WO2024034592A1 - Aqueous pharmaceutical composition containing udca or salt thereof - Google Patents

Aqueous pharmaceutical composition containing udca or salt thereof Download PDF

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Publication number
WO2024034592A1
WO2024034592A1 PCT/JP2023/028863 JP2023028863W WO2024034592A1 WO 2024034592 A1 WO2024034592 A1 WO 2024034592A1 JP 2023028863 W JP2023028863 W JP 2023028863W WO 2024034592 A1 WO2024034592 A1 WO 2024034592A1
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
salt
trometamol
content
ursodeoxycholic acid
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PCT/JP2023/028863
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French (fr)
Japanese (ja)
Inventor
仁志 佐々木
竜也 畑
健太 吉井
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参天製薬株式会社
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Publication of WO2024034592A1 publication Critical patent/WO2024034592A1/en

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    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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

Definitions

  • the present invention relates to an aqueous pharmaceutical composition containing ursodeoxycholic acid or a salt thereof.
  • Ursodeoxycholic acid is a compound that has the effect of promoting bile secretion and suppressing the production of cytokines and chemokines, and is therefore used as a therapeutic drug for liver diseases (Non-Patent Document 1). Moreover, since ursodeoxycholic acid improves the elasticity of the crystalline lens, it is expected to be used as a treatment or preventive agent for presbyopia (Patent Document 1). Further, a composition is known in which ursodeoxycholic acid is made water-soluble by adding a water-soluble starch conversion product and can be administered orally (Patent Document 2).
  • Tissue penetration of the active ingredient is an important factor for the drug to exert its efficacy. It is also desirable to develop aqueous pharmaceutical preparations containing ursodeoxycholic acid or its salts as an active ingredient that have good tissue penetration properties.
  • Urso (registered trademark) tablets 50mg Urso (registered trademark) tablets 100mg package inserts
  • An object of the present invention is to provide an aqueous pharmaceutical composition containing ursodeoxycholic acid or a salt thereof as an active ingredient, trometamol as a buffer, and having good tissue migration properties of ursodeoxycholic acid. .
  • the present inventors conducted intensive studies to solve the above problems, and found that an aqueous pharmaceutical composition containing ursodeoxycholic acid containing trometamol in a predetermined concentration range and having a predetermined osmotic pressure has a buffering effect. It has been found that it has good tissue migration properties. Furthermore, the present inventors have found that the preservative efficacy of the aqueous pharmaceutical composition is improved by using an ionic tonicity agent, particularly sodium chloride, as the tonicity agent.
  • the present invention includes the following aspects.
  • a pharmaceutical composition comprising ursodeoxycholic acid or a salt thereof, trometamol or a salt thereof, and water, The osmotic pressure of the pharmaceutical composition is 50 to 400 mOsm/L, A pharmaceutical composition in which the content of trometamol or a salt thereof is 0.01 to 3% (w/v).
  • Item 2 The pharmaceutical composition according to Item 1, wherein the content of ursodeoxycholic acid or its salt in the pharmaceutical composition is 0.0001 to 3% (w/v).
  • Section 3 Item 3.
  • a pharmaceutical composition comprising ursodeoxycholic acid or a salt thereof, trometamol or a salt thereof, sodium chloride, and water,
  • the osmotic pressure of the pharmaceutical composition is 220 to 330 mOsm/L, pH is 8.0 or more,
  • the content of ursodeoxycholic acid or its salt in the pharmaceutical composition is 0.1 to 1% (w/v)
  • the content of trometamol or its salt in the pharmaceutical composition is 0.3 to 1% (w/v)
  • the content of sodium chloride in the pharmaceutical composition is 0.01 to 2% (w/v)
  • a pharmaceutical composition free of preservatives is.
  • [Section 28] A pharmaceutical composition containing ursodeoxycholic acid or a salt thereof, trometamol or a salt thereof, and water,
  • the osmotic pressure of the pharmaceutical composition is 50 to 400 mOsm/L
  • a method of suppressing a decrease in pH of the pharmaceutical composition by controlling the content of trometamol or its salt in the pharmaceutical composition to 0.1% (w/v) or more.
  • the osmotic pressure of the pharmaceutical composition is 50 to 400 mOsm/L
  • a method of stabilizing the pH of the pharmaceutical composition by controlling the content of trometamol or its salt in the pharmaceutical composition to 0.1% (w/v) or more.
  • an aqueous pharmaceutical composition in which ursodeoxycholic acid or a salt thereof has excellent tissue migration properties is provided. Further, according to the present invention, an aqueous pharmaceutical composition with excellent antiseptic efficacy is provided.
  • FIG. 1 is a photograph showing the appearance of each test sample 28 days after inoculation with the test bacteria in Test Example 4.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising ursodeoxycholic acid or a salt thereof (hereinafter sometimes referred to as "active ingredient of the present disclosure”), trometamol or a salt thereof, and water
  • the osmotic pressure of the pharmaceutical composition is 50 to 400 mOsm/L
  • the content of trometamol or its salt in the pharmaceutical composition is 0.01 to 3% (w/v).
  • Pharmaceutical compositions of the present disclosure may exhibit excellent tissue penetration of the active ingredients of the present disclosure.
  • the present disclosure provides a pharmaceutical composition containing ursodeoxycholic acid or a salt thereof, trometamol or a salt thereof, and water, wherein the osmotic pressure is 50 to 400 mOsm/L, and the trometamol or
  • the present invention provides a method for improving tissue migration of ursodeoxycholic acid or a salt thereof by controlling the content of the salt to 0.01 to 3% (w/v).
  • the present disclosure provides for a pharmaceutical composition containing ursodeoxycholic acid or a salt thereof, trometamol or a salt thereof, and water by adding an ionic tonicity agent into the pharmaceutical composition.
  • a method of improving the preservative efficacy of a pharmaceutical composition is provided.
  • the present disclosure provides a pharmaceutical composition comprising ursodeoxycholic acid or a salt thereof, trometamol or a salt thereof, and water,
  • the osmotic pressure of the pharmaceutical composition is 50 to 400 mOsm/L
  • the present invention provides a method of suppressing a decrease in pH of the pharmaceutical composition by controlling the content of trometamol or its salt in the pharmaceutical composition to 0.1% (w/v) or more.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising ursodeoxycholic acid or a salt thereof, trometamol or a salt thereof, and water
  • the osmotic pressure of the pharmaceutical composition is 50 to 400 mOsm/L
  • a method for stabilizing the pH of the pharmaceutical composition by adjusting the content of trometamol or its salt in the pharmaceutical composition to 0.1% (w/v) or more.
  • the pharmaceutical composition of the present disclosure can be used to treat and/or prevent presbyopia, eye diseases associated with a decrease in the elasticity of the crystalline lens, or eye diseases associated with a decrease in the accommodation power of the eye.
  • ursodeoxycholic acid or "UDCA” has the following formula: (CAS registration number: 128-13-2) is a compound represented by ursodiol and 3 ⁇ ,7 ⁇ -Dihydroxy-5 ⁇ -cholan-24-oic acid. ) is also called.
  • ursodeoxycholic acid may be in a salt form, and the salt form is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • its salts include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, and phosphate; acetate, trifluoroacetate, benzoate, and oxalate.
  • Salt malonate, succinate, maleate, fumarate, tartrate, citrate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfone
  • Organic acid salts such as acid salts, glutamate salts, and aspartate 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. , preferably sodium salts and potassium salts.
  • Ursodeoxycholic acid or a salt thereof contained in the pharmaceutical composition of the present disclosure may be in the form of a hydrate or a solvate.
  • ursodeoxycholic acid or a salt thereof may be produced according to a conventional method in the field of organic chemistry, or may be obtained as a commercially available product.
  • the content of ursodeoxycholic acid or its salt in the pharmaceutical composition of the present disclosure is not particularly limited, and is, for example, 0.0001 to 3% (w/v), preferably 0.001 to 1%. (w/v), 0.1-1% (w/v), 0.003-0.9% (w/v), 0.01-0.7% (w/v), 0.1- 0.65% (w/v), 0.1-0.6% (w/v), 0.03-0.5% (w/v), 0.07-0.35% (w/v ), 0.1 to 0.3% (w/v).
  • An example of the lower limit of the content of ursodeoxycholic acid or its salt is 0.0001% (w/v), preferably 0.001% (w/v), and 0.003% (w/v). ) is more preferred, 0.01% (w/v) is even more preferred, 0.03% (w/v) is even more preferred, 0.07% (w/v) is particularly preferred, 0.1% ( w/v) is most preferred.
  • An example of the upper limit of the content of ursodeoxycholic acid or its salt is 3% (w/v), preferably 2.5% (w/v), and more preferably 2% (w/v).
  • ursodeoxycholic acid or its salt can be indicated by a combination of the above upper and lower limits.
  • % (w/v) means the mass (g) of the target component contained in 100 mL of the pharmaceutical composition.
  • 0.01% (w/v) of ursodeoxycholic acid means that 0.01 g of ursodeoxycholic acid is contained in 100 mL of the pharmaceutical composition.
  • the content of ursodeoxycholic acid or its salt in the pharmaceutical composition is the same as the content of the salt of ursodeoxycholic acid.
  • the content may be calculated as ursodeoxycholic acid, it is preferable that the content be calculated as ursodeoxycholic acid.
  • the value is the hydrate or solvate of ursodeoxycholic acid or its salt.
  • the content may be the content converted to ursodeoxycholic acid or its salt, it is preferably the content converted to ursodeoxycholic acid.
  • Ursodeoxycholic acid or a salt thereof contained in the pharmaceutical composition of the present disclosure can improve the elasticity of the crystalline lens, and therefore is useful as a treatment or prevention agent for presbyopia.
  • the pharmaceutical composition of the present disclosure comprises an active ingredient other than ursodeoxycholic acid or a salt thereof. In one embodiment, it does not contain any active ingredients other than ursodeoxycholic acid or a salt thereof. In one embodiment, it contains ursodeoxycholic acid or a salt thereof as the only active ingredient.
  • compositions of the present disclosure include trometamol or a salt thereof as a buffering agent.
  • the content of trometamol or its salt contained in the pharmaceutical composition of the present disclosure is 0.01 to 3% (w/v), preferably 0.05 to 2% (w/v), and more Preferably 0.1 to 2% (w/v), more preferably 0.1 to 1.5% (w/v), even more preferably 0.1 to 1% (w/v) It is particularly preferably 0.2 to 0.8% (w/v), particularly preferably 0.3 to 0.7% (w/v), and most preferably 0.4 to 0. 6% (w/v).
  • the lower limit of the content of trometamol or its salt is preferably 0.01% (w/v), more preferably 0.05% (w/v), and 0.1% (w/v).
  • v) is even more preferred, more than 0.1% (w/v) is even more preferred, 0.15% (w/v) is particularly preferred, 0.17% (w/v) is particularly preferred, 0.2 % (w/v) is especially more preferred, 0.3% (w/v) is especially more preferred and 0.4% (w/v) is most preferred.
  • the upper limit of the content of trometamol or its salt is preferably 3% (w/v), more preferably 2% (w/v), and 1.5% ( w/v) is even more preferred, 1% (w/v) is even more preferred, 0.8% (w/v) is particularly preferred, 0.7% (w/v) is particularly more preferred, 0.6 % (w/v) is most preferred.
  • a preferred range of the content of trometamol or its salt can be indicated by a combination of the above upper and lower limits.
  • the salt of trometamol is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include trometamol hydrochloride.
  • the pharmaceutical composition of the present disclosure further comprises a buffer other than trometamol or a salt thereof.
  • a buffer other than trometamol or a salt thereof One type of buffering agent may be used alone, or two or more types of buffering agents may be used in combination.
  • the pharmaceutical composition of the present disclosure does not contain a buffer other than trometamol or a salt thereof.
  • buffers other than trometamol or its salts are not particularly limited as long as they can be used as additives for pharmaceuticals, and examples include phosphoric acid or its salts, citric acid or its salts, acetic acid or its salts. , carbonic acid or its salt, tartaric acid or its salt, ⁇ -aminocaproic acid and the like.
  • phosphates include sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, etc.
  • citrates include citric acid.
  • Examples of the acetate include sodium acetate, potassium acetate, etc.
  • examples of the carbonate include sodium carbonate, sodium hydrogen carbonate, etc.
  • the tartrate includes sodium acetate, potassium acetate, etc.
  • Examples include sodium tartrate and potassium tartrate.
  • the content of buffering agents other than trometamol or its salts can be adjusted as appropriate depending on the type of the buffering agent, but for example, it is preferably 0.001 to 5% (w/v), and 0.01 to 3%. (w/v), more preferably 0.05-2% (w/v), even more preferably 0.1-1.5% (w/v), even more preferably 0.2-1% (w/v). /v) is particularly preferred, and 0.3 to 0.8% (w/v) is most preferred.
