TW202444342A - Aqueous composition - Google Patents

Abstract

The present invention relates 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

Water-based composition

The present invention relates to an aqueous composition.

It is known that sodium 4-phenylbutyrate is metabolized to phenylacetic acid in the body and excreted into urine after combining with glutamine, so sodium 4-phenylbutyrate is used as a therapeutic drug for urea cycle abnormalities (non-patent document 1). Recently, there have been reports that sodium 4-phenylbutyrate helps prevent or treat eye diseases such as myopia or presbyopia (for example, patent documents 1 and 2). Prior art documents Patent documents

Patent document 1: International Publication No. 2018/164113 Patent document 2: International Publication No. 2020/129965 Non-patent document

Non-patent document 1: Buphenyl (registered trademark) tablets 500 mg Buphenyl (registered trademark) granules 94% Accessories

[The problem that the invention wants to solve]

Therapeutic drugs for urea cycle disorders with sodium 4-phenylbutyrate as an active ingredient are commercially available in the form of tablets and granules suitable for oral administration. On the other hand, aqueous compositions such as eye drops are required to have a certain preservation effect, but there is no report on the preservation effect of liquid preparations containing sodium 4-phenylbutyrate. The purpose of the present invention is to provide an aqueous composition containing sodium 4-phenylbutyrate and having excellent preservation effect. [Technical means for solving the problem]

The inventors of the present invention have conducted in-depth research to solve the above problems and found that by adding disodium ethylenediaminetetraacetate as a chelating agent to an aqueous composition containing sodium 4-phenylbutyrate, the preservation performance of the aqueous composition is unexpectedly enhanced synergistically. The present invention is based on this finding and provides the following inventions.

[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 as described in [1], comprising 0.0002 to 1200 parts by mass of component (B) relative to 1 part by mass of the total content of component (A). [3] The aqueous composition as described in [1] or [2], further comprising (C) a buffer. [4] The aqueous composition as described in any one of [1] to [3], wherein the pH value is 5.0 or more and 9.0 or less. [Effects of the invention]

According to the present invention, an aqueous composition containing sodium 4-phenylbutyrate and having excellent preservation performance can be provided.

The following describes the embodiments of the present invention in detail. However, the present invention is not limited to the following embodiments.

The aqueous composition of the present embodiment contains (A) 4-phenylbutyric acid or its ester or a pharmacologically acceptable salt thereof (also referred to as "(A) ingredient").

[Component (A)] 4-phenylbutyric acid is also called 4-PBA and is a well-known compound represented by the following formula.

As for the ester of 4-phenylbutyric acid, for example, there can be mentioned esters formed by dehydration condensation of the carboxyl group of 4-phenylbutyric acid and 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 them, methyl ester, ethyl ester, n-propyl ester, and isopropyl ester are preferred.

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

4-phenylbutyric acid or its ester or its pharmacologically acceptable salt may be a solvent-free compound or a solvent compound (e.g., a hydrate).

The content of component (A) in the aqueous composition of the present embodiment is not particularly limited and can be appropriately set according to the types and contents of other blending components, the formulation form, etc. From the viewpoint of more significantly exerting the effect 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%, further preferably 0.05 to 4 w/v%, and even more preferably 0.1 to 3 w/v%, based on the total amount of the aqueous composition of the present embodiment.

[(B) component] The aqueous composition of this embodiment further contains (B) a chelating agent (also referred to as "(B) component"). There is no particular limitation on the chelating agent, as long as it is medically, pharmacologically (pharmaceutically) or physiologically acceptable.

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

As the chelating agent, ethylenediaminetetraacetic acid or a salt thereof is preferred, ethylenediaminetetraacetic acid sodium salt is more preferred, ethylenediaminetetraacetic acid disodium, ethylenediaminetetraacetic acid tetrasodium is further preferred, and ethylenediaminetetraacetic acid disodium is particularly preferred.

The content of component (B) in the aqueous composition of the present embodiment is not particularly limited and can be appropriately set according to the type of component (B), the type and content of other blending components, the purpose of the aqueous composition, the formulation form, etc. From the perspective of synergistically exerting the preservation effect by combining with component (A), the content of component (B) is preferably 0.001 to 12 w/v%, more preferably 0.003 to 8 w/v%, further preferably 0.006 to 4 w/v%, and even more preferably 0.01 to 2 w/v%, based on the total amount of the aqueous composition.

The content ratio of component (B) to component (A) in the aqueous composition of the present embodiment is not particularly limited and can be appropriately set according to the types of component (A) and component (B), the types and contents of other blending components, the use of the aqueous composition, the formulation form, etc. From the viewpoint of more synergistically exerting the preservation effect, the content ratio of component (B) to component (A) is preferably 0.0002 to 1200 parts by mass, more preferably 0.0006 to 320 parts by mass, further 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 component (A) contained in the aqueous composition of the present embodiment.

