Aqueous composition

Abstract

This aqueous composition contains (A) 4-phenylbutyric acid or an ester thereof, or a pharmacologically acceptable salt thereof, and has a pH of 6.0-9.0. The aqueous composition is housed in a dispensing container having a filter containing a hydrophilic material.

Description

aqueous composition

[0001] 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] On the other hand, preservatives are sometimes blended into eye drops to prevent contamination by microorganisms such as bacteria after opening. However, preservatives are known to cause corneal epithelial damage due to cytotoxicity and contact dermatitis due to allergic reactions (e.g., Non-Patent Document 2). For this reason, containers have been reported that can prevent microbial contamination after opening without adding preservatives by storing eye drops in a container equipped with a filter with a pore size smaller than that of microorganisms (e.g., Patent Document 3).

[0004] International Publication No. 2018 / 164113 International Publication No. 2020 / 129965 Japanese Patent Application Laid-Open No. 2004-051170

[0005] Bufenyl (registered trademark) Tablets 500 mg Bufenyl (registered trademark) Granules 94% Package insert Japanese Ophthalmology, Vol. 58, No. 10, pp. 945-950, 1987

[0006] There have been no reported findings regarding the storage state of sodium 4-phenylbutyrate when an aqueous composition containing sodium 4-phenylbutyrate is contained in a discharge container having a filter containing a hydrophilic material. An object of the present invention is to provide a novel aqueous composition that is contained in a discharge container having a filter containing a hydrophilic material and that suppresses the decrease in 4-phenylbutyric acid or its esters, or pharmacologically acceptable salts thereof in the composition.

[0007] As a result of extensive research aimed at solving the above-mentioned problems, the present inventors have unexpectedly found that adjusting the pH of an aqueous composition containing sodium 4-phenylbutyrate to 6.0 or higher unexpectedly improves the retention rate of sodium 4-phenylbutyrate when the aqueous composition is immersed in a filter containing a hydrophilic material. The present invention is based on this finding and provides the following inventions. [1] An aqueous composition containing (A) 4-phenylbutyric acid or an ester thereof, or a pharmacologically acceptable salt thereof, and having a pH of 6.0 or higher but 9.0 or lower, the aqueous composition being contained in a discharge container having a filter containing a hydrophilic material. [2] The aqueous composition according to [1], wherein the hydrophilic material is hydrophilic polyethersulfone or hydrophilic polyvinylidene fluoride. [3] The aqueous composition according to [1] or [2], wherein the filter containing the hydrophilic material has a pore size of 0.1 to 0.22 μm. [4] The aqueous composition according to any one of [1] to [3], further containing (B) a buffer. [5] The aqueous composition according to any one of [1] to [4], further comprising (C) a chelating agent.

[0008] According to the present invention, it is possible to provide a novel aqueous composition that is contained in a discharge container having a filter containing a hydrophilic material and that is inhibited from reducing 4-phenylbutyric acid or an ester thereof, or a pharmacologically acceptable salt thereof.

[0009] Hereinafter, embodiments of the present invention will be described in detail, but the present invention is not limited to the following embodiments.

[0010] The aqueous composition according to this embodiment contains (A) 4-phenylbutyric acid or an ester thereof, or a pharmacologically acceptable salt thereof (also referred to simply 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 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 effects of the present invention are 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 effects of the present invention, boric acid buffers (e.g., a combination of boric acid and borax), phosphate buffers (e.g., a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate), and Tris buffers (e.g., trometamol) are preferred, with boric acid buffers being more preferred, boric acid and salts 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 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 exhibiting the effects of the 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 0.03 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.

[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 effects of the present invention are more pronounced. 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] As the chelating agent, edetic acid or a salt thereof is preferred, sodium salt of edetic acid is more preferred, disodium edetate and tetrasodium edetate are even more preferred, and disodium edetate is particularly preferred.

