Aqueous composition

Abstract

A first invention pertains to an aqueous composition that contains (A) 4-phenylbutyric acid or an ester thereof, or a pharmacologically acceptable salt thereof, and that is housed in a container in which all or a portion thereof in contact with the aqueous composition is formed of a resin containing a polyolefin. A second invention pertains to an aqueous composition containing (A) 4-phenylbutyric acid or an ester thereof, or a pharmacologically acceptable salt thereof, and (B) a chelating agent.

Description

aqueous composition

[0001] The first and second aspects of the present invention will be described below in order. The first aspect of the present invention relates to an aqueous composition.

[0002] Sodium 4-phenylbutyrate is known to be metabolized in the body to phenylacetic acid, conjugated with glutamic acid, and excreted in urine, and is used as a therapeutic agent for urea cycle disorders (Non-Patent Document 1).Recently, it has been reported that sodium 4-phenylbutyrate is useful for the prevention or treatment of ocular diseases such as myopia and presbyopia (for example, Patent Documents 1 and 2).

[0003] International Publication No. WO 2018 / 164113 International Publication No. WO 2020 / 129965

[0004] Bufenyl® Tablets 500 mg Bufenyl® Granules 94% Package insert

[0005] Therapeutic drugs for treating urea cycle disorders containing sodium 4-phenylbutyrate as an active ingredient are commercially available as tablets and granules suitable for oral administration. However, no findings have been reported regarding the behavior of aqueous compositions containing sodium 4-phenylbutyrate, such as eye drops, when contained in a resin container. The present inventors have discovered a new problem in that when an aqueous composition containing sodium 4-phenylbutyrate is contained in a specific resin container, the elution of impurities from the resin container is promoted. The first object of the present invention is to provide a novel aqueous composition containing 4-phenylbutyric acid or a derivative thereof contained in a resin container, in which the elution of impurities from the resin container is suppressed.

[0006] As a result of intensive research aimed at solving the above problems, the present inventors have found that storing an aqueous composition containing sodium 4-phenylbutyrate in a container made of a resin containing polyolefin can suppress the elution of impurities from the resin. The first invention is based on this finding and provides the following inventions.

[0007] [1] An aqueous composition containing (A) 4-phenylbutyric acid or an ester thereof, or a pharmacologically acceptable salt thereof, the aqueous composition being contained in a container in which a part or all of the portion in contact with the aqueous composition is formed of a polyolefin-containing resin. [2] The aqueous composition according to [1], further containing (B) a buffering agent. [3] The aqueous composition according to [1] or [2], further containing (C) a chelating agent. [4] The aqueous composition according to any one of claims [1] to [3], having a pH of 6.0 or more and 9.0 or less.

[0008] According to the first aspect of the present invention, there can be provided an aqueous composition containing 4-phenylbutyric acid or a derivative thereof contained in a resin container, in which elution of impurities from the resin container is suppressed.

[0009] Hereinafter, a first embodiment of the present invention will be described in detail, although the first embodiment of the present invention is not limited to the following embodiment.

[0010] The aqueous composition according to this embodiment contains (A) 4-phenylbutyric acid or an ester thereof, or a pharmacologically acceptable salt thereof (also simply referred to as "component (A)").

[0011] [Component (A)] 4-phenylbutyric acid is also called 4-PBA and has the following formula: It is a known compound represented by the formula:

[0012] Examples of esters of 4-phenylbutyric acid include esters formed by dehydration condensation of the carboxyl group of 4-phenylbutyric acid with a monohydric alcohol having 1 to 6 carbon atoms. Specific examples include methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, sec-butyl ester, tert-butyl ester, n-pentyl ester, and n-hexyl ester. Among these, methyl ester, ethyl ester, n-propyl ester, and isopropyl ester are preferred.

[0013] The salts of 4-phenylbutyric acid and salts of esters of 4-phenylbutyric acid are not particularly limited as long as they are pharmacologically acceptable. Specific examples include metal salts such as sodium salt, potassium salt, calcium salt, and magnesium salt; inorganic salts such as ammonium salt; and organic amine salts such as triethylamine salt and guanidine salt. Among these, sodium salt and potassium salt are preferred, and sodium salt is more preferred.

[0014] 4-Phenylbutyric acid or an ester thereof, or a pharmacologically acceptable salt thereof may be a non-solvate or a solvate (for example, a hydrate).

[0015] The content of component (A) in the aqueous composition according to this embodiment is not particularly limited and is set appropriately depending on the types and contents of other blended components, the formulation form, etc. From the viewpoint of more significantly exhibiting the effects of the first present invention, the content of component (A) is preferably 0.01 to 6 w / v%, more preferably 0.025 to 5 w / v%, even more preferably 0.05 to 4 w / v%, and particularly preferably 0.1 to 3 w / v%, based on the total amount of the aqueous composition according to this embodiment.

[0016] [Component (B)] The aqueous composition according to this embodiment preferably further contains a buffer (B) (also simply referred to as "component (B)"). When the aqueous composition further contains component (B), the effect of the first aspect of the present invention is more pronounced. The buffer includes inorganic buffers and organic buffers, and is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical), or physiologically acceptable.

[0017] Inorganic buffers are buffers derived from inorganic acids, such as borate buffers, phosphate buffers, and carbonate buffers.

[0018] Examples of borate buffers include boric acid or its salts (alkali metal borates, alkaline earth metal borates, etc.). Examples of phosphate buffers include phosphoric acid or its salts (alkali metal phosphates, alkaline earth metal phosphates, etc.). Examples of carbonate buffers include carbonic acid or its salts (alkali metal carbonates, alkaline earth metal carbonates, etc.). Furthermore, borate or phosphate hydrates may be used as borate buffers or phosphate buffers. More specific examples of borate buffers include boric acid or its salts (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.); phosphate buffers include phosphoric acid or its salts (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); and carbonate buffers include carbonic acid or its salts (sodium bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, magnesium carbonate, etc.).