[Component (C)] The aqueous composition of the present embodiment preferably further contains a buffer (C) (also referred to as "component (C)"). By making the aqueous composition further contain component (C), the effect of the present invention can be more significantly exerted. The buffer includes inorganic buffers and organic buffers, and there is no particular limitation, as long as it is medically, pharmacologically (pharmaceutically) or physiologically permitted.

Inorganic buffers are buffers derived from inorganic acids. Examples of inorganic buffers include boric acid buffers, phosphoric acid buffers, and carbonic acid buffers.

Examples of boric acid buffers include boric acid or its salts (metal borate salts, earth metal borate salts, etc.). Examples of phosphate buffers include phosphoric acid or its salts (metal phosphate salts, earth metal phosphate salts, etc.). Examples of carbonate buffers include carbonic acid or its salts (metal carbonate salts, earth metal carbonate salts, etc.). In addition, hydrates of borate salts or phosphate salts may be used as boric acid buffers or phosphate buffers. As more specific examples, boric acid or its salts (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.) as a boric acid buffer; phosphoric acid or its salts (sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, etc.) as a phosphate buffer; carbonic acid or its salts (sodium bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, magnesium carbonate, etc.) as a carbonate buffer, etc.

Organic buffers are buffers derived from organic acids or organic bases. Examples of organic buffers include acetic acid buffer, tris (Tris) buffer, epsilon-aminocaproic acid buffer, AMPD buffer, and the like.

As an acetic acid buffer, acetic acid or its salt (acetic acid alkali metal salt, acetic acid alkali earth metal salt, etc.) can be cited. In addition, a hydrate of an acetic acid salt can also be used as an acetic acid buffer. As a more specific example, acetic acid or its salt (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.) as an acetic acid buffer can be cited. As a trihydroxymethylaminomethane buffer, for example, trometamol or its salt (trometamol hydrochloride, etc.) can be cited. As an ε-aminocaproic acid buffer, for example, ε-aminocaproic acid or its salt can be cited. Examples of the AMPD buffer include 2-amino-2-methyl-1,3-propanediol or a salt thereof.

As buffers, from the viewpoint of more significantly exerting the effect produced by the present invention, preferred are 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), trihydroxymethylaminomethane buffers (e.g., tromethamine), more preferred are boric acid buffers, further preferred are boric acid and its salts, and further preferred are a combination of boric acid and borax.

A commercially available buffer can be used. The buffer may be used alone or in combination of two or more.

The content of the component (C) in the aqueous composition of the present embodiment is not particularly limited and can be appropriately set according to the type of the component (C), the type and content of other blending components, the purpose of the aqueous composition, the formulation form, etc. From the perspective of more significantly exerting the effect of the present invention, the content of the component (C) is preferably 0.05 to 5.0 w/v%, more preferably 0.08 to 4.5 w/v%, further preferably 0.1 to 4.0 w/v%, and even more preferably 0.3 to 3.5 w/v%, based on the total amount of the aqueous composition.

The content ratio of component (C) to component (A) in the aqueous composition of the present embodiment is not particularly limited, and can be appropriately set according to the types of components (A) and (C), the types and contents of other blending components, the use of the aqueous composition, the formulation form, etc. From the viewpoint of more significantly exerting the effect of the 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, further preferably 0.03 to 80 parts by mass, and particularly preferably 0.1 to 35 parts by mass, relative to 1 part by mass of the total content of component (A) contained in the aqueous composition of the present embodiment.

The aqueous composition of the present embodiment may contain, in addition to the above-mentioned ingredients, an appropriate amount of ingredients selected from various pharmacologically active ingredients and physiologically active ingredients in combination, as long as the effect of the present invention is not impaired. The ingredients 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.

In the aqueous composition of the present embodiment, various additives may be appropriately selected according to the purpose and the preparation form, and one or more additives may be used in combination and contained in appropriate amounts, as long as the effects of the present invention are not impaired. Examples of such additives include carriers, pH adjusters, surfactants, fragrances or cooling agents, thickeners, stabilizers, preservatives, isotonic agents, etc.

The pH of the aqueous composition of the present embodiment is not particularly limited as long as it is within the range permitted medically, pharmacologically (pharmaceutically) or physiologically. From the viewpoint of more significantly exerting the effect of the present invention, the pH of the aqueous composition is preferably 9.0 or less, more preferably 8.5 or less, and further preferably 8.0 or less. Furthermore, from the viewpoint of further improving the stability of 4-phenylbutyric acid or its ester or its pharmacologically permitted salt, the pH of the aqueous composition is preferably 5.0 or more, more preferably 5.5 or more, and further preferably 6.0 or more.