  • these contents may be the total content of the buffers other than trometamol or its salt.
  • Whether the pharmaceutical composition of the present disclosure has a buffering effect can be determined by a method commonly used by those skilled in the art. For example, this can be determined based on the fact that there is no rapid change in pH, no rapid decomposition of the active ingredient, etc.
  • the osmotic pressure of the pharmaceutical composition of the present disclosure is 50 to 400 mOsm/L, preferably 80 to 380 mOsm/L, more preferably 100 to 370 mOsm/L, and even more preferably 150 to 360 mOsm/L. , even more preferably 200 to 350 mOsm/L, particularly preferably 220 to 330 mOsm/L, and most preferably 250 to 300 mOsm/L.
  • the lower limit of the osmotic pressure of the pharmaceutical composition of the present disclosure is 50 mOsm/L, preferably 80 mOsm/L, more preferably 100 mOsm/L, even more preferably 150 mOsm/L, even more preferably 200 mOsm/L, and even more preferably 220 mOsm/L.
  • L is particularly preferred, and 250 mOsm/L is most preferred.
  • the upper limit of the osmotic pressure of the pharmaceutical composition of the present disclosure is 400 mOsm/L, preferably 380 mOsm/L, more preferably 370 mOsm/L, even more preferably 360 mOsm/L, even more preferably 350 mOsm/L, and even more preferably 330 mOsm/L.
  • L is particularly preferred, and 300 mOsm/L is most preferred.
  • the preferred range of osmotic pressure of the pharmaceutical composition of the present disclosure can be indicated by a combination of the above upper and lower limits.
  • the method for measuring the osmotic pressure of the pharmaceutical composition of the present disclosure is not particularly limited, and may be measured by a conventional method in the technical field, for example, according to the method of Test Example 1 of the present specification.
  • the osmotic pressure of the pharmaceutical compositions of the present disclosure can be adjusted using additives known as tonicity agents, which can be used as additives in pharmaceuticals.
  • One type of isotonizing agent may be used alone, or two or more types of isotonizing agents may be used in combination.
  • tonicity agents include ionic tonicity agents, nonionic tonicity agents, and the like.
  • ionic tonicity agents include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and the like.
  • nonionic tonicity agents include glycerin, propylene glycol, sorbitol, mannitol, and the like.
  • Examples of preferred tonicity agents include sodium chloride and glycerin. From the viewpoint of improving the preservative effect of the pharmaceutical composition, more preferable tonicity agents include ionic tonicity agents, and a specific example thereof is sodium chloride.
  • the pharmaceutical composition of the present disclosure comprises sodium chloride, glycerin, or a combination thereof and is free of other tonicity agents.
  • the pharmaceutical composition of the present disclosure includes an ionic tonicity agent and does not include other tonicity agents, specifically, for example, non-ionic tonicity agents.
  • the pharmaceutical composition of the present disclosure includes sodium chloride and is free of other tonicity agents.
  • the pharmaceutical composition of the present disclosure comprises glycerin and no other tonicity agents.
  • the content of the tonicity agent that may be included in the pharmaceutical composition of the present disclosure can be adjusted as appropriate depending on the type of tonicity agent, the osmotic pressure of the pharmaceutical composition of the present disclosure, etc. 0.01 to 5% (w/v) is preferred, 0.1 to 4% (w/v) is more preferred, and 0.5 to 3% (w/v) is even more preferred.
  • the content of sodium chloride that may be included in the pharmaceutical composition of the present disclosure may be adjusted depending on the osmotic pressure of the pharmaceutical composition of the present disclosure, and is, for example, 0.01 to 2% (w/v), Preferably, it is 0.03 to 1.6% (w/v), more preferably 0.05 to 1.4% (w/v), and still more preferably 0.1 to 1.2% ( w/v), particularly preferably from 0.2 to 1.1% (w/v), most preferably from 0.3 to 1% (w/v).
  • the lower limit of the content of sodium chloride is preferably 0.01% (w/v), more preferably 0.03% (w/v), even more preferably 0.05% (w/v), and 0.01% (w/v) is more preferable.
  • the upper limit of the content of sodium chloride is preferably 2% (w/v), more preferably 1.6% (w/v), even more preferably 1.4% (w/v), and even more preferably 1.2%. (w/v) is even more preferred, 1.1% (w/v) is particularly preferred, and 1% (w/v) is most preferred.
  • a preferred range of the content of sodium chloride can be indicated by a combination of the above upper and lower limits.
  • the content of glycerin that can be contained in the pharmaceutical composition of the present disclosure can be adjusted depending on the osmotic pressure of the pharmaceutical composition of the present disclosure, and is preferably 0.1 to 5% (w/v), for example. is 0.2 to 4% (w/v), more preferably 0.3 to 3.5% (w/v), and even more preferably 0.4 to 3% (w/v). It is particularly preferably 0.5 to 2.5% (w/v), most preferably 1 to 2% (w/v).
  • the lower limit of the glycerin content is preferably 0.1% (w/v), more preferably 0.2% (w/v), even more preferably 0.3% (w/v), and 0.4% (w/v).
  • % (w/v) is even more preferred, 0.5% (w/v) is particularly preferred and 1% (w/v) is most preferred.
  • the upper limit of the glycerin content is preferably 5% (w/v), more preferably 4% (w/v), even more preferably 3.5% (w/v), and 3% (w/v) is even more preferred, 2.5% (w/v) is particularly preferred, and 2% (w/v) is most preferred.
  • a preferred range of the glycerin content can be indicated by a combination of the above upper and lower limits.
  • the pharmaceutical composition of the present disclosure contains water as a base.
  • the amount thereof is not particularly limited and can be adjusted according to the amounts of other components.
  • the grade of water added is not particularly limited as long as it is pharmaceutically acceptable. An example is purified water.
  • the pharmaceutical composition of the present disclosure further comprises a base other than water.
  • a base may be used alone, or two or more types of bases may be used in combination.
  • the pharmaceutical composition of the present disclosure does not contain a base other than water.
  • the base other than water is not particularly limited as long as it can be used as an additive for pharmaceuticals.
  • the content of the base other than water can be adjusted depending on the osmotic pressure of the pharmaceutical composition of the present disclosure, but is, for example, 1 to 50% (w/v), preferably 2 to 40% (w/v). v), more preferably 3 to 30% (w/v).
  • the content of these bases other than water may be the total content of the bases other than water.
  • the pH of the pharmaceutical composition of the present disclosure is not particularly limited, but is preferably 8.0 or higher, more preferably 8.1 to 9.5, more preferably 8.2 to 9.3, and It is preferably 8.3 to 9.3, even more preferably 8.4 to 9.3, particularly preferably 8.4 to 9.1, and most preferably 8.4 to 9.0. be.
  • the method for adjusting the pH of the pharmaceutical composition of the present disclosure is not particularly limited, and for example, a pH adjuster that can be used as an additive for pharmaceuticals can be appropriately blended.
  • pH adjusters include hydrochloric acid, sodium hydroxide, potassium hydroxide, and the like.
  • Preferred examples of pH adjusters include hydrochloric acid and sodium hydroxide.
  • the content of the pH adjuster can be adjusted as appropriate depending on the type of pH adjuster, but 0.001 to 5% (w/v) is preferable. It is preferably 0.01 to 1% (w/v), more preferably 0.1 to 0.5% (w/v).
  • the form of the pharmaceutical composition of the present disclosure is not particularly limited as long as it is a composition containing water as a base.
  • Examples include paste, mousse, gel, solution, emulsion, suspension, and cream.
  • the form of the pharmaceutical composition of the present disclosure is a solution.
  • solution means a clear or transparent liquid when visually observed.
  • ursodeoxycholic acid is known to be almost insoluble in water, ursodeoxycholic acid can be dissolved by making the pH of the pharmaceutical composition alkaline.
  • additives may be used in the pharmaceutical composition of the present invention, if necessary.
  • the other additives are not particularly limited as long as they are pharmaceutically acceptable additives, and may be appropriately selected according to the route of administration, dosage form, etc. Examples of such other additives include preservatives, surfactants, stabilizers, antioxidants, high molecular weight polymers, and the like.
  • the content of the preservative can be adjusted appropriately depending on the type of preservative, etc., but for example, it is 0.0001 to 3.5% (w/v), and 0.001 to 2% (w/v) is Preferably, 0.003 to 1.5% (w/v), more preferably 0.004 to 1.2% (w/v), even more preferably 0.005 to 1% (w/v), particularly Preferably, 0.006 to 0.8% (w/v) is particularly more preferable, 0.00675 to 0.6% (w/v) is particularly more preferable, 0.0075 to 0.5% (w/v) ) is even more preferred.
  • One type of preservative may be used alone, or two or more types of preservatives may be used in any combination. When two or more types of preservatives are included, the content of these preservatives indicates the total content of the preservatives.
  • the content of the surfactant can be adjusted as appropriate depending on the type of surfactant, and is, for example, 0.01 to 1% (w/v).
  • One type of surfactant may be used alone, or two or more types of surfactants may be used in any combination. When two or more types of surfactants are included, the content of these surfactants indicates the total content of the surfactants.
  • the content of the stabilizer can be adjusted as appropriate depending on the type of stabilizer, but for example, it is 0.001 to 10% (w/v), and 0.01 to 5% (w/v) is It is preferably 0.05 to 3% (w/v), more preferably 0.1 to 2% (w/v).
  • One type of stabilizer may be used alone, or two or more types of stabilizers may be used in any combination. When two or more types of stabilizers are included, the content of these stabilizers indicates the total content of the stabilizers.
  • the content of the antioxidant can be adjusted as appropriate depending on the type of antioxidant, but for example, it is 0.0001 to 1% (w/v), and 0.0005 to 0.1% (w/v). ) is preferred, 0.001 to 0.02% (w/v) is more preferred, and 0.005 to 0.010% (w/v) is even more preferred.
  • One type of antioxidant may be used alone, or two or more types of antioxidants may be used in any combination. When two or more types of antioxidants are included, the content of these antioxidants indicates the total content of antioxidants.
  • the content of the high molecular weight polymer can be adjusted appropriately depending on the type of high molecular weight polymer, etc., but it is preferably 0.001 to 5% (w/v), and 0.01 to 1% (w/v). More preferably, 0.1 to 0.5% (w/v) is most preferred.
  • the high molecular weight polymer may be used alone or in any combination of two or more components. When two or more types of high molecular weight polymers are included, the content of these high molecular weight polymers indicates the total content of high molecular weight polymers.
  • preservatives include Benzalkonium halide (benzalkonium chloride, benzalkonium bromide), benzethonium halide (benzethonium chloride, benzethonium bromide), chlorhexidine, chlorhexidine gluconate, polyquaternium-1, polyhexamethylene biguanide; Examples include boric acid or its salts, sorbic acid, potassium sorbate, methyl paraoxybenzoate, propyl paraoxybenzoate; and chlorobutanol.
  • boric acid or its salts include boric acid, alkali metal salts of boric acid (potassium tetraborate, sodium borate, potassium borate, borax, potassium metaborate), alkaline earth metal boric acids, etc.
  • alkali metal salts of boric acid potassium tetraborate, sodium borate, potassium borate, borax, potassium metaborate
  • alkaline earth metal boric acids etc.
  • salts calcium salts, magnesium salts
  • borate hydrates include calcium salts, magnesium salts.
  • the pharmaceutical composition of the present disclosure comprises benzalkonium chloride in a content of, for example, 0.005 to 0.01% (w/v) and boric acid in a content of, for example, 0.3 to 0.01% (w/v). With a content of 0.5% (w/v), it does not contain borax, for example with a content of 0.3-1.0% (w/v).
  • the pharmaceutical composition of the present disclosure is free of benzalkonium chloride, boric acid, and borax.
  • the pharmaceutical composition of the present disclosure is free of preservatives described below, for example in a content of 0.0001 to 3.5% (w/v). In one embodiment, the pharmaceutical compositions of the present disclosure are free of preservatives described below.
  • Benzalkonium halide benzalkonium chloride, benzalkonium bromide
  • benzethonium halide benzethonium chloride, benzethonium bromide
  • chlorhexidine chlorhexidine gluconate, polyquaternium-1, polyhexamethylene biguanide
  • Boric acid or its salts boric acid, alkali metal salts of boric acid (potassium tetraborate, sodium borate, potassium borate, borax, potassium metaborate), alkaline earth metal salts of boric acid (calcium salt, magnesium salt) ), borate hydrate), sorbic acid, potassium sorbate, methyl parabenzoate, propyl parabenzoate; and chlorobutanol
  • the pharmaceutical composition of the present disclosure is free of preservatives, for example in a content of 0.0001-3.5% (w/v). In one embodiment, the pharmaceutical compositions of the present disclosure are free of preservatives.
  • the preservative used herein means a preservative that can be used as a preservative for pharmaceuticals.