[0019] The organic buffer is a buffer derived from an organic acid or an organic base, and examples of the organic buffer include citrate buffer, acetate buffer, Tris buffer, epsilon aminocaproic acid buffer, and AMPD buffer.

[0020] Examples of citrate buffers include citric acid or salts thereof (such as alkali metal citrates and alkaline earth metal citrates). Examples of acetate buffers include acetic acid or salts thereof (such as alkali metal acetates and alkaline earth metal acetates). Furthermore, citrates or hydrates of acetates may be used as citrate buffers or acetate buffers. More specific examples of citrate buffers include citric acid or salts thereof (such as sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, and disodium citrate); and examples of acetate buffers include acetic acid or salts thereof (such as ammonium acetate, potassium acetate, calcium acetate, and sodium acetate). Examples of Tris buffers include trometamol or salts thereof (such as trometamol hydrochloride). Examples of epsilon aminocaproic acid buffers include epsilon aminocaproic acid or salts thereof. Examples of AMPD buffers include 2-amino-2-methyl-1,3-propanediol or salts thereof.

[0021] As the buffer, from the viewpoint of more significantly exhibiting the effect of the first present invention, a boric acid buffer (e.g., a combination of boric acid and borax), a phosphate buffer (e.g., a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate), or a Tris buffer (e.g., trometamol) is preferred, with a boric acid buffer being more preferred, boric acid and a salt thereof being even more preferred, and a combination of boric acid and borax being even more preferred.

[0022] The buffering agent may be a commercially available product. One type of buffering agent may be used alone, or two or more types may be used in combination.

[0023] The content of component (B) in the aqueous composition according to this embodiment is not particularly limited and is set appropriately depending on the type of component (B), the types and contents of other blended components, the intended use of the aqueous composition, the formulation form, etc. From the viewpoint of more significantly exhibiting the effects of the first present invention, the content of component (B) is preferably 0.05 to 5.0 w / v%, more preferably 0.08 to 4.5 w / v%, even more preferably 0.1 to 4.0 w / v%, and particularly preferably 0.3 to 3.5 w / v%, based on the total amount of the aqueous composition.

[0024] The content ratio of component (B) to component (A) in the aqueous composition according to this embodiment is not particularly limited and is set appropriately depending on the types of components (A) and (B), the types and contents of other blended components, the intended use and formulation form of the aqueous composition, etc. From the viewpoint of more significantly achieving the effect of the first present invention, the content ratio of component (B) to component (A) is preferably 0.008 to 500 parts by mass, more preferably 0.02 to 180 parts by mass, even more preferably 0.02 to 80 parts by mass, and particularly preferably 0.1 to 35 parts by mass, per part by mass of the total content of component (A) contained in the aqueous composition according to this embodiment.

[0025] [Component (C)] The aqueous composition according to this embodiment preferably further contains a chelating agent (C) (also simply referred to as "component (C)"). When the aqueous composition further contains component (C), the preservative effect is synergistically exhibited in combination with component (A). The chelating agent is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical), or physiologically acceptable.

[0026] Examples of chelating agents include ethylenediaminediacetic acid (EDDA), ethylenediaminetriacetic acid, ethylenediaminetetraacetic acid (edetic acid) (EDTA), N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), gluconic acid, and salts thereof. Examples of these salts include metal salts such as sodium salts, potassium salts, calcium salts, and magnesium salts.

[0027] The chelating agent is preferably edetic acid or a salt thereof, more preferably a sodium salt of edetic acid, further preferably disodium edetate or tetrasodium edetate, and particularly preferably disodium edetate.

[0028] The content of component (C) in the aqueous composition according to this embodiment is not particularly limited and is set appropriately depending on the type of component (C), the types and contents of other blended components, the intended use and formulation of the aqueous composition, etc. From the viewpoint of synergistically exerting preservative effectiveness in combination with component (A), the content of component (C) is preferably 0.001 to 12 w / v%, more preferably 0.003 to 8 w / v%, even more preferably 0.006 to 4 w / v%, and particularly preferably 0.01 to 2 w / v%, based on the total amount of the aqueous composition.

[0029] The content ratio of the component (C) relative to the component (A) in the aqueous composition according to this embodiment is not particularly limited and is set appropriately depending on the types of the components (A) and (C), the types and contents of other blended components, the intended use and formulation of the aqueous composition, etc. From the viewpoint of synergistically exerting preservative effectiveness in combination with the component (A), the content ratio of the component (C) relative to the component (A) is preferably 0.0002 to 1200 parts by mass, more preferably 0.0006 to 320 parts by mass, even more preferably 0.0015 to 80 parts by mass, and particularly preferably 0.003 to 20 parts by mass, relative to 1 part by mass of the total content of the component (A) contained in the aqueous composition according to this embodiment.

[0030] The aqueous composition according to this embodiment may contain, in addition to the above-mentioned components, an appropriate amount of a combination of various pharmacologically active components and physiologically active components, so long as the combination does not impair the effects of the first invention. The components are not particularly limited, and examples thereof include antiallergic agents, antihistamines, anti-inflammatory agents, steroids, decongestants, eye muscle regulating agents, vitamins, amino acids, astringents, etc.

[0031] The aqueous composition according to this embodiment may contain one or more additives selected appropriately in a conventional manner depending on the intended use and formulation, as long as the effects of the first aspect of the present invention are not impaired. Examples of such additives include carriers, pH adjusters, surfactants, fragrances or refreshing agents, thickeners, stabilizers, preservatives, and tonicity agents.

[0032] The pH of the aqueous composition according to this embodiment is not particularly limited as long as it is within a medicamentarily, pharmacologically (pharmaceutical), or physiologically acceptable range, but from the viewpoint of more significantly exhibiting the effect of the first present invention, the pH of the aqueous composition is preferably 9.0 or less, more preferably 8.5 or less, and even more preferably 8.0 or less. Furthermore, from the viewpoint of further improving the stability of 4-phenylbutyric acid or an ester thereof, or a pharmacologically acceptable salt thereof, the pH of the aqueous composition is preferably 6.0 or more, more preferably 6.5 or more, and even more preferably 7.0 or more.