The aqueous composition of this embodiment can be adjusted to an osmotic pressure ratio within the range allowed by the organism as needed. The appropriate osmotic pressure ratio can be appropriately set according to the purpose, formulation form, and method of use of the aqueous composition, for example, it can be set to 0.4 to 5.0. The osmotic pressure ratio is based on the 18th revised edition of the Japanese Pharmacopoeia and is set as 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). The osmotic pressure is measured with reference to the osmotic pressure measurement method (freezing point depression method) recorded in the Japanese Pharmacopoeia. Furthermore, regarding the standard solution for osmotic pressure ratio measurement (0.9 w/v% sodium chloride aqueous solution), sodium chloride (Japanese Pharmacopoeia standard reagent) can be dried at 500-650°C for 40-50 minutes, cooled in a desiccator (silicone), and 0.900 g of the sodium chloride is accurately weighed and dissolved in purified water to accurately prepare 100 mL, or a commercially available standard solution for osmotic pressure ratio measurement (0.9 w/v% sodium chloride aqueous solution) can be used.

The viscosity of the aqueous composition of the present embodiment is not particularly limited as long as it is within the range permitted in medicine, pharmacology (pharmaceuticals) or physiology. The viscosity of the aqueous composition of the present embodiment, for example, can be 1 to 10000 mPa･s at 20°C measured using a rotational viscometer (TV-20 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor; 1°34'×R24).

The aqueous composition of the present embodiment can be prepared, for example, by adding and mixing the (A) component, the (B) component, and other components added as needed at the desired content. Specifically, it can be prepared, for example, by dissolving or suspending the above components in purified water and sterilizing them by filtration sterilization.

When the aqueous composition of the present embodiment is an ophthalmic composition, it can be used, for example, as eye drops (also called eye drops or eye drops; and eye drops include eye drops that can be dropped into the eyes when wearing contact lenses), artificial tears, eye washes (also called eye washes or eye washes; and eye washes include eye washes that can be used to wash the eyes when wearing contact lenses). Furthermore, "contact lenses" include hard contact lenses, soft contact lenses (including both ionic and non-ionic, and including both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses).

Since the aqueous composition of the present embodiment contains sodium 4-phenylbutyrate as an active ingredient, it can be suitably used as a preventive, inhibitory or therapeutic agent for myopia. In addition, since the aqueous composition of the present embodiment contains sodium 4-phenylbutyrate as an active ingredient, it can also be suitably used as a preventive, inhibitory or therapeutic agent for presbyopia.

In order to more significantly exert the effects of the present invention, the aqueous composition of the present embodiment is preferably an ophthalmic composition, and more preferably an eye drop (including eye drops that can be dropped while wearing contact lenses). When the aqueous composition of the present embodiment is an eye drop, there is no particular limitation on its usage and dosage, as long as it is an usage and dosage that exerts the effect and has few side effects. For example, in the case of adults (over 15 years old) and children over 7 years old, the following method can be exemplified: 1 to 6 times a day, and 1 to 3 drops each time.

The aqueous composition of the present embodiment can be provided in any container. There is no particular limitation on the container for containing the aqueous composition of the present embodiment, and it can be made of glass or plastic. It is preferably made of plastic. Examples of plastics include polyolefin resins such as polyethylene, polypropylene, cyclic olefin copolymers, and mixtures of two or more thereof, and polyester resins such as polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, and mixtures of two or more thereof. As the material of the container, polyolefin resins are more preferred from the viewpoint of further improving the effect of the present invention. Plastics may also include other polymers such as polycarbonate, (meth) acrylic polymers, polystyrene (PS), and polyarylate. In addition, the plastic may also contain additives such as stabilizers, modifiers, colorants, ultraviolet absorbers, metal oxides, oxygen absorbers, antibacterial agents, plasticizers, and glass fibers. In addition, the container for containing the aqueous composition of the present embodiment may also use an elastic body such as a styrene-based thermoplastic elastomer and a styrene-butadiene-based thermoplastic elastomer. The container for containing the aqueous composition of the present embodiment may be a transparent container that allows the inside of the container to be visible, or an opaque container that makes it difficult to see the inside of the container. A transparent container is preferred. Here, "transparent container" includes both colorless transparent containers and colored transparent containers.