[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 of the aqueous composition, the formulation form, etc. From the viewpoint of more significantly exhibiting the effects of the present invention, 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 form of the aqueous composition, etc. 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 0.002 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.

[0030] 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, as long as the effects of the present invention are 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.

[0031] The aqueous composition according to the present embodiment may contain one or more additives selected appropriately in a conventional manner depending on the intended use and formulation, in an appropriate amount, as long as the effects 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.

[0032] The pH of the aqueous composition according to this embodiment is 6.0 or more and 9.0 or less. By setting the pH within this range, the effect of suppressing the decrease of component (A) is significantly improved. From the viewpoint of more significantly exhibiting the effects of the present invention, the pH of the aqueous composition is preferably 8.5 or less, more preferably 8.0 or less. Furthermore, the pH of the aqueous composition is preferably 6.5 or more, 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 as measured using 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 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 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 with filter containing hydrophilic material] The aqueous composition according to this embodiment is contained in a discharge container having a filter containing a hydrophilic material (hereinafter also referred to as "container with filter containing hydrophilic material").

[0040] Examples of the hydrophilic material in the container with a filter containing a hydrophilic material include hydrophilic polyethersulfone (hydrophilic PES), hydrophilic polyvinylidene fluoride (hydrophilic PVDF), hydrophilic polytetrafluoroethylene (hydrophilic PTFE), nylon, polycarbonate, mixed cellulose esters, polyamide, etc. Among these, hydrophilic polyethersulfone, hydrophilic polyvinylidene fluoride, and hydrophilic polytetrafluoroethylene are preferred, hydrophilic polyethersulfone and hydrophilic polyvinylidene fluoride are more preferred, and hydrophilic polyethersulfone is even more preferred. Furthermore, the filter containing a hydrophilic material may be one in which the entire filter is made of a hydrophilic material, or one in which only a portion of the filter (for example, the surface of the filter) is made of a hydrophilic material.

[0041] Hydrophilic polyethersulfone (hydrophilic PES), hydrophilic polyvinylidene fluoride (hydrophilic PVDF), and hydrophilic polytetrafluoroethylene (hydrophilic PTFE) refer to, for example, polyethersulfone (PES), hydrophilic polyvinylidene fluoride (PVDF), and hydrophilic polytetrafluoroethylene (PTFE) that have been treated to improve hydrophilicity (hydrophilization treatment). The hydrophilization treatment can be carried out by, for example, a method known to those skilled in the art.

[0042] The container with a filter containing a hydrophilic material may further include another filter, such as a filter containing a hydrophilic material or a filter containing a hydrophobic material.

[0043] Examples of filters containing hydrophobic materials include hydrophobic polyvinylidene fluoride (hydrophobic PVDF) and hydrophobic polytetrafluoroethylene (hydrophobic PTFE).

[0044] The pore size of the filter containing a hydrophilic material is not particularly limited as long as it is large enough to remove microorganisms and the like, and may be, for example, 0.1 μm or more, 0.15 μm or more, or 0.2 μm or more, or 0.22 μm or less.

[0045] The material of the filter-equipped container containing a hydrophilic material is not particularly limited and may be, for example, glass or plastic. When the filter-equipped container containing a hydrophilic material is made of plastic, specific examples include polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polyethylene naphthalate, polyarylate, polycarbonate, polyethylene (PE; high-density polyethylene (HDPE), low-density polyethylene (LDPE)), polypropylene (PP), polystyrene (PS), acrylonitrile butadiene styrene (ABS), polymethylpentene (PMP), polyimide, copolymers of monomers constituting these, and mixtures of two or more of these. Among these, polyethylene (PE) and polypropylene (PP) are preferred. These plastics may contain additives such as stabilizers and reinforcing agents such as glass fibers.