[0033] The aqueous composition according to this embodiment can be adjusted to an osmotic pressure ratio within a biologically acceptable range, as needed. The appropriate osmotic pressure ratio can be appropriately determined depending on the intended use, formulation, and method of use of the aqueous composition, but can be, for example, 0.4 to 5.0. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (the osmotic pressure of a 0.9 w / v% sodium chloride aqueous solution) according to the 18th Revised Japanese Pharmacopoeia. The osmotic pressure is measured with reference to the osmotic pressure measurement method (freezing point depression method) described in the Japanese Pharmacopoeia. The standard solution for measuring the osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution) can be prepared by drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500 to 650°C for 40 to 50 minutes, allowing it to cool in a desiccator (silica gel), accurately weighing 0.900 g of the solution, dissolving it in purified water, and preparing a solution of exactly 100 mL. Alternatively, a commercially available standard solution for measuring the osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution) can be used.

[0034] The viscosity of the aqueous composition according to this embodiment is not particularly limited as long as it is within a medicamentarily, pharmacologically (pharmaceutical), or physiologically acceptable range. The viscosity of the aqueous composition according to this embodiment may be, for example, 1 to 10,000 mPa s at 20°C measured with a rotational viscometer (TV-20 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1°34' x R24).

[0035] The aqueous composition according to the present embodiment can be prepared, for example, by adding and mixing the component (A) and, if necessary, other components to obtain a desired content. Specifically, the aqueous composition can be prepared, for example, by dissolving or suspending the components in purified water and sterilizing the mixture by filtration or the like.

[0036] When the aqueous composition according to this embodiment is an ophthalmic composition, it can be used, for example, as eye drops (also called eye drops or eye drops; eye drops include eye drops that can be applied while wearing contact lenses), artificial tears, or eyewash (also called eyewash or eyewash; eyewash includes eyewash that can be used while wearing contact lenses). The term "contact lenses" includes hard contact lenses and soft contact lenses (including both ionic and non-ionic contact lenses, and both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses).

[0037] The aqueous composition according to this embodiment contains sodium 4-phenylbutyrate as an active ingredient and can therefore be suitably used as an agent for preventing, suppressing, or treating myopia. Furthermore, the aqueous composition according to this embodiment contains sodium 4-phenylbutyrate as an active ingredient and can therefore be suitably used as an agent for preventing, suppressing, or treating presbyopia.

[0038] The aqueous composition according to this embodiment is preferably an ophthalmic composition, and more preferably an eye drop (including an eye drop that can be applied while wearing contact lenses), because it can more significantly exhibit the effects of the first invention. When the aqueous composition according to this embodiment is an eye drop, the dosage and administration method are not particularly limited as long as they are effective and cause few side effects, but for example, for adults (15 years of age or older) and children aged 7 years or older, 1 to 3 drops, 1 to 2 drops, or 2 to 3 drops are applied 1 to 4 times or 5 to 6 times a day.

[0039] [Container] The aqueous composition according to this embodiment is provided in a container in which a part or all of the part that comes into contact with the aqueous composition is formed of a polyolefin-containing resin (hereinafter also referred to as "the resin according to this embodiment"). Examples of polyolefin-containing resins include polyethylene (PE), polypropylene (PP), ethylene-propylene copolymer, ethylene-vinyl acetate copolymer, polymethylpentene, cyclic olefin polymer (COP), cyclic olefin copolymer (COC), and resins containing combinations thereof.

[0040] Examples of polyethylene include high density polyethylene (HDPE), low density polyethylene (LDPE), and linear low density polyethylene (LLDPE).

[0041] The cyclic olefin polymer is not particularly limited as long as it contains a polymer obtained by copolymerizing one kind of cyclic olefin alone, a polymer obtained by copolymerizing two or more kinds of cyclic olefins, or a hydrogenated product thereof. The cyclic olefin polymer is preferably one containing a ring-opening polymer of a cyclic olefin or a hydrogenated product thereof. Furthermore, the cyclic olefin polymer is preferably one containing an amorphous polymer.

[0042] The cyclic olefin copolymer is not particularly limited as long as it contains a polymer obtained by copolymerizing a cyclic olefin and a non-cyclic olefin, or a hydrogenated product thereof.

[0043] Examples of cyclic olefins include monocyclic or polycyclic cycloalkanes and monocyclic or polycyclic cycloalkenes having a vinyl group, and derivatives thereof. Preferred cyclic olefins are norbornene, tetracyclododecene, and derivatives thereof. Examples of acyclic olefins include α-olefins such as ethylene, propylene, 1-butene, 1-pentene, and 1-hexene.

[0044] The cyclic olefin polymer preferably contains a polymer of a cyclic olefin having a norbornene skeleton or a hydrogenated product thereof, from the viewpoint of more significantly achieving the effect of the first invention. The cyclic olefin copolymer preferably contains a polymer obtained by copolymerizing norbornene and ethylene, from the viewpoint of more significantly achieving the effect of the first invention. The polymer obtained by copolymerizing a cyclic olefin and a non-cyclic olefin may contain other monomers as constituent components of the polymer.

[0045] The resin according to this embodiment is preferably a resin containing at least one selected from the group consisting of polyethylene (PE), polypropylene (PP) and cyclic olefin copolymer (COC), and more preferably a resin containing only polyethylene, a resin containing only polypropylene, or a resin containing a cyclic olefin copolymer and polyethylene.

[0046] When the resin according to this embodiment is a resin containing a cyclic olefin copolymer and polyethylene, the content ratio of the cyclic olefin copolymer to the polyethylene in the resin may be, for example, 50:50 to 95:5, 55:45 to 90:10, or 60:40 to 85:15.

[0047] The resin according to this embodiment may contain other polymers such as polycarbonate, (meth)acrylic acid polymer, polystyrene (PS), polyethylene naphthalate (PEN), polybutylene terephthalate (PBT), polyethylene terephthalate (PET), polyarylate, etc. The resin according to this embodiment may also contain additives such as stabilizers, modifiers, colorants, ultraviolet absorbers, metal oxides, oxygen absorbers, antibacterial agents, plasticizers, glass fibers, etc.