A nozzle may also be installed in the container for accommodating the aqueous composition of the present embodiment. There is no particular limitation on the material of the nozzle, and it may be made of 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 thereof, and polyester resins such as polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, and mixtures of two or more thereof. From the viewpoint of further improving the effect of the present invention, polyolefin resins are more preferred as the material of the nozzle. Plastics may also include other polymers such as polycarbonate, (meth) acrylic polymers, polystyrene (PS), and polyarylate. Furthermore, the plastic may also contain additives such as stabilizers, modifiers, colorants, ultraviolet absorbers, metal oxides, oxygen absorbers, antibacterial agents, plasticizers, glass fibers, etc. Furthermore, the nozzle installed in the container containing the aqueous composition of the present embodiment may also use polysilicone.

The shape and capacity of the container are not particularly limited, and can be appropriately set according to the purpose. In addition, the container can be a container for storing multiple doses of the aqueous composition (multi-dose container) or a container for storing a single dose of the aqueous composition (single-dose container).

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 single-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.

The aqueous composition of this embodiment can also be provided in the form of an aqueous composition in a container. In addition, the present invention can also be understood as a pharmaceutical product (ophthalmic products such as eye drops) containing the aqueous composition of the present invention in a container. Example

The present invention is specifically described below based on test examples, but the present invention is not limited thereto. In addition, unless otherwise specified, the unit of each component in the table is w/v%.

[Test Example 1: Preservation Efficacy Test] The aqueous compositions shown in Table 1 were prepared by conventional methods and sterilized by filtration using a 0.2 μm membrane filter. The units of the components in Table 1 are w/v%. Subsequently, the preservation efficacy test of each aqueous composition was carried out based on the 18th revised edition of the Japanese Pharmacopoeia. Pseudomonas aeruginosa was inoculated on the surface of a soybean-casein-digest slant culture medium and cultured at 30-35°C for 24 hours. The cultured bacteria were aseptically collected with platinum fungus and suspended in an appropriate amount of sterile physiological saline water to prepare a bacterial suspension containing about 1×10 ⁷ CFU/mL of live bacteria. Furthermore, the bacterial count of the bacterial suspension is cultured and measured separately. Then, 10 mL of each prepared aqueous composition is filled into each 15 mL centrifuge tube (PET). In each of these aqueous compositions, the bacterial suspension is inoculated in such a manner that the bacterial count (final concentration) is approximately 5×10 ⁵ CFU/mL, and the sample is prepared by sufficient stirring. The sample containing bacteria is stored at 20-25°C for 7 days. Thereafter, the sample containing bacteria is adjusted to a concentration suitable for counting, and the bacteria are recovered according to the agar pouring method, and after culturing in soybean-casein-digest agar medium at 30-35°C for 2-3 days, the number of colonies observed is counted to determine the number of bacterial counts. The number of bacteria immediately after inoculation was compared with the number of bacteria in the sample after 7 days of storage, and the reduction in the number of bacteria was calculated as the storage efficiency (Log Reduction). The results are shown in Table 1.

[Table 1] Ingredient Name Comparison Example 1 Comparison Example 2 Comparison Example 3 Embodiment 1 Sodium 4-phenylbutyrate 0 0 2 2 Boric acid 0.5 0.5 0.5 0.5 Borax 0.025 0.025 0.025 0.025 Disodium EDTA 0 0.03 0 0.03 Hydrochloric acid/sodium hydroxide Moderate Moderate Moderate Moderate Purified water Remaining amount Remaining amount Remaining amount Remaining amount Total 100 mL 100 mL 100 mL 100 mL pH 7.5 7.5 7.5 7.5 Log Reduction 1.3 1.7 2.9 ＞4.7

It can be confirmed that in an aqueous composition containing sodium 4-phenylbutyrate and disodium ethylenediaminetetraacetate, the inoculated bacteria are reduced to a value below the detection limit, and the preservation efficiency (Log Reduction) value is greater than 4.7 (Example 1). In an aqueous composition not containing sodium 4-phenylbutyrate, the preservation efficiency (Log Reduction) is increased by only 0.4 by admixing disodium ethylenediaminetetraacetate (Comparison of Examples 1 and 2). On the other hand, in an aqueous composition containing sodium 4-phenylbutyrate, the preservation efficiency (Log Reduction) is increased by at least about 2 by admixing disodium ethylenediaminetetraacetate (Comparison of Example 3 and Example 1). From the above, it was confirmed that the preservation efficiency was synergistically improved by combining sodium 4-phenylbutyrate and disodium ethylenediaminetetraacetate.

without

without

Claims (4)

An aqueous composition comprising (A) 4-phenylbutyric acid or an ester thereof or a pharmacologically acceptable salt thereof, and (B) a chelating agent. The aqueous composition of claim 1 contains 0.0002 to 1200 parts by mass of component (B) relative to 1 part by mass of the total content of component (A). The aqueous composition of claim 1 or 2, further comprising (C) a buffer. The pH of the aqueous composition of claim 1 or 2 is 5.0 or more and 9.0 or less.