[0046] In a filter-equipped container containing a hydrophilic material, at least a portion of the portion that comes into contact with the aqueous composition may be made of the above material. Here, examples of the portion of a filter-equipped container containing a hydrophilic material that comes into contact with the aqueous composition include the inner surface of the container body (the innermost layer if the container has a multi-layer structure) and the stopper (nozzle). For example, in a container having a stopper (nozzle), only the stopper (nozzle) may be made of the above material (preferably polyethylene or polypropylene), or the container body and the like other than the stopper (nozzle) may be made of the above material (preferably polyethylene or polypropylene), or the entire portion that comes into contact with the aqueous composition may be made of the above material (preferably polyethylene or polypropylene). In order to more significantly exhibit the effects of the present invention, it is preferable that the entire portion of a filter-equipped container containing a hydrophilic material that comes into contact with the aqueous composition is made of the above material (preferably polyethylene or polypropylene).

[0047] In a filter-equipped container containing a hydrophilic material, the filter may be provided inside the container body or inside the inner plug (nozzle).

[0048] The filter-equipped container containing a hydrophilic material can be a known filter-equipped container, for example, a PF Delami container (manufactured by Rohto Nitten Co., Ltd.), an NP container (manufactured by Wakamoto Pharmaceutical Co., Ltd. and Nipro Corporation), or an ABAK bottle (manufactured by Laboratoires Thea). The filter-equipped container may be an eye drop container, an eyewash container, or the like, depending on the intended use of the aqueous composition.

[0049] The shape and capacity of the filter-equipped container containing the hydrophilic material 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), but is preferably a multi-dose container because it has the function of preventing the entry of bacteria through the filter.

[0050] When the filter-equipped container containing a hydrophilic material is a multi-dose container, the volume 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 volume may be, for example, 0.1 to 1.0 mL, 0.2 to 0.9 mL, or 0.3 to 0.8 mL.

[0051] The present invention will be specifically explained below based on test examples, but the present invention is not limited to these. Unless otherwise specified, the unit of each component in the tables is w / v %.

[0052] Test Example 1: Evaluation of residual rate of sodium 4-phenylbutyrate Each aqueous composition shown in Table 1 was prepared by a conventional method, and 5 mL of each was placed in a 10 mL screw-cap glass bottle. ２After soaking two hydrophilic polyethersulfone filters (pore size: 0.22 μm) of 100 ml each in water, the aqueous compositions were stored at 25°C for 48 hours. The concentration of sodium 4-phenylbutyrate was determined using HPLC for each aqueous composition immediately after preparation and after 48 hours of storage at 25°C. The residual rate of sodium 4-phenylbutyrate was calculated according to Equation 1. The results are summarized in Table 1. Equation 1: Residual rate of sodium 4-phenylbutyrate (%) = (sodium 4-phenylbutyrate concentration of stored product / sodium 4-phenylbutyrate concentration immediately after preparation) × 100. The HPLC method was performed under the following measurement conditions: Mobile phase: 0.2% formic acid solution / acetonitrile (3:2) Column: a stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm packed with 5 μm octadecylsilylated silica gel for liquid chromatography Detection method: ultraviolet absorption spectrophotometer (measurement wavelength: 260 nm)

[0053]

[0054] From Table 1, it was confirmed that when the pH of the aqueous composition was 6.0 or higher, the residual rate of sodium 4-phenylbutyrate was 95% or higher, and the decrease of sodium 4-phenylbutyrate was sufficiently suppressed.

Claims

1. (A) An aqueous composition containing 4-phenylbutyric acid or an ester thereof, or a pharmacologically acceptable salt thereof, and having a pH of 6.0 or more and 9.0 or less, said aqueous composition being contained in a discharge container having a filter containing a hydrophilic material.

2. The aqueous composition of claim 1, wherein said hydrophilic material is hydrophilic polyethersulfone or hydrophilic polyvinylidene fluoride.

3. The aqueous composition according to claim 1 or 2, wherein the pore size of the filter containing the hydrophilic material is 0.1 to 0.22 μm.

4. The aqueous composition according to claim 1 or 2, further comprising (B) a buffering agent.

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

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