[0048] The type of container may be any container commonly used in the ophthalmology field, specifically, for example, an eye dropper. The part of the container that comes into contact with the aqueous composition may be, for example, the inner stopper, the perforated inner stopper, or the inner surface of the container (if the container has a multi-layer structure, the innermost layer).

[0049] A part or all of the portion of the container that comes into contact with the aqueous composition is formed of a resin containing polyolefin. For example, when the container has a perforated inner plug (nozzle), only the perforated inner plug portion may be formed of the resin according to this embodiment, or the storage portion other than the perforated inner plug may be formed of the resin according to this embodiment, or the entire container may be formed of the resin according to this embodiment.

[0050] It is sufficient that only a portion of the container that comes into contact with the aqueous composition is formed from the resin according to this embodiment, but from the viewpoint of more significantly achieving the effect of the first invention, it is preferable that the entire portion that comes into contact with the aqueous composition is formed from the resin according to this embodiment. When only a portion of the container is formed from the resin according to this embodiment, the type of resin that forms the other portions is not particularly limited, and examples thereof include polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polyethylene naphthalate (PEN), polystyrene (PS), polyarylate (PAR), polycarbonate (PC), polyimide (PI), acrylonitrile butadiene styrene (ABS), copolymers of monomers that constitute these, and mixtures of two or more of these.

[0051] The shape and capacity of the container are not particularly limited and may be appropriately determined depending on the application. The container may be a container that contains an amount of aqueous composition for multiple uses (multi-dose container) or a container that contains an amount of aqueous composition for a single use (unit-dose container).

[0052] When the container is a multi-dose container, the capacity may be, for example, 1.5 to 7.5 mL, 2 to 6 mL, or 2.5 to 5.0 mL. When the container is a unit-dose container, the capacity may be, for example, 0.1 to 1.0 mL, 0.2 to 0.9 mL, or 0.3 to 0.8 mL.

[0053] The aqueous composition according to this embodiment may also be provided as a container-packed aqueous composition. The first invention can also be understood as a pharmaceutical product (an ophthalmic product such as eye drops) containing the aqueous composition of the first invention in a container.

[0054] [Examples of the First Invention] The first invention will be specifically described below based on test examples, but the first invention is not limited to these. Unless otherwise specified, the unit of each component in the tables is w / v %.

[0055] Test Example 1: Stability test in multi-dose container Preparation of formulations Each aqueous composition (formulations 1-0 to 1-4) shown in Table 1-1 was prepared by a conventional method, and 5 mL of each was filled into 5 mL multi-dose containers made of polyethylene (PE), polypropylene (PP), and polyethylene terephthalate (PET).

[0056] <Stability of Sodium 4-phenylbutyrate> Sodium 4-phenylbutyrate was quantified using liquid chromatography. 10 μL of a 0.05 w / v% sodium 4-phenylbutyrate solution was used as the standard solution, and 10 μL of a formulation diluted 10-fold with the mobile phase was used as the sample solution. The standard solution and the sample solution were each loaded onto a reverse-phase column (YMC-Pack ODS-A (I.D. 4.6 mm × 150 mm, 5 μm), manufactured by YMC Co., Ltd.) maintained at 30°C, and eluted with a mobile phase mixture of 0.2% formic acid solution / acetonitrile. Detection was performed using an ultraviolet absorption spectrophotometer (measurement wavelength: 260 nm). The peak area of ​​sodium 4-phenylbutyrate was then measured for each of the standard solution and the sample solution, and the concentration of sodium 4-phenylbutyrate for each formulation immediately after preparation and after one week of storage at 60°C was calculated using the following equation 1. The results, assuming the concentration immediately after preparation to be 100, are shown in Table 1-2. Equation 1: Concentration of sodium 4-phenylbutyrate (w / v%)=0.05×(peak area of ​​4-phenylbutyric acid in sample solution / peak area of ​​4-phenylbutyric acid in standard solution)×10

[0057] <Measurement of Total Impurities> Total impurities were measured using liquid chromatography. 50 μL of a formulation diluted 100-fold with purified water was used as the standard solution, and 50 μL of the formulation was used as the sample solution. The standard solution and the sample solution were each loaded onto a reverse-phase column (Inertsil Ph-3 HP (I.D. 4.6 mm × 250 mm, 3 μm), GL Sciences Inc.) maintained at 45°C, and elution was performed using a gradient program using mobile phase A: water / acetic acid (99:1) and mobile phase B: acetonitrile / acetic acid (99:1). Detection was performed using an ultraviolet absorption spectrophotometer (measurement wavelength: 254 nm). Thereafter, the peak area of ​​sodium 4-phenylbutyrate was measured for the standard solution, and the peak areas of each component other than sodium 4-phenylbutyrate were measured for the sample solution. The ratios of each impurity relative to sodium 4-phenylbutyrate were calculated using the following formula 2 for each formulation immediately after preparation and after storage at 60°C for 1 week, and the sum was calculated. The area measurement range was set to approximately twice the retention time of sodium 4-phenylbutyrate. Formulation 1-0 was used as the base. The results, assuming the total amount of impurities immediately after preparation as 1, are shown in Table 1-3. Equation 2: Ratio of individual impurities to 4-phenylbutyric acid = (peak area of ​​components other than 4-phenylbutyric acid - peak area of ​​components other than 4-phenylbutyric acid in the base) / peak area of ​​4-phenylbutyric acid

[0058]

[0059]

[0060]

[0061] As shown in Table 1-2, there was no difference in the stability of sodium 4-phenylbutyrate itself between the container resins. On the other hand, as shown in Table 1-3, it was confirmed that the generation of impurities was suppressed in the formulations contained in polyethylene resin and polypropylene resin compared to the formulation contained in polyethylene terephthalate resin.

