Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/02—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism

Definitions

• the present invention relates to an aqueous composition.
• Non-Patent Document 1 Sodium 4-phenylbutyrate is known to be metabolized in the body to phenylacetic acid, which is then bound to glutamic acid and excreted in the urine, and is used as a treatment for urea cycle disorders.
• Non-Patent Document 1 Recently, it has been reported that sodium 4-phenylbutyrate is useful for preventing or treating eye diseases such as myopia and presbyopia (for example, Patent Documents 1 and 2).
• the object of the present invention is to provide an aqueous composition that contains sodium 4-phenylbutyrate and has excellent preservative effectiveness.
• 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 according to [1] comprising 0.0002 to 1200 parts by mass of the (B) component per 1 part by mass of the total content of the (A) component.
• the present invention provides an aqueous composition that contains sodium 4-phenylbutyrate and has excellent preservative properties.
• the aqueous composition according to this embodiment contains (A) 4-phenylbutyric acid or its ester, or a pharmacologically acceptable salt thereof (also referred to simply as “component (A)").
• Esters of 4-phenylbutyric acid include, for example, 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.
• salts of 4-phenylbutyric acid and the salts of esters of 4-phenylbutyric acid are no particular limitations.
• 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.
• metal salts such as sodium salts, potassium salts, calcium salts, and magnesium salts
• inorganic salts such as ammonium salts
• organic amine salts such as triethylamine salts and guanidine salts.
• sodium salts and potassium salts are preferred, and sodium salts are more preferred.
• 4-Phenylbutyric acid or its ester, or a pharmacologically acceptable salt thereof may be unsolvated or may be a solvate (e.g., a hydrate).
• the content of component (A) in the aqueous composition according to this embodiment is not particularly limited, and is set appropriately depending on the type and content of other blended components, the formulation form, etc. From the viewpoint of more prominently 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.
• the aqueous composition according to the present embodiment further contains a chelating agent (B) (also referred to simply as “component (B)”).
• the chelating agent is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical) or physiologically acceptable.
• Chelating agents include, for example, ethylenediaminediacetic acid (EDDA), ethylenediaminetriacetic acid, ethylenediaminetetraacetic acid (edetic acid) (EDTA), N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), citric acid, gluconic acid, and salts thereof.
• EDDA ethylenediaminediacetic acid
• EDTA ethylenediaminetetraacetic acid
• HEDTA ethylenediaminetetraacetic acid
• HEDTA ethylenediaminetetraacetic acid
• HEDTA ethylenediaminetetraacetic acid
• HEDTA N-(2-hydroxyethyl)ethylenediaminetriacetic acid
• DTPA diethylenetriaminepentaacetic acid
• citric acid gluconic acid
• salts include metal salts such as sodium salts, potassium salts, calcium salts
• 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.
• 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 type and content of other blended components, the application and formulation form of the aqueous composition, etc. From the viewpoint of exerting a synergistic preservative effect 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.
• the content ratio of the (B) component to the (A) component in the aqueous composition according to this embodiment is not particularly limited, and is set appropriately depending on the types of the (A) and (B) components, the types and contents of other blended components, the use and formulation form of the aqueous composition, etc. From the viewpoint of exerting the preservative effect more synergistically, the content ratio of the (B) component to the (A) component 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 1 part by mass of the total content of the (A) component contained in the aqueous composition according to this embodiment.
• the aqueous composition according to the present embodiment preferably further contains a buffer (C) (also simply referred to as “component (C)").
• a buffer also simply referred to as “component (C)”
• component (C) 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.
• Inorganic buffers are buffers derived from inorganic acids.
• examples of inorganic buffers include borate buffers, phosphate buffers, and carbonate buffers.
• the borate buffer includes boric acid or its salts (alkali metal borate, alkaline earth metal borate, etc.).
• the phosphate buffer includes phosphoric acid or its salts (alkali metal phosphate, alkaline earth metal phosphate, etc.).
• the carbonate buffer includes carbonic acid or its salts (alkali metal carbonate, alkaline earth metal carbonate, etc.).
• borate or phosphate hydrates may be used as the borate buffer or phosphate buffer.
• boric acid or its salts sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.
• borate buffer sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.
• phosphoric acid or its salts diisodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, calcium dihydrogen phosphate, calcium dihydrogen phosphate, etc.