  • surfactants include polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, vitamin E TPGS, polyoxyethylene fatty acid ester, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid ester, etc. can be mentioned.
  • the pharmaceutical compositions of the present disclosure are free of surfactants.
  • stabilizers examples include edetic acid, sodium edetate, and the like.
  • the pharmaceutical compositions of the present disclosure are free of stabilizers.
  • antioxidants examples include tocophenol, dibutylated hydroxytoluene, butylated hydroxyanisole, sodium erythorbate, propyl gallate, sodium sulfite, and the like.
  • the pharmaceutical compositions of the present disclosure are free of antioxidants.
  • the pharmaceutical composition of the present disclosure may appropriately contain a high molecular weight polymer that can be used as an additive for pharmaceuticals.
  • high molecular weight polymers include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose (hypromellose), carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropyl
  • examples include methylcellulose phthalate, carboxymethylethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, polyethylene glycol, and the like.
  • the pharmaceutical compositions of the present disclosure are free of high molecular weight polymers.
  • the pharmaceutical compositions of the present disclosure are free of water-soluble starch conversion products such as maltodextrin, hydroxypropyl- ⁇ -cyclodextrin. In one embodiment, the pharmaceutical composition of the present disclosure is maltodextrin-free. In one embodiment, the pharmaceutical composition of the present disclosure does not include hydroxypropyl- ⁇ -cyclodextrin.
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.0001-3% (w/v), Trometamol or its salt 0.01-3% (w/v), A pharmaceutical composition comprising 0.01-2% (w/v) sodium chloride and/or 0.1-5% (w/v) glycerin, and water, Furthermore, it may optionally contain a pH adjuster, The osmotic pressure of the pharmaceutical composition is 50 to 400 mOsm/L.
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.0001-3% (w/v), Trometamol or its salt 0.01-3% (w/v), A pharmaceutical composition comprising 0.01-2% (w/v) sodium chloride and water, the composition comprising: Furthermore, it may optionally contain a pH adjuster, The osmotic pressure of the pharmaceutical composition is 50 to 400 mOsm/L.
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.0001-3% (w/v), Trometamol or its salt 0.01-3% (w/v), A pharmaceutical composition comprising 0.1 to 5% (w/v) glycerin and water, the composition comprising: Furthermore, it may optionally contain a pH adjuster, The osmotic pressure of the pharmaceutical composition is 50 to 400 mOsm/L.
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.07-0.35% (w/v), Trometamol or its salt 0.3-0.7% (w/v), A pharmaceutical composition consisting of 0.2-1.1% (w/v) sodium chloride and/or 0.5-2.5% (w/v) glycerin, and water, Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
  • the osmotic pressure of the pharmaceutical composition is 220-330 mOsm/L.
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.07-0.35% (w/v), Trometamol or its salt 0.3-0.7% (w/v), A pharmaceutical composition comprising 0.2-1.1% (w/v) sodium chloride and water, the composition comprising: Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
  • the osmotic pressure of the pharmaceutical composition is 220-330 mOsm/L.
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.07-0.35% (w/v), Trometamol or its salt 0.3-0.7% (w/v), A pharmaceutical composition comprising 0.5-2.5% (w/v) glycerin and water, the composition comprising: Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide, The osmotic pressure of the pharmaceutical composition is 220-330 mOsm/L.
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.07-0.35% (w/v), Trometamol or its salt 0.1-2% (w/v), A pharmaceutical composition consisting of 0.2-1.1% (w/v) sodium chloride and/or 0.5-2.5% (w/v) glycerin, and water, Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
  • the osmotic pressure of the pharmaceutical composition is 220-330 mOsm/L.
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.07-0.6% (w/v), Trometamol or its salt 0.3-0.7% (w/v), A pharmaceutical composition consisting of 0.2-1.1% (w/v) sodium chloride and/or 0.5-2.5% (w/v) glycerin, and water, Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
  • the osmotic pressure of the pharmaceutical composition is 220-330 mOsm/L.
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.07-0.6% (w/v), Trometamol or its salt 0.3-0.7% (w/v), A pharmaceutical composition comprising 0.2-1.1% (w/v) sodium chloride and water, the composition comprising: Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
  • the osmotic pressure of the pharmaceutical composition is 220-330 mOsm/L.
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.07-0.6% (w/v), Trometamol or its salt 0.3-0.7% (w/v), A pharmaceutical composition comprising 0.5-2.5% (w/v) glycerin and water, the composition comprising: Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide, The osmotic pressure of the pharmaceutical composition is 220-330 mOsm/L.
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.07-0.6% (w/v), Trometamol or its salt 0.1-2% (w/v), A pharmaceutical composition consisting of 0.2-1.1% (w/v) sodium chloride and/or 0.5-2.5% (w/v) glycerin, and water, Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
  • the osmotic pressure of the pharmaceutical composition is 220-330 mOsm/L.
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.07-1% (w/v), Trometamol or its salt 0.3-0.7% (w/v), A pharmaceutical composition consisting of 0.2-1.1% (w/v) sodium chloride and/or 0.5-2.5% (w/v) glycerin, and water, Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
  • the osmotic pressure of the pharmaceutical composition is 220-330 mOsm/L.
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.07-1% (w/v), Trometamol or its salt 0.3-0.7% (w/v), A pharmaceutical composition comprising 0.2-1.1% (w/v) sodium chloride and water, the composition comprising: Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
  • the osmotic pressure of the pharmaceutical composition is 220-330 mOsm/L.
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.07-1% (w/v), Trometamol or its salt 0.3-0.7% (w/v), A pharmaceutical composition comprising 0.5-2.5% (w/v) glycerin and water, the composition comprising: Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide, The osmotic pressure of the pharmaceutical composition is 220-330 mOsm/L.
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.07-1% (w/v), Trometamol or its salt 0.1-2% (w/v), A pharmaceutical composition consisting of 0.2-1.1% (w/v) sodium chloride and/or 0.5-2.5% (w/v) glycerin, and water, Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
  • the osmotic pressure of the pharmaceutical composition is 220-330 mOsm/L.
  • a pharmaceutical composition "consisting of" a given ingredient refers to a pharmaceutical composition that is substantially free of other ingredients.
  • a pharmaceutical composition "consisting" of a given ingredient further optionally contains a pH adjuster, it means that the pH adjuster can be added in addition to the given ingredient.
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.0001-3% (w/v), Trometamol or its salt 0.3-0.7% (w/v), A pharmaceutical composition comprising 0.2-1.1% (w/v) sodium chloride and/or 0.5-2.5% (w/v) glycerin, and water, Furthermore, it may optionally contain a pH adjuster, Contains no preservatives
  • the osmotic pressure of the pharmaceutical composition is 220 to 330 mOsm/L (referred to as pharmaceutical composition A).
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.0001-3% (w/v), Trometamol or its salt 0.3-0.7% (w/v), A pharmaceutical composition comprising 0.2-1.1% (w/v) sodium chloride and water, the composition comprising: Furthermore, it may optionally contain a pH adjuster, Contains no preservatives
  • the osmotic pressure of the pharmaceutical composition is 220 to 330 mOsm/L (referred to as pharmaceutical composition B).
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.0001-3% (w/v), Trometamol or its salt 0.3-0.7% (w/v), A pharmaceutical composition comprising 0.5-2.5% (w/v) glycerin and water, the composition comprising: Furthermore, it may optionally contain a pH adjuster, Contains no preservatives The osmotic pressure of the pharmaceutical composition is 220 to 330 mOsm/L (referred to as pharmaceutical composition C).
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.0001-3% (w/v), Trometamol or its salt 0.3-0.7% (w/v), A pharmaceutical composition consisting of 0.2-1.1% (w/v) sodium chloride and/or 0.5-2.5% (w/v) glycerin, and water, Furthermore, it may optionally contain a pH adjuster,
  • the osmotic pressure of the pharmaceutical composition is 220 to 330 mOsm/L (referred to as pharmaceutical composition D).
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.0001-3% (w/v), Trometamol or its salt 0.3-0.7% (w/v), A pharmaceutical composition comprising 0.2-1.1% (w/v) sodium chloride and water, the composition comprising: Furthermore, it may optionally contain a pH adjuster,
  • the osmotic pressure of the pharmaceutical composition is 220 to 330 mOsm/L (referred to as pharmaceutical composition E).
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.0001-3% (w/v), Trometamol or its salt 0.3-0.7% (w/v), A pharmaceutical composition comprising 0.5-2.5% (w/v) glycerin and water, the composition comprising: Furthermore, it may optionally contain a pH adjuster,
  • the osmotic pressure of the pharmaceutical composition is 220 to 330 mOsm/L (referred to as pharmaceutical composition F).
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.0001-3% (w/v), Trometamol or its salt 0.1-2% (w/v), A pharmaceutical composition consisting of 0.2-1.1% (w/v) sodium chloride and/or 0.5-2.5% (w/v) glycerin, and water, Furthermore, it may optionally contain a pH adjuster,
  • the osmotic pressure of the pharmaceutical composition is 220 to 330 mOsm/L (referred to as pharmaceutical composition G).
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.001-1% (w/v), Trometamol or its salt 0.4-0.6% (w/v), A pharmaceutical composition comprising 0.3-1% (w/v) sodium chloride and/or 1-2% (w/v) glycerin, and water, Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide, Contains no preservatives
  • the osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition H).
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.001-1% (w/v), Trometamol or its salt 0.4-0.6% (w/v), A pharmaceutical composition comprising 0.3-1% (w/v) sodium chloride and water, the composition comprising: Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide, Contains no preservatives
  • the osmotic pressure of the pharmaceutical composition is 250-300 mOsm/L (referred to as pharmaceutical composition I).
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.001-1% (w/v), Trometamol or its salt 0.4-0.6% (w/v), A pharmaceutical composition comprising 1-2% (w/v) glycerin and water, the composition comprising: Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide, Contains no preservatives
  • the osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition J).
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.001-1% (w/v), Trometamol or its salt 0.4-0.6% (w/v), A pharmaceutical composition consisting of 0.3-1% (w/v) sodium chloride and/or 1-2% (w/v) glycerin, and water, Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
  • the osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition K).
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.001-1% (w/v), Trometamol or its salt 0.4-0.6% (w/v), A pharmaceutical composition comprising 0.3-1% (w/v) sodium chloride and water, the composition comprising: Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
  • the osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition L).
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.001-1% (w/v), Trometamol or its salt 0.4-0.6% (w/v), A pharmaceutical composition comprising 1-2% (w/v) glycerin and water, the composition comprising: Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
  • the osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition M).
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.001-1% (w/v), Trometamol or its salt 0.1-2% (w/v), A pharmaceutical composition comprising 0.3-1% (w/v) sodium chloride and/or 1-2% (w/v) glycerin, and water, Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide, Contains no preservatives
  • the osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition N).
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.1-0.6% (w/v), Trometamol or its salt 0.4-0.6% (w/v), A pharmaceutical composition comprising 0.3-1% (w/v) sodium chloride and/or 1-2% (w/v) glycerin, and water, Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide, Contains no preservatives
  • the osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition O).
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.1-0.6% (w/v), Trometamol or its salt 0.4-0.6% (w/v), A pharmaceutical composition comprising 0.3-1% (w/v) sodium chloride and water, the composition comprising: Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide, Contains no preservatives
  • the osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition P).
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.1-0.6% (w/v), Trometamol or its salt 0.4-0.6% (w/v), A pharmaceutical composition comprising 1-2% (w/v) glycerin and water, the composition comprising: Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide, Contains no preservatives
  • the osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition Q).
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.1-0.6% (w/v), Trometamol or its salt 0.4-0.6% (w/v), A pharmaceutical composition consisting of 0.3-1% (w/v) sodium chloride and/or 1-2% (w/v) glycerin, and water, Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
  • the osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition R).
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.1-0.6% (w/v), Trometamol or its salt 0.4-0.6% (w/v), A pharmaceutical composition comprising 0.3-1% (w/v) sodium chloride and water, the composition comprising: Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
  • the osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition S).
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.1-0.6% (w/v), Trometamol or its salt 0.4-0.6% (w/v), A pharmaceutical composition comprising 1-2% (w/v) glycerin and water, the composition comprising: Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
  • the osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition T).
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.1-0.6% (w/v), Trometamol or its salt 0.1-2% (w/v), A pharmaceutical composition consisting of 0.3-1% (w/v) sodium chloride and/or 1-2% (w/v) glycerin, and water, Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
  • the osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition U).
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.07-0.35% (w/v), Trometamol or its salt 0.4-0.6% (w/v), A pharmaceutical composition comprising 0.3-1% (w/v) sodium chloride and/or 1-2% (w/v) glycerin, and water, Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide, Contains no preservatives
  • the osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition V).
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.07-0.35% (w/v), Trometamol or its salt 0.4-0.6% (w/v), A pharmaceutical composition comprising 0.3-1% (w/v) sodium chloride and water, the composition comprising: Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide, Contains no preservatives
  • the osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition W).