[0062] Test Example 2: Stability test in unit-dose container Preparation of formulations The aqueous compositions (formulations 2-1) shown in Table 1-4 were prepared by a conventional method, and 0.5 mL of each was filled into a 0.5 mL unit-dose container made of polyethylene (PE) and a resin unit-dose container made of a mixture of cyclic olefin copolymer (COC) and polyethylene (PE).

[0063] <Stability of Sodium 4-phenylbutyrate> Sodium 4-phenylbutyrate was quantified using liquid chromatography. 20 μL of a 0.02 w / v% sodium 4-phenylbutyrate solution was used as the standard solution, and 20 μL of Formulation 2-1 diluted 10-fold with the mobile phase was used as the sample solution. The standard solution and the sample solution were each loaded onto a reverse-phase column (YMC-Pack ODS-A (I.D. 4.6 mm × 150 mm, 5 μm), manufactured by YMC Co., Ltd.) maintained at 30°C, and eluted with a mobile phase mixture of 0.2% formic acid solution / acetonitrile. Detection was performed using an ultraviolet absorption spectrophotometer (measurement wavelength: 260 nm). The peak areas of sodium 4-phenylbutyrate were then measured for the standard solution and the sample solution, and the concentrations of sodium 4-phenylbutyrate for Formulation 2-1 immediately after preparation and after one month of storage at 40°C were calculated using the following equation 3. The results, assuming the concentration immediately after preparation as 100, are shown in Table 1-5. Equation 3: Concentration of sodium 4-phenylbutyrate (w / v%)=0.02×(peak area of ​​4-phenylbutyric acid in sample solution / peak area of ​​4-phenylbutyric acid in standard solution)×10

[0064] <Measurement of Total Impurities> Total impurities were measured using liquid chromatography. 80 μL of a formulation diluted 100-fold with purified water was used as the standard solution, and 80 μL of the formulation was used as the sample solution. The standard solution and the sample solution were each loaded onto a reverse-phase column (Inertsil Ph-3 (I.D. 4.6 mm × 250 mm, 5 μm), GL Sciences Inc.) maintained at 40°C, and elution was performed using a gradient program using mobile phase A: water / acetic acid (99:1) and mobile phase B: acetonitrile / acetic acid (99:1). Detection was performed using an ultraviolet spectrophotometer (measurement wavelength: 254 nm). Thereafter, the peak area of ​​sodium 4-phenylbutyrate was measured for the standard solution, and the peak areas of each component other than sodium 4-phenylbutyrate were measured for the sample solution. The ratios of each impurity relative to sodium 4-phenylbutyrate were calculated using the following equation 4 for Formulation 2-1 immediately after preparation and after one month of storage at 40°C, and the sum was calculated. The area measurement range was set to approximately twice the retention time of sodium 4-phenylbutyrate. The results, assuming the total amount of impurities immediately after preparation as 1, are shown in Table 1-6. Equation 4: Ratio of individual impurities to 4-phenylbutyric acid = Peak area of ​​components other than 4-phenylbutyric acid / Peak area of ​​4-phenylbutyric acid

[0065]

[0066]

[0067]

[0068] As shown in Table 1-5, there was no difference in the stability of sodium 4-phenylbutyrate itself among the container resins. Furthermore, as shown in Table 1-6, it was confirmed that the generation of impurities was suppressed for both formulations contained in polyethylene resin and resin containing cyclic olefin copolymer and polyethylene.

[0069] This concludes the description of the first aspect of the present invention, and the second aspect of the present invention will now be described.

[0070] [Second Invention] The second invention relates to an aqueous composition.

[0071] [Background Art] Sodium 4-phenylbutyrate is known to be metabolized in the body to phenylacetic acid, conjugated with glutamic acid, and excreted in urine, and is used as a therapeutic agent for urea cycle disorders (Non-Patent Document 1). Recently, it has been reported that sodium 4-phenylbutyrate is useful for the prevention or treatment of ophthalmic diseases such as myopia and presbyopia (for example, Patent Documents 1 and 2).

[0072] [Prior art documents] [Patent documents] [Patent document 1] International Publication No. 2018 / 164113 [Patent document 2] International Publication No. 2020 / 129965 [Non-patent documents] [Non-patent document 1] Bufenyl (registered trademark) Tablets 500 mg Bufenyl (registered trademark) Granules 94% Package insert [Summary of the second invention] [Problem to be solved by the second invention]

[0073] Drugs for treating urea cycle disorders containing sodium 4-phenylbutyrate as an active ingredient are commercially available as tablets and granules suitable for oral administration. However, while aqueous compositions such as eye drops require a certain level of preservative effectiveness, no findings have been reported regarding the preservative effectiveness of liquid preparations containing sodium 4-phenylbutyrate. The second object of the present invention is to provide an aqueous composition containing sodium 4-phenylbutyrate and having excellent preservative effectiveness.

[0074] [Means for Solving the Problems of the Second Invention] As a result of extensive research aimed at solving the above-mentioned problems, the present inventors have unexpectedly found that by incorporating a chelating agent, disodium edetate, into an aqueous composition containing sodium 4-phenylbutyrate, the preservative effectiveness of the aqueous composition is synergistically enhanced. The second invention is based on this finding and provides the following inventions.

[0075] [1] An aqueous composition comprising (A) 4-phenylbutyric acid or an ester thereof, or a pharmacologically acceptable salt thereof, and (B) a chelating agent. [2] The aqueous composition according to [1], which contains 0.0002 to 1,200 parts by mass of component (B) per part by mass of the total content of component (A). [3] The aqueous composition according to [1] or [2], which further contains (C) a buffering agent. [4] The aqueous composition according to any one of [1] to [3], which has a pH of 5.0 or more and 9.0 or less.

[0076] [Effects of the Second Invention] According to the second invention, an aqueous composition containing sodium 4-phenylbutyrate and having excellent preservative effect can be provided.

[0077] [Second embodiment of the present invention] Hereinafter, a second embodiment of the present invention will be described in detail, although the second embodiment of the present invention is not limited to the following embodiment.