• carbonic acid or its salts sodium hydrogen carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate, magnesium carbonate, etc.
• Organic buffers are buffers derived from organic acids or organic bases.
• organic buffers include acetate buffers, Tris buffers, epsilon aminocaproic acid buffers, AMPD buffers, etc.
• acetate buffers include acetic acid or its salts (alkali metal acetate, alkaline earth metal acetate, etc.). Hydrates of acetate may also be used as acetate buffers. More specific examples of acetate buffers include acetic acid or its salts (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.). Examples of tris buffers include trometamol or its salts (trometamol hydrochloride, etc.). Examples of epsilon aminocaproic acid buffers include epsilon aminocaproic acid or its salts. Examples of AMPD buffers include 2-amino-2-methyl-1,3-propanediol or its salts.
• the buffer is preferably 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), more preferably a boric acid buffer, further preferably boric acid and its salts, and even more preferably a combination of boric acid and borax.
• 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
• Tris buffer e.g., trometamol
• buffers may be used. One type of buffer may be used alone, or two or more types may be used in combination.
• 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 type and content of other blended components, the application and formulation form of the aqueous composition, etc. From the viewpoint of more significantly achieving the effects of the 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.
• 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 application and formulation form of the aqueous composition, etc. From the viewpoint of more prominently exhibiting the effects 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, 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.
• the aqueous composition according to this embodiment may contain appropriate amounts of a combination of components selected from various pharmacologically active components and physiologically active components in addition to the above components, so long as the effects of the present invention are not impaired.
• the components are not particularly limited, and examples include antiallergic agents, antihistamines, anti-inflammatory agents, steroids, congestion decongestants, eye muscle regulating agents, vitamins, amino acids, astringents, etc.
• the aqueous composition according to this embodiment may contain various additives in appropriate amounts, selected according to the intended use and formulation, in accordance with conventional methods, one or more of which may be used in combination, as long as the effects of the present invention are not impaired.
• additives include carriers, pH regulators, surfactants, fragrances or refreshing agents, thickeners, stabilizers, preservatives, isotonicity agents, etc.
• the pH of the aqueous composition according to this embodiment is not particularly limited as long as it is within a medicamentously, pharmacologically (pharmaceutical) or physiologically acceptable range, but from the viewpoint of more significantly exhibiting the effects of the 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 its ester, 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.
• the aqueous composition according to this embodiment can be adjusted to an osmotic pressure ratio within a range acceptable to the living body, if necessary.
• the appropriate osmotic pressure ratio can be set appropriately depending on the application, formulation, and method of use of the aqueous composition, and 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) based on the 18th Revised Japanese Pharmacopoeia, and 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 it, dissolving it in purified water to make exactly 100 mL, or a commercially available standard solution for measuring the osmotic pressure ratio (0.9 w/v% sodium chloride aqueous solution) can be used.
• the viscosity of the aqueous composition according to this embodiment is not particularly limited as long as it is within a range that is medicamentally, pharmacologically (pharmaceutical), or physiologically acceptable.
• the viscosity of the aqueous composition according to this embodiment may be, for example, 1 to 10,000 at 20°C measured using a rotational viscometer (TV-20 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1°34' x R24).
• the aqueous composition according to this embodiment can be prepared, for example, by adding and mixing component (A), component (B), and, if necessary, other components to obtain the desired content.
• the aqueous composition can be prepared by dissolving or suspending the above components in purified water and sterilizing the composition by filtration sterilization or the like.
• 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, and eyewash (also called eyewash or eyewash. Eyewash includes eyewash that can be applied while wearing contact lenses).
• eyewash includes eyewash that can be applied while wearing contact lenses).
• contact lenses includes hard contact lenses and soft contact lenses (including both ionic and non-ionic, and both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses).
• the aqueous composition according to this embodiment contains sodium 4-phenylbutyrate as an active ingredient, and therefore can be suitably used as a preventive, suppressive or therapeutic agent for myopia.
• the aqueous composition according to this embodiment contains sodium 4-phenylbutyrate as an active ingredient, and therefore can be suitably used as a preventive, suppressive or therapeutic agent for presbyopia.