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.07-0.35% (w/v), Trometamol or its salt 0.4-0.6% (w/v), A pharmaceutical composition comprising 1-2% (w/v) glycerin and water, the composition comprising: Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide, Contains no preservatives
  • the osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition X).
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.07-0.35% (w/v), Trometamol or its salt 0.4-0.6% (w/v), A pharmaceutical composition consisting of 0.3-1% (w/v) sodium chloride and/or 1-2% (w/v) glycerin, and water, Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
  • the osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition Y).
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.07-0.35% (w/v), Trometamol or its salt 0.4-0.6% (w/v), A pharmaceutical composition comprising 0.3-1% (w/v) sodium chloride and water, the composition comprising: Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
  • the osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition Z).
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.07-0.35% (w/v), Trometamol or its salt 0.4-0.6% (w/v), A pharmaceutical composition comprising 1-2% (w/v) glycerin and water, the composition comprising: Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
  • the osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition AA).
  • the pharmaceutical composition of the present disclosure comprises: Ursodeoxycholic acid or its salt 0.07-0.35% (w/v), Trometamol or its salt 0.1-2% (w/v), A pharmaceutical composition comprising 0.3-1% (w/v) sodium chloride and/or 1-2% (w/v) glycerin, and water, Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide, Contains no preservatives
  • the osmotic pressure of the pharmaceutical composition is 250-300 mOsm/L (referred to as pharmaceutical composition AB).
  • the above pharmaceutical compositions A to AB do not contain preservatives, the tissue migration properties of ursodeoxycholic acid are equivalent to those of previously developed products contained in multi-dose containers containing preservatives. Therefore, it is useful for developing preservative-free products that are pharmaceutically equivalent to previously developed products. Since the above pharmaceutical compositions A to AB do not contain preservatives, they are preferably filled in PFMD (Preservative Free Multi Dose) containers that do not require preservatives or single-use unit dose containers (unit volume containers). .
  • PFMD Preservative Free Multi Dose
  • the pharmaceutical composition of the present disclosure can be administered orally or parenterally.
  • Administration routes include oral administration, intravenous administration, transdermal administration, and topical ocular administration (e.g., ophthalmic administration, intraconjunctival sac administration, intravitreal administration, subconjunctival administration, and subtenon's administration). Most preferred.
  • the dosage form of the pharmaceutical composition of the present disclosure is not particularly limited as long as it can be used as a pharmaceutical, and examples thereof include eye drops, eye gels, injections, and the like.
  • the pharmaceutical composition of the present invention is particularly preferably used as eye drops. These can be manufactured according to conventional methods in the art.
  • compositions of the present disclosure can be stored in containers made of a variety of materials.
  • the container for filling it is not particularly limited, but for example, a multi-dose container, a PFMD (Preservative Free Multi Dose) container, or a single-use unit dose container (unit volume container). is filled with.
  • PFMD Preservative Free Multi Dose
  • unit volume container unit volume container
  • the material of the container is not particularly limited, and examples thereof include polyethylene, polypropylene, polyethylene terephthalate, polybutylene terephthalate, polypropylene-polyethylene copolymer, polyvinyl chloride, acrylic resin, polystyrene, polycyclic olefin copolymer, and the like.
  • polyethylene is classified according to its density, and examples thereof include low density polyethylene (LDPE), medium density polyethylene (MDPE), and high density polyethylene (HDPE).
  • presbyopia refers to a symptom/disease that is determined to be presbyopia based on general criteria used by doctors or specialists.
  • the diagnostic criteria for presbyopia is ⁇ a person who has a subjective symptom of decreased near visual acuity in a binocular test, and whose binocular daily visual acuity (binocular distance visual acuity measured under the same conditions as in daily life) has a visual acuity of 40 cm of 0.4.
  • eye disease accompanied by a decrease in the elasticity of the crystalline lens refers to an eye disease that is considered to be accompanied by a decrease in the elasticity of the crystalline lens in the field of ophthalmology, such as presbyopia (e.g., presbyopia due to aging), and lens hardening induced by drugs and the like.
  • accommodation power of the eye refers to the ability of the eye to automatically focus when viewing far and/or near.
  • "Eye disease accompanied by a decline in the accommodation power of the eye” means an eye disease that is considered to be accompanied by a decline in the accommodation power of the eye in the field of ophthalmology, such as presbyopia (e.g. presbyopia due to aging), drugs, etc. These include lens stiffness induced by ophthalmopathy, and accommodative loss induced by long-term near vision.
  • the term "patient” refers not only to humans but also to other animals such as dogs, cats, and horses.
  • the patient is preferably a mammal, more preferably a human.
  • treatment and prevention include not only treating and preventing a disease, but also alleviating the symptoms of a disease, delaying the progression of a disease, suppressing symptoms of a disease, and preventing a disease. May include inducing improvement in symptoms.
  • a "therapeutically and/or prophylactically effective amount” refers to an amount that provides a therapeutic and/or preventive effect on a disease and its symptoms, or an amount that can delay the progression of a disease and its symptoms. .
  • tissue penetration of ursodeoxycholic acid or its salts refers to tissues, particularly ocular tissues (e.g., cornea, conjunctiva, uvea, eyelids, anterior chamber (aqueous humor), ciliary body, iris, refers to the transfer of ursodeoxycholic acid or its salts to the lens, vitreous body, retina, choroid, etc.).
  • ocular tissues e.g., cornea, conjunctiva, uvea, eyelids, anterior chamber (aqueous humor), ciliary body, iris.
  • the osmotic pressure is set to 50 to 400 mOsm/L
  • trometamol or its salt in the pharmaceutical composition is By controlling the content to 0.01 to 3% (w/v), the tissue migration of ursodeoxycholic acid or its salt can be improved.
  • Improving tissue migration of ursodeoxycholic acid or a salt thereof means, for example, that the amount of tissue migration of ursodeoxycholic acid or a salt thereof increases compared to when a composition other than the pharmaceutical composition of the present disclosure is administered. It can mean something.
  • the tissue migration properties of ursodeoxycholic acid or its salts can be evaluated, for example, by the method of Test Example 1 or Test Example 3 of the present application.
  • the "preservative efficacy of a pharmaceutical composition” refers to the fact that microorganisms do not proliferate or are difficult to proliferate even if microorganisms are mixed into the pharmaceutical composition, and is also referred to as the preservative efficacy of the pharmaceutical composition.
  • the pharmaceutical composition containing ursodeoxycholic acid or a salt thereof, trometamol or a salt thereof, and water, by adding an ionic tonicity agent to the pharmaceutical composition, the pharmaceutical composition
  • the preservative efficacy of can be improved.
  • the ionic tonicity agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and the like, with sodium chloride being preferred.
  • Improving the preservative efficacy of a pharmaceutical composition means, for example, in a pharmaceutical composition containing ursodeoxycholic acid or a salt thereof, trometamol or a salt thereof, and water, if the preservative efficacy of the pharmaceutical composition is improved before the ionic tonicity agent is added. In comparison, it may mean that microbial growth is more inhibited in the pharmaceutical composition after adding the ionic tonicity agent.
  • the preservative efficacy of a pharmaceutical composition can be evaluated, for example, by the method of Test Example 4 of the present application, in addition to the standard test such as the Japanese Pharmacopoeia. Microorganisms used in the test include bacteria, yeast, mold, etc., with Cladosporium Cladosporioides being particularly preferred.
  • “suppressing the decrease in pH” and “stabilizing the pH” mean that there is little or no decrease in the pH of the pharmaceutical composition after storage for a certain period of time.
  • the pH decrease is 0.14 or less, preferably 0.1 or less, more preferably 0.07 or less, even more preferably 0.05 or less, particularly preferably 0.02 or less.
  • the pH decrease is 0.14 or less, preferably 0.1 or less, more preferably 0.07 or less, even more preferably 0.05 or less, particularly preferably 0.02 or less.
  • compositions of the present disclosure may also be applied to other embodiments, such as embodiments of the methods disclosed herein.
  • Formulation Examples Typical formulation examples using the pharmaceutical composition of the present invention are shown below.
  • the amount of each component is the content in 100 mL of the composition.
  • Test example 1 Migration evaluation test-1 The ability of the active ingredient of the pharmaceutical composition of the present disclosure to migrate into aqueous humor was evaluated.
  • Osmotic pressure of the formulation was measured using 1 mL of the test formulation using an automatic osmotic pressure analyzer (OM-6060, manufactured by ARKRAY, Inc.) based on the principle of molar freezing point depression method.
  • Test method 50 ⁇ L of each test sample (Examples 1 to 11 and Comparative Examples 1 to 2) was instilled once into the eyes of rabbits (male Japanese white breed). Two hours after instillation, local anesthesia was administered to the rabbit eyeballs, and aqueous humor was collected (eyes 2 to 9). The ursodeoxycholic acid concentration in the aqueous humor was measured using a high performance liquid chromatograph/tandem mass spectrometer (LC-MS/MS).
  • LC-MS/MS high performance liquid chromatograph/tandem mass spectrometer
  • ratio to Example 2 is the ratio of the aqueous humor transfer amount of each test preparation to the aqueous humor transfer amount (ng/mL) of Example 2.
  • ratio to Example 8 is the ratio of the aqueous humor transfer amount of each test preparation to the aqueous humor transfer amount (ng/mL) of Example 8.
  • Test example 2 Pharmacological Test The effect of a solution composition containing UDCA on the elasticity of the crystalline lens was evaluated.
  • test samples In the same manner as in Test Example 1, the bases shown in Table 2 and the formulations of Examples 20 to 22 were prepared. According to the method described in Test Example 1, pH and osmotic pressure were measured.
  • Test method 1 Each test sample was instilled into both eyes of 8-month-old C57BL/6J mice using a pipetteman once a day for 1 week. 2) Approximately 0.5 hours after the final eye instillation, the mouse was euthanized by inhaling carbon dioxide, and the eyeball was removed and rinsed with Hank's balanced salt solution (HBSS). 3) The sclera near the optic nerve was cut with a razor, the crystalline lens was removed from the incision, and the removed crystalline lens was immersed in HBSS. 4) The crystalline lens was placed on a slide glass, and an image of the crystalline lens was captured using an all-in-one fluorescence microscope BZ-9000 (Keyence) (image a).
  • HBSS Hank's balanced salt solution
  • Test example 3 Migration evaluation test-2 Regarding the lenses collected from the 0.1% (w/v), 0.3% (w/v) and 1.0% (w/v) UDCA solution groups in "Test Example 2. Pharmacological Test", UDCA Lens migration properties were evaluated. 3-1. Test method In “Test Example 2. Pharmacological Test”, the mouse was sacrificed and collected approximately 0.5 hours after the final instillation, and the lens elasticity improvement amount was measured. The UDCA concentration in the lens was measured by high performance liquid chromatography and It was measured using tandem mass spectrometry (LC-MS/MS).
  • Table 3 shows the average value of the UDCA concentration in the crystalline lens approximately 0.5 hours after the final instillation of each solution. Note that the average value is the average of 10 eyes.
  • 0.1% (w/v), 0.3% (w/v) and 1.0% (w/v) UDCA solutions were instilled into the eye once a day for one week, the UDCA concentration in the lens was , showed a concentration-dependent increase.
  • pharmacological tests showed that there is a correlation between the concentration-dependent lens elasticity improving effect and the UDCA concentration in the lens.
  • a drug when a drug is applied to the eye, it passes through the cornea and transfers to the aqueous humor, and then the medicinal ingredient is delivered to the crystalline lens. It was thought that this increased the drug concentration in the crystalline lens.
  • Test example 4 Preservative Efficacy Evaluation Test The preservative efficacy of the pharmaceutical composition of the present disclosure was evaluated.
  • test formulations Examples 12 to 16 shown in Table 4 were prepared in the same manner as in Examples 1 to 11. According to the method described in Test Example 1, pH and osmotic pressure were measured.
  • test method (bacterial species) Cladosporium Cladosporioides, a typical mold that exists in the environment, was used as the inoculum.
  • Examples 12 to 16 were each placed in a test tube as a test sample. The inoculum solution was inoculated into the test samples so that the concentration of the bacterial solution in each test sample was 2 ⁇ 10 6 cfu/mL. Specifically, an inoculum solution was prepared to have a concentration of 2 ⁇ 10 8 cfu/mL, and this inoculum solution was inoculated to each test sample to a concentration of 2 ⁇ 10 6 cfu/mL, and the mixture was uniformly mixed. and used as a sample. All samples were clear at the start of the test. These samples were stored at 20 to 25°C in the dark, and the appearance of each test sample was observed and photographed 28 days after inoculation with the test bacteria.