[0078] The aqueous composition according to this embodiment contains (A) 4-phenylbutyric acid or an ester thereof, or a pharmacologically acceptable salt thereof (also simply referred to as "component (A)").

[0079] [Component (A)] 4-phenylbutyric acid is also called 4-PBA and has the following formula: It is a known compound represented by the formula:

[0080] Examples of esters of 4-phenylbutyric acid include esters formed by dehydration condensation of the carboxyl group of 4-phenylbutyric acid with a monohydric alcohol having 1 to 6 carbon atoms. Specific examples include methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, sec-butyl ester, tert-butyl ester, n-pentyl ester, and n-hexyl ester. Among these, methyl ester, ethyl ester, n-propyl ester, and isopropyl ester are preferred.

[0081] The salts of 4-phenylbutyric acid and salts of esters of 4-phenylbutyric acid are not particularly limited as long as they are pharmacologically acceptable. Specific examples include metal salts such as sodium salt, potassium salt, calcium salt, and magnesium salt; inorganic salts such as ammonium salt; and organic amine salts such as triethylamine salt and guanidine salt. Among these, sodium salt and potassium salt are preferred, and sodium salt is more preferred.

[0082] 4-Phenylbutyric acid or an ester thereof, or a pharmacologically acceptable salt thereof may be a non-solvate or a solvate (for example, a hydrate).

[0083] The content of component (A) in the aqueous composition according to this embodiment is not particularly limited and is set appropriately depending on the types and contents of other blended components, the formulation form, etc. From the viewpoint of more significantly exhibiting the effect of the second present invention, the content of component (A) is preferably 0.01 to 6 w / v%, more preferably 0.025 to 5 w / v%, even more preferably 0.05 to 4 w / v%, and particularly preferably 0.1 to 3 w / v%, based on the total amount of the aqueous composition according to this embodiment.

[0084] [Component (B)] The aqueous composition according to this embodiment further contains a chelating agent (B) (also simply referred to as "component (B)"). The chelating agent is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical), or physiologically acceptable.

[0085] Examples of chelating agents include ethylenediaminediacetic acid (EDDA), ethylenediaminetriacetic acid, ethylenediaminetetraacetic acid (edetic acid) (EDTA), N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), gluconic acid, and salts thereof. Examples of these salts include metal salts such as sodium salts, potassium salts, calcium salts, and magnesium salts.

[0086] The chelating agent is preferably edetic acid or a salt thereof, more preferably a sodium salt of edetic acid, further preferably disodium edetate or tetrasodium edetate, and particularly preferably disodium edetate.

[0087] The content of component (B) in the aqueous composition according to this embodiment is not particularly limited and is set appropriately depending on the type of component (B), the types and contents of other blended components, the intended use and formulation of the aqueous composition, etc. From the viewpoint of synergistically exerting preservative effectiveness in combination with component (A), the content of component (B) is preferably 0.001 to 12 w / v%, more preferably 0.003 to 8 w / v%, even more preferably 0.006 to 4 w / v%, and particularly preferably 0.01 to 2 w / v%, based on the total amount of the aqueous composition.

[0088] The content ratio of the component (B) to the component (A) in the aqueous composition according to this embodiment is not particularly limited and is set appropriately depending on the types of the components (A) and (B), the types and contents of other blended components, the intended use and formulation of the aqueous composition, etc. From the viewpoint of more synergistically exerting the preservative effect, the content ratio of the component (B) to the component (A) is preferably 0.0002 to 1200 parts by mass, more preferably 0.0006 to 320 parts by mass, even more preferably 0.0015 to 80 parts by mass, and particularly preferably 0.003 to 20 parts by mass, per part by mass of the total content of the component (A) contained in the aqueous composition according to this embodiment.

[0089] [Component (C)] The aqueous composition according to this embodiment preferably further contains a buffer (C) (also simply referred to as "component (C)"). When the aqueous composition further contains component (C), the effect of the second aspect of the present invention is more pronounced. The buffer includes inorganic buffers and organic buffers, and is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical), or physiologically acceptable.

[0090] Inorganic buffers are buffers derived from inorganic acids, such as borate buffers, phosphate buffers, and carbonate buffers.

[0091] Examples of borate buffers include boric acid or its salts (alkali metal borates, alkaline earth metal borates, etc.). Examples of phosphate buffers include phosphoric acid or its salts (alkali metal phosphates, alkaline earth metal phosphates, etc.). Examples of carbonate buffers include carbonic acid or its salts (alkali metal carbonates, alkaline earth metal carbonates, etc.). Furthermore, borate or phosphate hydrates may be used as borate buffers or phosphate buffers. More specific examples of borate buffers include boric acid or its salts (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.); phosphate buffers include phosphoric acid or its salts (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); and carbonate buffers include carbonic acid or its salts (sodium bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, magnesium carbonate, etc.).

[0092] The organic buffer is a buffer derived from an organic acid or an organic base, and examples of the organic buffer include citrate buffer, acetate buffer, Tris buffer, epsilon aminocaproic acid buffer, and AMPD buffer.

[0093] Examples of citrate buffers include citric acid or salts thereof (such as alkali metal citrates and alkaline earth metal citrates). Examples of acetate buffers include acetic acid or salts thereof (such as alkali metal acetates and alkaline earth metal acetates). Furthermore, citrates or hydrates of acetates may be used as citrate buffers or acetate buffers. More specific examples of citrate buffers include citric acid or salts thereof (such as sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, and disodium citrate); and examples of acetate buffers include acetic acid or salts thereof (such as ammonium acetate, potassium acetate, calcium acetate, and sodium acetate). Examples of Tris buffers include trometamol or salts thereof (such as trometamol hydrochloride). Examples of epsilon aminocaproic acid buffers include epsilon aminocaproic acid or salts thereof. Examples of AMPD buffers include 2-amino-2-methyl-1,3-propanediol or salts thereof.

