisting of tafluprost, latanoprost, isopropyl unoprostone, travoprost, and bimatoprost. The product according to claims 1 to 3, wherein the prostaglandin F2α derivative is tafluprost. The product according to any one of claims 1 to 4, wherein the thermoplastic resin container is a polymer composition containing 72% by weight or more of a cyclic polyolefin having hydrogenated aromatic vinyl polymer block units, which are hydrogenated products of polymer blocks consisting of aromatic vinyl monomer units, and hydrogenated conjugated diene polymer block units, which are hydrogenated products of polymer blocks consisting of conjugated diene monomer units. The product according to claim 5, wherein the polymer composition contains 2% by weight or more and 25% by weight or less of a hydrogenated C9 petroleum resin. The product according to claim 5 or 6, wherein the polymer composition contains 2% by weight or more and 25% by weight or less of a styrene-based block copolymer. The hydrogenated aromatic vinyl polymer block unit constituting the cyclic polyolefin is a hydrogenated polystyrene block unit which is a hydrogenated product of a polystyrene block unit composed of a styrene monomer unit, and
The product according to any one of claims 1 to 7, wherein the hydrogenated conjugated diene polymer block unit constituting the cyclic polyolefin is a hydrogenated butadiene polymer block unit which is a hydrogenated product of a butadiene polymer block consisting of butadiene monomer units. The product according to any one of claims 1 to 8, which is an eye drop. The product according to any one of claims 1 to 9, wherein the aqueous liquid contains a surfactant. A method for suppressing a decrease in the content of a prostaglandin F2α derivative in an aqueous liquid preparation by storing the aqueous liquid preparation in a thermoplastic resin container containing a cyclic polyolefin. A thermoplastic resin container for storing an aqueous liquid preparation containing a prostaglandin F2α derivative, the thermoplastic resin container comprising a cyclic polyolefin, a hydrogenated C9 petroleum resin, and/or a styrene block copolymer.