  • test formulation Purified water was added to 0.3 g of trometamol, 2.1 g of sodium chloride, and 0.9 g of ursodeoxycholic acid, and the mixture was stirred. An appropriate amount of sodium hydroxide solution or diluted hydrochloric acid was added to adjust the pH, and an appropriate amount of purified water was added to make the total volume 300 mL to prepare Example 17 shown in Table 5-1. Examples 18 to 19 were prepared in the same manner, except for changing the amount of trometamol. According to the method described in Test Example 1, pH and osmotic pressure were measured.
  • the pharmaceutical composition of the present disclosure is useful as a medicine because ursodeoxycholic acid or its salt has excellent tissue migration properties.

Abstract

The present disclosure provides a pharmaceutical composition containing ursodeoxycholic acid or a salt thereof, trometamol or a salt thereof, and water, the pharmaceutical composition having an osmotic pressure of 50-400 mOsm/L, and the amount of trometamol or a salt thereof contained in the pharmaceutical composition being 0.01-3%(w/v).

Description

ＵＤＣＡまたはその塩を含有する水性医薬組成物Aqueous pharmaceutical composition containing UDCA or its salt
　本発明は、ウルソデオキシコール酸またはその塩を含有する水性医薬組成物に関する。 The present invention relates to an aqueous pharmaceutical composition containing ursodeoxycholic acid or a salt thereof.
　ウルソデオキシコール酸は、胆汁分泌の促進作用やサイトカイン・ケモカイン産生抑制作用などを有する化合物であり、そのため肝疾患の治療薬に用いられている（非特許文献１）。また、ウルソデオキシコール酸は、水晶体の弾性を向上させることから、老視の治療または予防薬としても期待される（特許文献１）。さらに、水可溶性澱粉転化物を加えることによりウルソデオキシコール酸を水可溶化して、経口投与などし得る組成物も知られている（特許文献２）。 Ursodeoxycholic acid is a compound that has the effect of promoting bile secretion and suppressing the production of cytokines and chemokines, and is therefore used as a therapeutic drug for liver diseases (Non-Patent Document 1). Moreover, since ursodeoxycholic acid improves the elasticity of the crystalline lens, it is expected to be used as a treatment or preventive agent for presbyopia (Patent Document 1). Further, a composition is known in which ursodeoxycholic acid is made water-soluble by adding a water-soluble starch conversion product and can be administered orally (Patent Document 2).
　有効成分の組織移行性はその薬物が効能を発揮するのに重要なファクターである。ウルソデオキシコール酸またはその塩を有効成分として含有する水性医薬製剤においても、良好な組織移行性を有する製剤の開発が望まれる。 Tissue penetration of the active ingredient is an important factor for the drug to exert its efficacy. It is also desirable to develop aqueous pharmaceutical preparations containing ursodeoxycholic acid or its salts as an active ingredient that have good tissue penetration properties.
国際公開第２０２０／１２９９６４号パンフレットInternational Publication No. 2020/129964 pamphlet 日本公表特許公報第２０１９－５３２０８２号Japanese Patent Publication No. 2019-532082
　本願発明者らは、ウルソデオキシコール酸またはその塩を有効成分として含有し、トロメタモールを緩衝剤として使用したとき、トロメタモールが当該有効成分の組織移行性を阻害するという問題に直面した。
　本発明の課題は、ウルソデオキシコール酸またはその塩を有効成分として含有し、トロメタモールを緩衝剤として含有し、良好なウルソデオキシコール酸の組織移行性を有する水性医薬組成物を提供することである。 The inventors of the present application encountered the problem that when a composition contains ursodeoxycholic acid or a salt thereof as an active ingredient and trometamol is used as a buffering agent, trometamol inhibits the tissue migration of the active ingredient.
An object of the present invention is to provide an aqueous pharmaceutical composition containing ursodeoxycholic acid or a salt thereof as an active ingredient, trometamol as a buffer, and having good tissue migration properties of ursodeoxycholic acid. .
　本発明者らは、上記課題を解決すべく鋭意検討を行った結果、所定の濃度範囲にあるトロメタモールを含有し、所定の浸透圧を有するウルソデオキシコール酸含有水性医薬組成物が、緩衝効果を有しつつ、良好な組織移行性を有することを見出した。
　さらに、本発明者らは、等張化剤としてイオン性等張化剤、特に塩化ナトリウムを用いることで、当該水性医薬組成物の防腐効力は向上することを見出した。 The present inventors conducted intensive studies to solve the above problems, and found that an aqueous pharmaceutical composition containing ursodeoxycholic acid containing trometamol in a predetermined concentration range and having a predetermined osmotic pressure has a buffering effect. It has been found that it has good tissue migration properties.
Furthermore, the present inventors have found that the preservative efficacy of the aqueous pharmaceutical composition is improved by using an ionic tonicity agent, particularly sodium chloride, as the tonicity agent.
　具体的に、本発明は以下の態様を含む。
［項１]
　ウルソデオキシコール酸またはその塩、トロメタモールまたはその塩、および水を含有する医薬組成物であって、
　該医薬組成物の浸透圧は５０～４００ｍＯｓｍ／Ｌであり、
　該医薬組成物中のトロメタモールまたはその塩の含有量は、０．０１～３％（ｗ／ｖ）である、医薬組成物。
［項２]
　該医薬組成物中のウルソデオキシコール酸またはその塩の含有量は、０．０００１～３％（ｗ／ｖ）である、項１に記載の医薬組成物。
［項３]
　該医薬組成物中のウルソデオキシコール酸またはその塩の含有量は、０．１～１％（ｗ／ｖ）である、項１または２に記載の医薬組成物。
［項４]
　該医薬組成物中のトロメタモールまたはその塩の含有量は、０．１～２％（ｗ／ｖ）である、項１～３のいずれか一項に記載の医薬組成物。
［項５]
　該医薬組成物中のトロメタモールまたはその塩の含有量は、０．１～１％（ｗ／ｖ）である、項１～４のいずれか一項に記載の医薬組成物。
［項６]
　該医薬組成物中のトロメタモールまたはその塩の含有量は、０．３～１％（ｗ／ｖ）である、項１～５のいずれか一項に記載の医薬組成物。
［項７]
　該医薬組成物の浸透圧は８０～３８０ｍＯｓｍ／Ｌである、項１～６のいずれか一項に記載の医薬組成物。
［項８]
　該医薬組成物の浸透圧は２２０～３３０ｍＯｓｍ／Ｌである、項１～７のいずれか一項に記載の医薬組成物。
［項９]
　イオン性等張化剤および／または非イオン性等張化剤を含有する、項１～８のいずれか一項に記載の医薬組成物。
［項１０]
　該イオン性等張化剤が塩化ナトリウムであり、該非イオン性等張化剤がグリセリンである、項９に記載の医薬組成物。
［項１１]
　塩化ナトリウムを含有する、項１～１０のいずれか一項に記載の医薬組成物。
［項１２]
　グリセリンを含有する、項１～１１のいずれか一項に記載の医薬組成物。
［項１３]
　ｐＨが８．０以上である、項１～１２のいずれか一項に記載の医薬組成物。
［項１４］
　該医薬組成物中の塩化ナトリウムの含有量が、０．０１～２％（ｗ／ｖ）である、項１０～１３のいずれか一項に記載の医薬組成物。
［項１５］
　該医薬組成物中のグリセリンの含有量が、０．１～５％（ｗ／ｖ）である、項１０～１４のいずれか一項に記載の医薬組成物。
［項１６］
　ベンザルコニウム塩化物、ホウ酸、およびホウ砂からなる群から選択される少なくとも１つの防腐剤を含まない、項１～１５のいずれか一項に記載の医薬組成物。
［項１７］
　防腐剤を含まない、項１～１６のいずれか一項に記載の医薬組成物。
［項１８］
　ウルソデオキシコール酸またはその塩、トロメタモールまたはその塩、塩化ナトリウム、および水を含有する医薬組成物であって、
　該医薬組成物の浸透圧は２２０～３３０ｍＯｓｍ／Ｌであり、
　ｐＨが８．０以上であり、
　該医薬組成物中のウルソデオキシコール酸またはその塩の含有量は、０．１～１％（ｗ／ｖ）であり、
　該医薬組成物中のトロメタモールまたはその塩の含有量は、０．３～１％（ｗ／ｖ）であり、
　該医薬組成物中の塩化ナトリウムの含有量が、０．０１～２％（ｗ／ｖ）であって、
　防腐剤を含まない、医薬組成物。
［項１９］
　溶液である、項１～１８のいずれか一項に記載の医薬組成物。
［項２０]
　眼投与用である、項１～１９のいずれか一項に記載の医薬組成物。
［項２１]
　点眼剤である、項１～２０のいずれか一項に記載の医薬組成物。
［項２２]
　老視、水晶体の弾性の低下を伴う眼疾患、または眼の調節力の低下を伴う眼疾患の治療および／または予防のための、項１～２１のいずれか一項に記載の医薬組成物。
［項２３]
　老視、水晶体の弾性の低下を伴う眼疾患、または眼の調節力の低下を伴う眼疾患の治療および／または予防するのに使用するための、項１～２１のいずれか一項に記載の医薬組成物。
［項２４]
　老視、水晶体の弾性の低下を伴う眼疾患、または眼の調節力の低下を伴う眼疾患を治療および／または予防するための薬剤の製造における、項１～２１のいずれか一項に記載の医薬組成物の使用。
［項２５]
　項１～２１のいずれか一項に記載の医薬組成物の治療および／または予防上の有効量を患者に投与することを含む、老視、水晶体の弾性の低下を伴う眼疾患、または眼の調節力の低下を伴う眼疾患の治療および／または予防方法。
［項２６]
　ウルソデオキシコール酸またはその塩、トロメタモールまたはその塩、および水を含有する医薬組成物において、
　該医薬組成物の浸透圧を５０～４００ｍＯｓｍ／Ｌとし、
該医薬組成物中のトロメタモールまたはその塩の含有量を０．０１～３％（ｗ／ｖ）とすることにより、ウルソデオキシコール酸またはその塩の組織移行性を向上する方法。
［項２７]
　ウルソデオキシコール酸またはその塩、トロメタモールまたはその塩、および水を含有する医薬組成物において、
該医薬組成物中にイオン性等張化剤を加えることにより、該医薬組成物の防腐効力を向上する方法。
［項２８]
　ウルソデオキシコール酸またはその塩、トロメタモールまたはその塩、および水を含有する医薬組成物において、
　該医薬組成物の浸透圧を５０～４００ｍＯｓｍ／Ｌとし、
該医薬組成物中のトロメタモールまたはその塩の含有量を０．１％（ｗ／ｖ）以上とすることにより、該医薬組成物のｐＨの低下を抑制する方法。
［項２９]
　ウルソデオキシコール酸またはその塩、トロメタモールまたはその塩、および水を含有する医薬組成物において、
　該医薬組成物の浸透圧を５０～４００ｍＯｓｍ／Ｌとし、
該医薬組成物中のトロメタモールまたはその塩の含有量を０．１％（ｗ／ｖ）以上とすることにより、該医薬組成物のｐＨを安定化する方法。 Specifically, the present invention includes the following aspects.
[Section 1]
A pharmaceutical composition comprising ursodeoxycholic acid or a salt thereof, trometamol or a salt thereof, and water,
The osmotic pressure of the pharmaceutical composition is 50 to 400 mOsm/L,
A pharmaceutical composition in which the content of trometamol or a salt thereof is 0.01 to 3% (w/v).
[Section 2]
Item 2. The pharmaceutical composition according to Item 1, wherein the content of ursodeoxycholic acid or its salt in the pharmaceutical composition is 0.0001 to 3% (w/v).
[Section 3]
Item 3. The pharmaceutical composition according to item 1 or 2, wherein the content of ursodeoxycholic acid or its salt in the pharmaceutical composition is 0.1 to 1% (w/v).
[Section 4]
4. The pharmaceutical composition according to any one of Items 1 to 3, wherein the content of trometamol or its salt in the pharmaceutical composition is 0.1 to 2% (w/v).
[Section 5]
Item 5. The pharmaceutical composition according to any one of Items 1 to 4, wherein the content of trometamol or a salt thereof in the pharmaceutical composition is 0.1 to 1% (w/v).
[Section 6]
Item 6. The pharmaceutical composition according to any one of Items 1 to 5, wherein the content of trometamol or a salt thereof in the pharmaceutical composition is 0.3 to 1% (w/v).
[Section 7]
Item 7. The pharmaceutical composition according to any one of Items 1 to 6, wherein the pharmaceutical composition has an osmotic pressure of 80 to 380 mOsm/L.
[Section 8]
Item 8. The pharmaceutical composition according to any one of Items 1 to 7, wherein the pharmaceutical composition has an osmotic pressure of 220 to 330 mOsm/L.
[Section 9]
Item 9. The pharmaceutical composition according to any one of Items 1 to 8, which contains an ionic tonicity agent and/or a nonionic tonicity agent.