[0094] As the buffer, from the viewpoint of more significantly exhibiting the effect of the second present invention, a boric acid buffer (e.g., a combination of boric acid and borax), a phosphate buffer (e.g., a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate), or a Tris buffer (e.g., trometamol) is preferred, with a boric acid buffer being more preferred, boric acid and a salt thereof being even more preferred, and a combination of boric acid and borax being even more preferred.

[0095] The buffering agent may be a commercially available product. One type of buffering agent may be used alone, or two or more types may be used in combination.

[0096] The content of component (C) in the aqueous composition according to this embodiment is not particularly limited and is set appropriately depending on the type of component (C), the types and contents of other blended components, the intended use of the aqueous composition, the formulation form, etc. From the viewpoint of more significantly exhibiting the effect of the second present invention, the content of component (C) is preferably 0.05 to 5.0 w / v%, more preferably 0.08 to 4.5 w / v%, even more preferably 0.1 to 4.0 w / v%, and particularly preferably 0.3 to 3.5 w / v%, based on the total amount of the aqueous composition.

[0097] The content ratio of component (C) to component (A) in the aqueous composition according to this embodiment is not particularly limited and is set appropriately depending on the types of components (A) and (C), the types and contents of other blended components, the intended use and formulation form of the aqueous composition, etc. From the viewpoint of more significantly exhibiting the effect of the second present invention, the content ratio of component (C) to component (A) is preferably 0.008 to 500 parts by mass, more preferably 0.02 to 180 parts by mass, even more preferably 0.03 to 80 parts by mass, and particularly preferably 0.1 to 35 parts by mass, per part by mass of the total content of component (A) contained in the aqueous composition according to this embodiment.

[0098] The aqueous composition according to this embodiment may contain, in addition to the above-mentioned components, an appropriate amount of a combination of components selected from various pharmacologically active components and physiologically active components, so long as the effect of the second invention is not impaired. The components are not particularly limited, and examples thereof include antiallergic agents, antihistamines, anti-inflammatory agents, steroids, decongestants, eye muscle regulating agents, vitamins, amino acids, astringents, etc.

[0099] The aqueous composition according to this embodiment may contain one or more additives selected appropriately in a conventional manner depending on the intended use and formulation, as long as the effects of the second aspect of the present invention are not impaired. Examples of such additives include carriers, pH adjusters, surfactants, fragrances or freshening agents, thickeners, stabilizers, preservatives, and isotonicity agents.

[0100] The pH of the aqueous composition according to this embodiment is not particularly limited as long as it is within a medicamentarily, pharmacologically (pharmaceutical), or physiologically acceptable range, but from the viewpoint of more significantly exhibiting the effect of the second present invention, the pH of the aqueous composition is preferably 9.0 or less, more preferably 8.5 or less, and even more preferably 8.0 or less. Furthermore, from the viewpoint of further improving the stability of 4-phenylbutyric acid or an ester thereof, or a pharmacologically acceptable salt thereof, the pH of the aqueous composition is preferably 5.0 or more, more preferably 5.5 or more, and even more preferably 6.0 or more.

[0101] The aqueous composition according to this embodiment can be adjusted to an osmotic pressure ratio within a biologically acceptable range, as needed. The appropriate osmotic pressure ratio can be appropriately determined depending on the intended use, formulation, and method of use of the aqueous composition, but can be, for example, 0.4 to 5.0. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (the osmotic pressure of a 0.9 w / v% sodium chloride aqueous solution) according to the 18th Revised Japanese Pharmacopoeia. The osmotic pressure is measured with reference to the osmotic pressure measurement method (freezing point depression method) described in the Japanese Pharmacopoeia. The standard solution for measuring the osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution) can be prepared by drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500 to 650°C for 40 to 50 minutes, allowing it to cool in a desiccator (silica gel), accurately weighing 0.900 g of the solution, dissolving it in purified water, and preparing a solution of exactly 100 mL. Alternatively, a commercially available standard solution for measuring the osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution) can be used.

[0102] The viscosity of the aqueous composition according to this embodiment is not particularly limited as long as it is within a medicamentarily, pharmacologically (pharmaceutical), or physiologically acceptable range. The viscosity of the aqueous composition according to this embodiment may be, for example, 1 to 10,000 as measured at 20°C using a rotational viscometer (TV-20 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1°34' x R24).

[0103] The aqueous composition according to the present embodiment can be prepared, for example, by adding and mixing the components (A), (B), and, if necessary, other components to a desired content. Specifically, the aqueous composition can be prepared, for example, by dissolving or suspending the components in purified water and sterilizing the resulting mixture by filtration or the like.

[0104] When the aqueous composition according to this embodiment is an ophthalmic composition, it can be used, for example, as eye drops (also called eye drops or eye drops; eye drops include eye drops that can be applied while wearing contact lenses), artificial tears, or eyewash (also called eyewash or eyewash; eyewash includes eyewash that can be used while wearing contact lenses). The term "contact lenses" includes hard contact lenses and soft contact lenses (including both ionic and non-ionic contact lenses, and both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses).

[0105] The aqueous composition according to this embodiment contains sodium 4-phenylbutyrate as an active ingredient and can therefore be suitably used as an agent for preventing, suppressing, or treating myopia. Furthermore, the aqueous composition according to this embodiment contains sodium 4-phenylbutyrate as an active ingredient and can therefore be suitably used as an agent for preventing, suppressing, or treating presbyopia.

[0106] The aqueous composition according to this embodiment is preferably an ophthalmic composition, and more preferably an eye drop (including an eye drop that can be applied while wearing contact lenses), because it can more significantly exhibit the effect of the second present invention. When the aqueous composition according to this embodiment is an eye drop, the dosage and administration method are not particularly limited as long as they are effective and have few side effects, but for example, for adults (15 years of age or older) and children 7 years of age or older, 1 to 3 drops, 1 to 2 drops, or 2 to 3 drops are applied 1 to 4 times or 5 to 6 times a day.