• the aqueous composition according to this embodiment is preferably an ophthalmic composition, and more preferably an eye drop (including eye drops that can be applied while wearing contact lenses), since this allows the aqueous composition according to this embodiment to exhibit the effects of the present invention more significantly.
• the aqueous composition according to this embodiment is an eye drop
• the method of use and dosage are not particularly limited as long as it is effective and has few side effects, but for adults (15 years or older) and children aged 7 years or older, one example is a method of instilling 1 to 3 drops at a time, 1 to 6 times a day.
• the aqueous composition according to this embodiment is provided in any 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. It is preferably made of plastic.
• plastic include polyolefin resins such as polyethylene, polypropylene, cyclic olefin copolymer, 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 present invention, polyolefin resins are more preferable as the material for the container.
• 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, ultraviolet 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 that holds the aqueous composition according to this embodiment may be a transparent container that allows the inside of the container to be seen, or an opaque container that makes it difficult to see the inside of the container. A transparent container is preferable.
• the term "transparent container” includes both colorless transparent containers and colored transparent containers.
• a nozzle may be attached to the container that contains the aqueous composition according to this embodiment.
• the material of the nozzle is not particularly limited, and may be made of glass or plastic.
• the nozzle is preferably made of plastic.
• plastic include polyolefin resins such as polyethylene, polypropylene, cyclic olefin copolymer, 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 present invention, polyolefin resins are more preferable as the material of the nozzle.
• the plastic may include other polymers such as polycarbonate, (meth)acrylic acid polymer, polystyrene (PS), and polyarylate.
• the plastic may also include additives such as stabilizers, modifiers, colorants, ultraviolet absorbers, metal oxides, oxygen absorbers, antibacterial agents, plasticizers, and glass fibers. Silicone may also be used for the nozzle attached to the container that contains the aqueous composition according to this embodiment.
• the shape and capacity of the container are not particularly limited and may be set appropriately depending on the application.
• the container may be a container that contains an amount of aqueous composition for multiple uses (multi-dose type container), or a container that contains an amount of aqueous composition for a single use (unit dose type 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. Also, if the container is a unit-dose type 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 according to this embodiment can also be provided as a containerized aqueous composition.
• the present invention can also be considered as a pharmaceutical product (ophthalmic product such as eye drops) in which the aqueous composition of the present invention is contained in a container.
• Test Example 1 Preservative Effectiveness Test Each aqueous composition shown in Table 1 was prepared by a conventional method, filtered through a 0.2 ⁇ m membrane filter, and sterilized. The units of each component in Table 1 are w/v%. Then, a preservative effectiveness test of each aqueous composition was performed based on the 18th revised Japanese Pharmacopoeia. Pseudomonas aeruginosa was inoculated on the surface of a soybean casein digest slant medium and cultured at 30 to 35° C. for 24 hours.
• the cultured bacteria was aseptically collected with a platinum loop and suspended in an appropriate amount of sterile physiological saline to prepare a bacterial suspension containing about 1 ⁇ 10 7 CFU/mL of live bacteria.
• the viable cell count of the bacterial suspension was measured by culturing separately.
• 10 mL of each prepared aqueous composition was filled into a 15 mL centrifuge tube (PET).
• PET centrifuge tube
• a bacterial suspension was inoculated into each of these aqueous compositions so that the viable cell count (final concentration) was about 5 x 10 5 CFU/mL, and the mixture was thoroughly stirred to prepare a sample.
• the sample containing the bacteria was stored at 20 to 25°C for 7 days.
• the sample containing the bacteria was adjusted to a concentration appropriate for counting, and the bacteria were collected according to the agar pour plate method. After culturing the sample on a soybean casein digest agar medium at 30 to 35°C for 2 to 3 days, the number of colonies observed was counted to determine the viable cell count. The viable cell count immediately after inoculation was compared with the viable cell count in the sample after storage for 7 days, and the reduction in the cell count was calculated as the preservative efficacy (Log Reduction). The results are shown in Table 1.
• the incorporation of disodium edetate increased the preservative efficacy (Log Reduction) by at least about 2 (Comparison between Comparative Example 3 and Example 1). From the above, it was confirmed that the preservative efficacy is synergistically increased by combining sodium 4-phenylbutyrate and disodium edetate.

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  • 2024-03-21 WO PCT/JP2024/011038 patent/WO2024203727A1/ja not_active Ceased
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