[Section 10]
10. The pharmaceutical composition according to item 9, wherein the ionic tonicity agent is sodium chloride and the nonionic tonicity agent is glycerin.
[Section 11]
The pharmaceutical composition according to any one of Items 1 to 10, containing sodium chloride.
[Section 12]
Item 12. The pharmaceutical composition according to any one of Items 1 to 11, containing glycerin.
[Section 13]
Item 13. The pharmaceutical composition according to any one of Items 1 to 12, which has a pH of 8.0 or higher.
[Section 14]
The pharmaceutical composition according to any one of Items 10 to 13, wherein the content of sodium chloride in the pharmaceutical composition is 0.01 to 2% (w/v).
[Section 15]
The pharmaceutical composition according to any one of Items 10 to 14, wherein the content of glycerin in the pharmaceutical composition is 0.1 to 5% (w/v).
[Section 16]
16. The pharmaceutical composition according to any one of paragraphs 1 to 15, which is free of at least one preservative selected from the group consisting of benzalkonium chloride, boric acid, and borax.
[Section 17]
17. The pharmaceutical composition according to any one of paragraphs 1 to 16, which is free of preservatives.
[Section 18]
A pharmaceutical composition comprising ursodeoxycholic acid or a salt thereof, trometamol or a salt thereof, sodium chloride, and water,
The osmotic pressure of the pharmaceutical composition is 220 to 330 mOsm/L,
pH is 8.0 or more,
The content of ursodeoxycholic acid or its salt in the pharmaceutical composition is 0.1 to 1% (w/v),
The content of trometamol or its salt in the pharmaceutical composition is 0.3 to 1% (w/v),
The content of sodium chloride in the pharmaceutical composition is 0.01 to 2% (w/v),
A pharmaceutical composition free of preservatives.
[Section 19]
19. The pharmaceutical composition according to any one of paragraphs 1 to 18, which is a solution.
[Section 20]
Item 20. The pharmaceutical composition according to any one of items 1 to 19, which is for ocular administration.
[Section 21]
Item 21. The pharmaceutical composition according to any one of Items 1 to 20, which is an eye drop.
[Section 22]
Item 22. The pharmaceutical composition according to any one of Items 1 to 21, for the treatment and/or prevention of presbyopia, an eye disease accompanied by a decrease in the elasticity of the crystalline lens, or an eye disease accompanied by a decrease in the accommodation power of the eye.
[Section 23]
Items 1 to 21 for use in the treatment and/or prevention of presbyopia, eye diseases accompanied by a decrease in the elasticity of the crystalline lens, or eye diseases accompanied by a decrease in the accommodative power of the eye. Pharmaceutical composition.
[Section 24]
The method according to any one of Items 1 to 21 in the manufacture of a medicament for treating and/or preventing presbyopia, an eye disease accompanied by a decrease in the elasticity of the crystalline lens, or an eye disease accompanied by a decrease in the accommodation power of the eye. Uses of pharmaceutical compositions.
[Section 25]
The method of treating presbyopia, eye diseases accompanied by decreased elasticity of the crystalline lens, or ocular diseases, comprising administering to a patient a therapeutically and/or prophylactically effective amount of the pharmaceutical composition according to any one of items 1 to 21. A method for treating and/or preventing eye diseases associated with decreased accommodation.
[Section 26]
A pharmaceutical composition containing ursodeoxycholic acid or a salt thereof, trometamol or a salt thereof, and water,
The osmotic pressure of the pharmaceutical composition is 50 to 400 mOsm/L,
A method for improving tissue penetration of ursodeoxycholic acid or a salt thereof by controlling the content of trometamol or a salt thereof in the pharmaceutical composition to 0.01 to 3% (w/v).
[Section 27]
A pharmaceutical composition containing ursodeoxycholic acid or a salt thereof, trometamol or a salt thereof, and water,
A method of improving the preservative efficacy of a pharmaceutical composition by adding an ionic tonicity agent to the pharmaceutical composition.
[Section 28]
A pharmaceutical composition containing ursodeoxycholic acid or a salt thereof, trometamol or a salt thereof, and water,
The osmotic pressure of the pharmaceutical composition is 50 to 400 mOsm/L,
A method of suppressing a decrease in pH of the pharmaceutical composition by controlling the content of trometamol or its salt in the pharmaceutical composition to 0.1% (w/v) or more.
[Section 29]
A pharmaceutical composition containing ursodeoxycholic acid or a salt thereof, trometamol or a salt thereof, and water,
The osmotic pressure of the pharmaceutical composition is 50 to 400 mOsm/L,
A method of stabilizing the pH of the pharmaceutical composition by controlling the content of trometamol or its salt in the pharmaceutical composition to 0.1% (w/v) or more.
　上記［項１]から［項２９]の各構成は、任意に２以上を選択して組み合わせることができる。 Two or more of the configurations from [Item 1] to [Item 29] above can be arbitrarily selected and combined.
　本発明によれば、ウルソデオキシコール酸またはその塩の組織移行性が優れた、水性医薬組成物が提供される。さらに、本発明によれば、防腐効力の優れた、水性医薬組成物が提供される。 According to the present invention, an aqueous pharmaceutical composition in which ursodeoxycholic acid or a salt thereof has excellent tissue migration properties is provided. Further, according to the present invention, an aqueous pharmaceutical composition with excellent antiseptic efficacy is provided.
図１は、試験例４における試験菌接種２８日後の各試験試料の外観を示す写真である。FIG. 1 is a photograph showing the appearance of each test sample 28 days after inoculation with the test bacteria in Test Example 4.
　以下に、本発明について詳細に説明する。 The present invention will be explained in detail below.
　１つの態様として、本開示は、ウルソデオキシコール酸またはその塩（以下、「本開示の有効成分」と称することがある）、トロメタモールまたはその塩、および水を含有する医薬組成物であって、該医薬組成物の浸透圧は５０～４００ｍＯｓｍ／Ｌであり、該医薬組成物中のトロメタモールまたはその塩の含有量は、０．０１～３％（ｗ／ｖ）である、医薬組成物（以下「本開示の医薬組成物」と称することがある）提供する。本開示の医薬組成物は本開示の有効成分の優れた組織移行性を示し得る。 In one aspect, the present disclosure provides a pharmaceutical composition comprising ursodeoxycholic acid or a salt thereof (hereinafter sometimes referred to as "active ingredient of the present disclosure"), trometamol or a salt thereof, and water, The osmotic pressure of the pharmaceutical composition is 50 to 400 mOsm/L, and the content of trometamol or its salt in the pharmaceutical composition is 0.01 to 3% (w/v). (sometimes referred to as "pharmaceutical compositions of the present disclosure"). Pharmaceutical compositions of the present disclosure may exhibit excellent tissue penetration of the active ingredients of the present disclosure.
　１つの態様として、本開示は、ウルソデオキシコール酸またはその塩、トロメタモールまたはその塩、および水を含有する医薬組成物において、浸透圧を５０～４００ｍＯｓｍ／Ｌとし、該医薬組成物中のトロメタモールまたはその塩の含有量を０．０１～３％（ｗ／ｖ）とすることにより、ウルソデオキシコール酸またはその塩の組織移行性を向上する方法を提供する。 In one embodiment, the present disclosure provides a pharmaceutical composition containing ursodeoxycholic acid or a salt thereof, trometamol or a salt thereof, and water, wherein the osmotic pressure is 50 to 400 mOsm/L, and the trometamol or The present invention provides a method for improving tissue migration of ursodeoxycholic acid or a salt thereof by controlling the content of the salt to 0.01 to 3% (w/v).
　１つの態様として、本開示は、ウルソデオキシコール酸またはその塩、トロメタモールまたはその塩、および水を含有する医薬組成物において、該医薬組成物中にイオン性等張化剤を加えることにより、該医薬組成物の防腐効力を向上する方法を提供する。 In one embodiment, the present disclosure provides for a pharmaceutical composition containing ursodeoxycholic acid or a salt thereof, trometamol or a salt thereof, and water by adding an ionic tonicity agent into the pharmaceutical composition. A method of improving the preservative efficacy of a pharmaceutical composition is provided.
　１つの態様として、本開示は、ウルソデオキシコール酸またはその塩、トロメタモールまたはその塩、および水を含有する医薬組成物において、
　該医薬組成物の浸透圧を５０～４００ｍＯｓｍ／Ｌとし、
該医薬組成物中のトロメタモールまたはその塩の含有量を０．１％（ｗ／ｖ）以上とすることにより、該医薬組成物のｐＨの低下を抑制する方法を提供する。 In one aspect, the present disclosure provides a pharmaceutical composition comprising ursodeoxycholic acid or a salt thereof, trometamol or a salt thereof, and water,
The osmotic pressure of the pharmaceutical composition is 50 to 400 mOsm/L,
The present invention provides a method of suppressing a decrease in pH of the pharmaceutical composition by controlling the content of trometamol or its salt in the pharmaceutical composition to 0.1% (w/v) or more.
　１つの態様として、本開示は、ウルソデオキシコール酸またはその塩、トロメタモールまたはその塩、および水を含有する医薬組成物において、
　該医薬組成物の浸透圧を５０～４００ｍＯｓｍ／Ｌとし、
該医薬組成物中のトロメタモールまたはその塩の含有量を０．１％（ｗ／ｖ）以上とすることにより、該医薬組成物のｐＨを安定化する方法を提供する。 In one aspect, the present disclosure provides a pharmaceutical composition comprising ursodeoxycholic acid or a salt thereof, trometamol or a salt thereof, and water,
The osmotic pressure of the pharmaceutical composition is 50 to 400 mOsm/L,
Provided is a method for stabilizing the pH of the pharmaceutical composition by adjusting the content of trometamol or its salt in the pharmaceutical composition to 0.1% (w/v) or more.
　本開示の医薬組成物は、老視、水晶体の弾性の低下を伴う眼疾患、または眼の調節力の低下を伴う眼疾患を治療および／または予防するために使用され得る。 The pharmaceutical composition of the present disclosure can be used to treat and/or prevent presbyopia, eye diseases associated with a decrease in the elasticity of the crystalline lens, or eye diseases associated with a decrease in the accommodation power of the eye.
　本開示において、「ウルソデオキシコール酸」または「ＵＤＣＡ」は、下式：
Figure JPOXMLDOC01-appb-C000001
 で表される化合物（ＣＡＳ登録番号：１２８－１３－２）であり、ウルソジオールや３α，７β－ジヒドロキシ－５β－コラン－２４－酸（3α,7β-Dihydroxy-5β-cholan-24-oic acid）とも呼ばれる。 In the present disclosure, "ursodeoxycholic acid" or "UDCA" has the following formula:
Figure JPOXMLDOC01-appb-C000001
 (CAS registration number: 128-13-2) is a compound represented by ursodiol and 3α,7β-Dihydroxy-5β-cholan-24-oic acid. ) is also called.
　本開示において、ウルソデオキシコール酸は、塩形態であってもよく、その塩形態は医薬的に許容される塩であれば特に制限されない。その塩としては、例えば、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硝酸塩、硫酸塩、リン酸塩等の無機酸塩；酢酸塩、トリフルオロ酢酸塩、安息香酸塩、シュウ酸塩、マロン酸塩、コハク酸塩、マレイン酸塩、フマル酸塩、酒石酸塩、クエン酸塩、メタンスルホン酸塩、エタンスルホン酸塩、トリフルオロメタンスルホン酸塩、ベンゼンスルホン酸塩、ｐ－トルエンスルホン酸塩、グルタミン酸塩、アスパラギン酸塩等の有機酸塩；ナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩等の金属塩；アンモニウム塩等の無機塩；およびトリエチルアミン塩、グアニジン塩等の有機アミン塩等が挙げられ、好ましくは、ナトリウム塩、カリウム塩が挙げられる。 In the present disclosure, ursodeoxycholic acid may be in a salt form, and the salt form is not particularly limited as long as it is a pharmaceutically acceptable salt. Examples of its salts include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, and phosphate; acetate, trifluoroacetate, benzoate, and oxalate. Salt, malonate, succinate, maleate, fumarate, tartrate, citrate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfone Organic acid salts such as acid salts, glutamate salts, and aspartate salts; 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. , preferably sodium salts and potassium salts.
　本開示の医薬組成物中に含有されるウルソデオキシコール酸またはその塩は、水和物または溶媒和物の形態をとってもよい。 Ursodeoxycholic acid or a salt thereof contained in the pharmaceutical composition of the present disclosure may be in the form of a hydrate or a solvate.
　本開示において、ウルソデオキシコール酸またはその塩は、有機化学の分野における通常の方法にしたがって製造してもよく、また、市販品として入手してもよい。 In the present disclosure, ursodeoxycholic acid or a salt thereof may be produced according to a conventional method in the field of organic chemistry, or may be obtained as a commercially available product.