[0107] The aqueous composition according to this embodiment is provided in any suitable container. The container for containing the aqueous composition according to this embodiment is not particularly limited and may be made of glass or plastic, for example. Plastic is preferred. Examples of plastic include polyolefin resins such as polyethylene, polypropylene, cyclic olefin copolymers, and mixtures of two or more of these, and polyester resins such as polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, and mixtures of two or more of these. From the viewpoint of further enhancing the effects of the second aspect of the present invention, polyolefin resins are more preferred. The plastic may contain other polymers such as polycarbonate, (meth)acrylic acid-based polymers, polystyrene (PS), and polyarylate. The plastic may also contain additives such as stabilizers, modifiers, colorants, UV absorbers, metal oxides, oxygen absorbers, antibacterial agents, plasticizers, and glass fibers. The container for containing the aqueous composition according to this embodiment may also contain elastomers such as styrene-based thermoplastic elastomers and styrene-butadiene-based thermoplastic elastomers. The container for storing the aqueous composition according to the present embodiment may be a transparent container that allows the interior of the container to be seen, or an opaque container that makes it difficult to see the interior of the container. A transparent container is preferred. Here, the term "transparent container" includes both a colorless transparent container and a colored transparent container.

[0108] A nozzle may be attached to the container containing the aqueous composition according to this embodiment. The material of the nozzle is not particularly limited and may be, for example, glass or plastic. Plastic is preferred. Examples of plastic include polyolefin resins such as polyethylene, polypropylene, cyclic olefin copolymers, and mixtures of two or more of these, and polyester resins such as polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, and mixtures of two or more of these. From the viewpoint of further enhancing the effects of the second aspect of the present invention, polyolefin resin is more preferred. The plastic may contain other polymers such as polycarbonate, (meth)acrylic acid-based polymers, polystyrene (PS), and polyarylate. The plastic may also contain additives such as stabilizers, modifiers, colorants, UV absorbers, metal oxides, oxygen absorbers, antibacterial agents, plasticizers, and glass fibers. Silicone may also be used for the nozzle attached to the container containing the aqueous composition according to this embodiment.

[0109] The shape and capacity of the container are not particularly limited and may be appropriately determined depending on the application. The container may be a container that contains an amount of aqueous composition for multiple uses (multi-dose container) or a container that contains an amount of aqueous composition for a single use (unit-dose container).

[0110] When the container is a multi-dose container, the capacity may be, for example, 1.5 to 7.5 mL, 2.0 to 6.0 mL, or 2.5 to 5.0 mL. When the container is a unit-dose container, the capacity may be, for example, 0.1 to 1.0 mL, 0.2 to 0.9 mL, or 0.3 to 0.8 mL.

[0111] The aqueous composition according to this embodiment may also be provided as a container-packed aqueous composition. The second invention can also be understood as a pharmaceutical product (an ophthalmic product such as eye drops) containing the aqueous composition of the second invention in a container.

[0112] [Examples of the Second Invention] The second invention will be specifically described below based on test examples, but the second invention is not limited to these. Unless otherwise specified, the unit of each component in the tables is w / v %.

[0113] Test Example 1: Preservative Effectiveness Test Each aqueous composition shown in Table 2-1 was prepared by a conventional method and sterilized by filtering through a 0.2 μm membrane filter. The units of each component in Table 2-1 are w / v %. Thereafter, a preservative effectiveness test of each aqueous composition was carried out in accordance with the 18th edition of the Japanese Pharmacopoeia. Pseudomonas aeruginosa was inoculated onto the surface of a soybean casein digest slant medium and cultured at 30 to 35°C for 24 hours. The cultured cells were aseptically collected with a platinum loop and suspended in an appropriate amount of sterile physiological saline to obtain a concentration of approximately 1 x 10 ７ A bacterial suspension containing viable bacteria of 100 CFU / mL was prepared. The viable cell count of the bacterial suspension was measured by separate cultivation. Next, 10 mL of each of the prepared aqueous compositions was filled into a 15 mL centrifuge tube (PET). Each of these aqueous compositions was filled with a viable cell count (final concentration) of approximately 5 × 10 ５ A bacterial suspension was inoculated to a concentration of 0.01 CFU / mL and thoroughly stirred to prepare a sample. The sample containing the bacteria was stored at 20-25°C for 7 days. The sample containing the bacteria was then adjusted to a concentration appropriate for counting, and the bacteria were recovered according to the agar pour plate method. After culturing the sample on soybean casein digest agar medium at 30-35°C for 2-3 days, the number of colonies observed was counted to determine the viable bacterial count. The viable bacterial count immediately after inoculation was compared with the viable bacterial count in the sample after 7 days of storage, and the reduction in the bacterial count was calculated as the preservative efficacy (Log Reduction). The results are shown in Table 2-1.

[0114]

[0115] In the aqueous composition containing sodium 4-phenylbutyrate and disodium edetate, the inoculated bacteria were reduced to below the detection limit, and it was confirmed that the preservative effectiveness (Log Reduction) value was greater than 4.7 (Example 1). In the aqueous composition not containing sodium 4-phenylbutyrate, the incorporation of disodium edetate only increased the preservative effectiveness (Log Reduction) by 0.4 (Comparison between Comparative Examples 1 and 2). On the other hand, in the aqueous composition containing sodium 4-phenylbutyrate, the incorporation of disodium edetate increased the preservative effectiveness (Log Reduction) by at least about 2 (Comparison between Comparative Example 3 and Example 1). From the above, it was confirmed that the combination of sodium 4-phenylbutyrate and disodium edetate synergistically enhanced the preservative effectiveness.

Claims

1. (A) An aqueous composition containing 4-phenylbutyric acid or an ester thereof, or a pharmacologically acceptable salt thereof, the aqueous composition being contained in a container, part or all of which comes into contact with the aqueous composition being formed from a resin containing polyolefin.

2. The aqueous composition of claim 1 further comprising (B) a buffering agent.

3. The aqueous composition according to claim 1 or 2, further comprising (C) a chelating agent.

4. 3. The aqueous composition according to claim 1, wherein the pH is 6.0 or more and 9.0 or less.