　本開示の医薬組成物中のウルソデオキシコール酸またはその塩の含有量は、特に制限されず、例えば、０．０００１～３％（ｗ／ｖ）であり、好ましくは、０．００１～１％（ｗ／ｖ）、０．１～１％（ｗ／ｖ）、０．００３～０．９％（ｗ／ｖ）、０．０１～０．７％（ｗ／ｖ）、０．１～０．６５％（ｗ／ｖ）、０．１～０．６％（ｗ／ｖ）、０．０３～０．５％（ｗ／ｖ）、０．０７～０．３５％（ｗ／ｖ）、０．１～０．３％（ｗ／ｖ）である。具体的には、例えば、０．１％（ｗ／ｖ）、０．２％（ｗ／ｖ）、０．３％（ｗ／ｖ）、０．４％（ｗ／ｖ）、０．５％（ｗ／ｖ）、０．６％（ｗ／ｖ）、０．７％（ｗ／ｖ）、０．８％（ｗ／ｖ）、０．９％（ｗ／ｖ）、１％（ｗ／ｖ）、１．１％（ｗ／ｖ）、１．２％（ｗ／ｖ）、１．３％（ｗ／ｖ）、１．４％（ｗ／ｖ）、１．５％（ｗ／ｖ）、１．６％（ｗ／ｖ）、１．７％（ｗ／ｖ）、１．８％（ｗ／ｖ）、１．９％（ｗ／ｖ）、２％（ｗ／ｖ）、３％（ｗ／ｖ）である。
　ウルソデオキシコール酸またはその塩の含有量の下限値の例として、０．０００１％（ｗ／ｖ）が挙げられ、０．００１％（ｗ／ｖ）が好ましく、０．００３％（ｗ／ｖ）がより好ましく、０．０１％（ｗ／ｖ）がさらに好ましく、０．０３％（ｗ／ｖ）がさらにより好ましく、０．０７％（ｗ／ｖ）が特に好ましく、０．１％（ｗ／ｖ）が最も好ましい。
　ウルソデオキシコール酸またはその塩の含有量の上限値の例として、３％（ｗ／ｖ）が挙げられ、２．５％（ｗ／ｖ）が好ましく、２％（ｗ／ｖ）がより好ましく、１．５％（ｗ／ｖ）がさらに好ましく、１％（ｗ／ｖ）がさらにより好ましく、０．９％（ｗ／ｖ）がことさら好ましく、０．７％（ｗ／ｖ）がよりことさら好ましく、０．６５％（ｗ／ｖ）がさらにことさら好ましく、０．６％（ｗ／ｖ）が特に好ましく、０．５％（ｗ／ｖ）が特により好ましく、０．３５％（ｗ／ｖ）が特にさらに好ましく、０．３％（ｗ／ｖ）が最も好ましい。
　ウルソデオキシコール酸またはその塩の含有量の好ましい範囲は、上記の上限値と下限値の組合せにより示され得る。 The content of ursodeoxycholic acid or its salt in the pharmaceutical composition of the present disclosure is not particularly limited, and is, for example, 0.0001 to 3% (w/v), preferably 0.001 to 1%. (w/v), 0.1-1% (w/v), 0.003-0.9% (w/v), 0.01-0.7% (w/v), 0.1- 0.65% (w/v), 0.1-0.6% (w/v), 0.03-0.5% (w/v), 0.07-0.35% (w/v ), 0.1 to 0.3% (w/v). Specifically, for example, 0.1% (w/v), 0.2% (w/v), 0.3% (w/v), 0.4% (w/v), 0.5 % (w/v), 0.6% (w/v), 0.7% (w/v), 0.8% (w/v), 0.9% (w/v), 1% ( w/v), 1.1% (w/v), 1.2% (w/v), 1.3% (w/v), 1.4% (w/v), 1.5% ( w/v), 1.6% (w/v), 1.7% (w/v), 1.8% (w/v), 1.9% (w/v), 2% (w/v) v), 3% (w/v).
An example of the lower limit of the content of ursodeoxycholic acid or its salt is 0.0001% (w/v), preferably 0.001% (w/v), and 0.003% (w/v). ) is more preferred, 0.01% (w/v) is even more preferred, 0.03% (w/v) is even more preferred, 0.07% (w/v) is particularly preferred, 0.1% ( w/v) is most preferred.
An example of the upper limit of the content of ursodeoxycholic acid or its salt is 3% (w/v), preferably 2.5% (w/v), and more preferably 2% (w/v). , 1.5% (w/v) is more preferred, 1% (w/v) is even more preferred, 0.9% (w/v) is particularly preferred, and 0.7% (w/v) is even more preferred. Particularly preferred, 0.65% (w/v) even more preferred, 0.6% (w/v) particularly preferred, 0.5% (w/v) particularly more preferred, 0.35% (w/v) /v) is particularly more preferred, and 0.3% (w/v) is most preferred.
The preferred range of the content of ursodeoxycholic acid or its salt can be indicated by a combination of the above upper and lower limits.
　本開示において、「％（ｗ／ｖ）」は、医薬組成物１００ｍＬ中に含まれる対象成分の質量（ｇ）を意味する。例えば、ウルソデオキシコール酸０．０１％（ｗ／ｖ）とは、医薬組成物１００ｍＬ中に含まれるウルソデオキシコール酸が０．０１ｇであることを意味する。 In the present disclosure, "% (w/v)" means the mass (g) of the target component contained in 100 mL of the pharmaceutical composition. For example, 0.01% (w/v) of ursodeoxycholic acid means that 0.01 g of ursodeoxycholic acid is contained in 100 mL of the pharmaceutical composition.
　本開示において、ウルソデオキシコール酸の塩が配合される場合、医薬組成物中のウルソデオキシコール酸またはその塩の含有量はウルソデオキシコール酸の塩の含有量であっても、ウルソデオキシコール酸に換算された含有量であってもよいが、ウルソデオキシコール酸に換算された含有量であることが好ましい。また、本発明において、ウルソデオキシコール酸またはその塩が、水和物または溶媒和物の形態をとって配合される場合、その値はウルソデオキシコール酸またはその塩の水和物または溶媒和物の含有量であっても、ウルソデオキシコール酸またはその塩に換算された含有量であってもよいが、ウルソデオキシコール酸に換算された含有量であることが好ましい。 In the present disclosure, when a salt of ursodeoxycholic acid is blended, the content of ursodeoxycholic acid or its salt in the pharmaceutical composition is the same as the content of the salt of ursodeoxycholic acid. Although the content may be calculated as ursodeoxycholic acid, it is preferable that the content be calculated as ursodeoxycholic acid. In addition, in the present invention, when ursodeoxycholic acid or its salt is blended in the form of a hydrate or solvate, the value is the hydrate or solvate of ursodeoxycholic acid or its salt. Although the content may be the content converted to ursodeoxycholic acid or its salt, it is preferably the content converted to ursodeoxycholic acid.
　本開示の医薬組成物に含まれるウルソデオキシコール酸またはその塩は、水晶体の弾性を向上することができるため、老視の治療または予防薬として有用である。
　一つの実施形態において、本開示の医薬組成物は、ウルソデオキシコール酸またはその塩以外の有効成分を含む。
　一つの実施形態において、ウルソデオキシコール酸またはその塩以外の有効成分を含まない。
　一つの実施形態において、ウルソデオキシコール酸またはその塩を唯一の有効成分として含む。 Ursodeoxycholic acid or a salt thereof contained in the pharmaceutical composition of the present disclosure can improve the elasticity of the crystalline lens, and therefore is useful as a treatment or prevention agent for presbyopia.
In one embodiment, the pharmaceutical composition of the present disclosure comprises an active ingredient other than ursodeoxycholic acid or a salt thereof.
In one embodiment, it does not contain any active ingredients other than ursodeoxycholic acid or a salt thereof.
In one embodiment, it contains ursodeoxycholic acid or a salt thereof as the only active ingredient.
　本開示の医薬組成物は緩衝剤としてトロメタモールまたはその塩を含む。
　本開示の医薬組成物に含まれるトロメタモールまたはその塩の含有量は、０．０１～３％（ｗ／ｖ）であり、好ましくは、０．０５～２％（ｗ／ｖ）であり、より好ましくは０．１～２％（ｗ／ｖ）であり、さらに好ましくは０．１～１．５％（ｗ／ｖ）であり、さらにより好ましくは０．１～１％（ｗ／ｖ）であり、ことさら好ましくは０．２～０．８％（ｗ／ｖ）であり、特に好ましくは０．３～０．７％（ｗ／ｖ）であり、最も好ましくは０．４～０．６％（ｗ／ｖ）である。具体的には、例えば、０．１％（ｗ／ｖ）、０．２％（ｗ／ｖ）、０．３％（ｗ／ｖ）、０．４％（ｗ／ｖ）、０．５％（ｗ／ｖ）、０．６％（ｗ／ｖ）、０．７％（ｗ／ｖ）、０．８％（ｗ／ｖ）、０．９％（ｗ／ｖ）、１％（ｗ／ｖ）、１．１％（ｗ／ｖ）、１．２％（ｗ／ｖ）、１．３％（ｗ／ｖ）、１．４％（ｗ／ｖ）、１．５％（ｗ／ｖ）、１．６％（ｗ／ｖ）、１．７％（ｗ／ｖ）、１．８％（ｗ／ｖ）、１．９％（ｗ／ｖ）、２％（ｗ／ｖ）である。
　トロメタモールまたはその塩の含有量の下限値は、緩衝作用の観点から、０．０１％（ｗ／ｖ）が好ましく、０．０５％（ｗ／ｖ）がより好ましく、０．１％（ｗ／ｖ）がさらに好ましく、０．１％（ｗ／ｖ）超がさらにより好ましく、０．１５％（ｗ／ｖ）がことさら好ましく、０．１７％（ｗ／ｖ）が特に好ましく、０．２％（ｗ／ｖ）が特により好ましく、０．３％（ｗ／ｖ）が特にさらに好ましく、０．４％（ｗ／ｖ）が最も好ましい。
　トロメタモールまたはその塩の含有量の上限値は、ウルソデオキシコール酸の組織移行性の観点から、３％（ｗ／ｖ）が好ましく、２％（ｗ／ｖ）がより好ましく、１．５％（ｗ／ｖ）がさらに好ましく、１％（ｗ／ｖ）がさらにより好ましく、０．８％（ｗ／ｖ）が特に好ましく、０．７％（ｗ／ｖ）が特により好ましく、０．６％（ｗ／ｖ）が最も好ましい。
　トロメタモールまたはその塩の含有量の好ましい範囲は、上記の上限値と下限値の組合せにより示され得る。 Pharmaceutical compositions of the present disclosure include trometamol or a salt thereof as a buffering agent.
The content of trometamol or its salt contained in the pharmaceutical composition of the present disclosure is 0.01 to 3% (w/v), preferably 0.05 to 2% (w/v), and more Preferably 0.1 to 2% (w/v), more preferably 0.1 to 1.5% (w/v), even more preferably 0.1 to 1% (w/v) It is particularly preferably 0.2 to 0.8% (w/v), particularly preferably 0.3 to 0.7% (w/v), and most preferably 0.4 to 0. 6% (w/v). Specifically, for example, 0.1% (w/v), 0.2% (w/v), 0.3% (w/v), 0.4% (w/v), 0.5 % (w/v), 0.6% (w/v), 0.7% (w/v), 0.8% (w/v), 0.9% (w/v), 1% ( w/v), 1.1% (w/v), 1.2% (w/v), 1.3% (w/v), 1.4% (w/v), 1.5% ( w/v), 1.6% (w/v), 1.7% (w/v), 1.8% (w/v), 1.9% (w/v), 2% (w/v) v).
From the viewpoint of buffering effect, the lower limit of the content of trometamol or its salt is preferably 0.01% (w/v), more preferably 0.05% (w/v), and 0.1% (w/v). v) is even more preferred, more than 0.1% (w/v) is even more preferred, 0.15% (w/v) is particularly preferred, 0.17% (w/v) is particularly preferred, 0.2 % (w/v) is especially more preferred, 0.3% (w/v) is especially more preferred and 0.4% (w/v) is most preferred.
From the viewpoint of tissue migration of ursodeoxycholic acid, the upper limit of the content of trometamol or its salt is preferably 3% (w/v), more preferably 2% (w/v), and 1.5% ( w/v) is even more preferred, 1% (w/v) is even more preferred, 0.8% (w/v) is particularly preferred, 0.7% (w/v) is particularly more preferred, 0.6 % (w/v) is most preferred.
A preferred range of the content of trometamol or its salt can be indicated by a combination of the above upper and lower limits.
　トロメタモールの塩は、医薬的に許容される塩であれば特に制限されないが、例えばトロメタモール塩酸塩が挙げられる。 The salt of trometamol is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include trometamol hydrochloride.
　一つの実施形態において、本開示の医薬組成物は、トロメタモールまたはその塩以外の緩衝剤をさらに含む。１種単独で用いてもよく、２種以上の緩衝剤を組み合わせて使用してもよい。
　一つの実施形態において、本開示の医薬組成物は、トロメタモールまたはその塩以外の緩衝剤を含まない。 In one embodiment, the pharmaceutical composition of the present disclosure further comprises a buffer other than trometamol or a salt thereof. One type of buffering agent may be used alone, or two or more types of buffering agents may be used in combination.
In one embodiment, the pharmaceutical composition of the present disclosure does not contain a buffer other than trometamol or a salt thereof.
　本開示において、トロメタモールまたはその塩以外の緩衝剤は、医薬品の添加物として使用可能な緩衝剤であれば特に制限はなく、例えば、リン酸またはその塩、クエン酸またはその塩、酢酸またはその塩、炭酸またはその塩、酒石酸またはその塩、ε－アミノカプロン酸等が挙げられる。リン酸塩としては、リン酸ナトリウム、リン酸二水素ナトリウム、リン酸水素二ナトリウム、リン酸カリウム、リン酸二水素カリウム、リン酸水素二カリウム等が挙げられ、クエン酸塩としては、クエン酸ナトリウム、クエン酸二ナトリウム、クエン酸三ナトリウム等が挙げられ、酢酸塩としては、酢酸ナトリウム、酢酸カリウム等が挙げられ、炭酸塩としては、炭酸ナトリウム、炭酸水素ナトリウム等が挙げられ、酒石酸塩としては、酒石酸ナトリウム、酒石酸カリウム等が挙げられる。
　トロメタモールまたはその塩以外の緩衝剤の含有量は、当該緩衝剤の種類などにより適宜調整することができるが、例えば、０．００１～５％（ｗ／ｖ）が好ましく、０．０１～３％（ｗ／ｖ）がより好ましく、０．０５～２％（ｗ／ｖ）がさらに好ましく、０．１～１．５％（ｗ／ｖ）がさらにより好ましく、０．２～１％（ｗ／ｖ）が特に好ましく、０．３～０．８％（ｗ／ｖ）が最も好ましい。２種以上のトロメタモールまたはその塩以外の緩衝剤が含まれる場合、これらの含有量は、トロメタモールまたはその塩以外の緩衝剤の合計の含有量であり得る。 In the present disclosure, buffers other than trometamol or its salts are not particularly limited as long as they can be used as additives for pharmaceuticals, and examples include phosphoric acid or its salts, citric acid or its salts, acetic acid or its salts. , carbonic acid or its salt, tartaric acid or its salt, ε-aminocaproic acid and the like. Examples of phosphates include sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, etc., and examples of citrates include citric acid. Examples of the acetate include sodium acetate, potassium acetate, etc., examples of the carbonate include sodium carbonate, sodium hydrogen carbonate, etc., and the tartrate includes sodium acetate, potassium acetate, etc. Examples include sodium tartrate and potassium tartrate.
The content of buffering agents other than trometamol or its salts can be adjusted as appropriate depending on the type of the buffering agent, but for example, it is preferably 0.001 to 5% (w/v), and 0.01 to 3%. (w/v), more preferably 0.05-2% (w/v), even more preferably 0.1-1.5% (w/v), even more preferably 0.2-1% (w/v). /v) is particularly preferred, and 0.3 to 0.8% (w/v) is most preferred. When two or more types of buffers other than trometamol or its salt are included, these contents may be the total content of the buffers other than trometamol or its salt.
　本開示の医薬組成物が緩衝効果を有するかは、当業者が通常行う方法により判断され得る。例えば、急激なｐHの変化を呈さない、有効成分の急激な分解が認められない等により判断され得る。 Whether the pharmaceutical composition of the present disclosure has a buffering effect can be determined by a method commonly used by those skilled in the art. For example, this can be determined based on the fact that there is no rapid change in pH, no rapid decomposition of the active ingredient, etc.
　本開示の医薬組成物の浸透圧は５０～４００ｍＯｓｍ／Ｌであり、好ましくは、８０～３８０ｍＯｓｍ／Ｌであり、より好ましくは１００～３７０ｍＯｓｍ／Ｌであり、さらに好ましくは１５０～３６０ｍＯｓｍ／Ｌであり、さらにより好ましくは２００～３５０ｍＯｓｍ／Ｌであり、特に好ましくは２２０～３３０ｍＯｓｍ／Ｌであり、最も好ましくは２５０～３００ｍＯｓｍ／Ｌである。
　本開示の医薬組成物の浸透圧の下限値は、５０ｍＯｓｍ／Ｌであり、８０ｍＯｓｍ／Ｌが好ましく、１００ｍＯｓｍ／Ｌがより好ましく、１５０ｍＯｓｍ／Ｌがさらに好ましく、２００ｍＯｓｍ／Ｌがさらにより好ましく、２２０ｍＯｓｍ／Ｌが特に好ましく、２５０ｍＯｓｍ／Ｌが最も好ましい。
　本開示の医薬組成物の浸透圧の上限値は、４００ｍＯｓｍ／Ｌであり、３８０ｍＯｓｍ／Ｌが好ましく、３７０ｍＯｓｍ／Ｌがより好ましく、３６０ｍＯｓｍ／Ｌがさらに好ましく、３５０ｍＯｓｍ／Ｌがさらにより好ましく、３３０ｍＯｓｍ／Ｌが特に好ましく、３００ｍＯｓｍ／Ｌが最も好ましい。
　本開示の医薬組成物の浸透圧の好ましい範囲は、上記の上限値と下限値の組合せにより示され得る。 The osmotic pressure of the pharmaceutical composition of the present disclosure is 50 to 400 mOsm/L, preferably 80 to 380 mOsm/L, more preferably 100 to 370 mOsm/L, and even more preferably 150 to 360 mOsm/L. , even more preferably 200 to 350 mOsm/L, particularly preferably 220 to 330 mOsm/L, and most preferably 250 to 300 mOsm/L.
The lower limit of the osmotic pressure of the pharmaceutical composition of the present disclosure is 50 mOsm/L, preferably 80 mOsm/L, more preferably 100 mOsm/L, even more preferably 150 mOsm/L, even more preferably 200 mOsm/L, and even more preferably 220 mOsm/L. L is particularly preferred, and 250 mOsm/L is most preferred.
The upper limit of the osmotic pressure of the pharmaceutical composition of the present disclosure is 400 mOsm/L, preferably 380 mOsm/L, more preferably 370 mOsm/L, even more preferably 360 mOsm/L, even more preferably 350 mOsm/L, and even more preferably 330 mOsm/L. L is particularly preferred, and 300 mOsm/L is most preferred.
The preferred range of osmotic pressure of the pharmaceutical composition of the present disclosure can be indicated by a combination of the above upper and lower limits.
　本開示の医薬組成物の浸透圧の測定方法は特に限定されず、当該技術分野の通常の方法で測定され得るが、例えば、本願明細書の試験例１の方法に準して測定される。 The method for measuring the osmotic pressure of the pharmaceutical composition of the present disclosure is not particularly limited, and may be measured by a conventional method in the technical field, for example, according to the method of Test Example 1 of the present specification.
　本開示の医薬組成物の浸透圧は、医薬品の添加物として使用可能な等張化剤として知られる添加剤を用いて調整され得る。等張化剤は１種単独で用いてもよく、２種以上の等張化剤を組み合わせて使用してもよい。
　等張化剤の例としては、イオン性等張化剤や非イオン性等張化剤等が挙げられる。
　イオン性等張化剤としては、塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム等が挙げられる。
　非イオン性等張化剤としてはグリセリン、プロピレングリコール、ソルビトール、マンニトール等が挙げられる。
　好ましい等張化剤の例として、塩化ナトリウムおよびグリセリンが挙げられる。
　医薬組成物の防腐効力を向上させる観点から、より好ましい等張化剤として、イオン性等張化剤が挙げられ、その具体例として、塩化ナトリウムが挙げられる。 The osmotic pressure of the pharmaceutical compositions of the present disclosure can be adjusted using additives known as tonicity agents, which can be used as additives in pharmaceuticals. One type of isotonizing agent may be used alone, or two or more types of isotonizing agents may be used in combination.
Examples of tonicity agents include ionic tonicity agents, nonionic tonicity agents, and the like.
Examples of ionic tonicity agents include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and the like.
Examples of nonionic tonicity agents include glycerin, propylene glycol, sorbitol, mannitol, and the like.
Examples of preferred tonicity agents include sodium chloride and glycerin.
From the viewpoint of improving the preservative effect of the pharmaceutical composition, more preferable tonicity agents include ionic tonicity agents, and a specific example thereof is sodium chloride.
　１つの実施形態において、本開示の医薬組成物は、塩化ナトリウム、グリセリン、またはこれらの組み合わせを含み、かつ、他の等張化剤を含まない。 In one embodiment, the pharmaceutical composition of the present disclosure comprises sodium chloride, glycerin, or a combination thereof and is free of other tonicity agents.
　１つの実施形態において、本開示の医薬組成物は、イオン性等張化剤を含み、かつ、他の等張化剤、具体的には、例えば、非イオン性等張化剤を含まない。 In one embodiment, the pharmaceutical composition of the present disclosure includes an ionic tonicity agent and does not include other tonicity agents, specifically, for example, non-ionic tonicity agents.
　１つの実施形態において、本開示の医薬組成物は、塩化ナトリウムを含み、かつ、他の等張化剤を含まない。 In one embodiment, the pharmaceutical composition of the present disclosure includes sodium chloride and is free of other tonicity agents.
　１つの実施形態において、本開示の医薬組成物は、グリセリンを含み、かつ他の等張化剤を含まない。 In one embodiment, the pharmaceutical composition of the present disclosure comprises glycerin and no other tonicity agents.
　本開示の医薬組成物に含まれ得る等張化剤の含有量は、等張化剤の種類、本開示の医薬組成物の浸透圧等に応じて適宜調整することができるが、例えば、０．０１～５％（ｗ／ｖ）が好ましく、０．１～４％（ｗ／ｖ）がより好ましく、０．５～３％（ｗ／ｖ）がさらに好ましい。 The content of the tonicity agent that may be included in the pharmaceutical composition of the present disclosure can be adjusted as appropriate depending on the type of tonicity agent, the osmotic pressure of the pharmaceutical composition of the present disclosure, etc. 0.01 to 5% (w/v) is preferred, 0.1 to 4% (w/v) is more preferred, and 0.5 to 3% (w/v) is even more preferred.
　本開示の医薬組成物に含まれ得る塩化ナトリウムの含有量は、本開示の医薬組成物の浸透圧等に応じて調整され得るが、例えば０．０１～２％（ｗ／ｖ）であり、好ましくは、０．０３～１．６％（ｗ／ｖ）であり、より好ましくは０．０５～１．４％（ｗ／ｖ）であり、さらに好ましくは０．１～１．２％（ｗ／ｖ）であり、特に好ましくは０．２～１．１％（ｗ／ｖ）であり、最も好ましくは０．３～１％（ｗ／ｖ）である。
　塩化ナトリウムの含有量の下限値は、０．０１％（ｗ／ｖ）が好ましく、０．０３％（ｗ／ｖ）がより好ましく、０．０５％（ｗ／ｖ）がさらに好ましく、０．１％（ｗ／ｖ）がさらにより好ましく、０．２％（ｗ／ｖ）が特に好ましく、０．３％（ｗ／ｖ）が最も好ましい。
　塩化ナトリウムの含有量の上限値は、２％（ｗ／ｖ）が好ましく、１．６％（ｗ／ｖ）がより好ましく、１．４％（ｗ／ｖ）がさらに好ましく、１．２％（ｗ／ｖ）がさらにより好ましく、１．１％（ｗ／ｖ）が特に好ましく、１％（ｗ／ｖ）が最も好ましい。
　塩化ナトリウムの含有量の好ましい範囲は、上記の上限値と下限値の組合せにより示され得る。 The content of sodium chloride that may be included in the pharmaceutical composition of the present disclosure may be adjusted depending on the osmotic pressure of the pharmaceutical composition of the present disclosure, and is, for example, 0.01 to 2% (w/v), Preferably, it is 0.03 to 1.6% (w/v), more preferably 0.05 to 1.4% (w/v), and still more preferably 0.1 to 1.2% ( w/v), particularly preferably from 0.2 to 1.1% (w/v), most preferably from 0.3 to 1% (w/v).
The lower limit of the content of sodium chloride is preferably 0.01% (w/v), more preferably 0.03% (w/v), even more preferably 0.05% (w/v), and 0.01% (w/v) is more preferable. Even more preferred is 1% (w/v), particularly preferred is 0.2% (w/v), and most preferred is 0.3% (w/v).
The upper limit of the content of sodium chloride is preferably 2% (w/v), more preferably 1.6% (w/v), even more preferably 1.4% (w/v), and even more preferably 1.2%. (w/v) is even more preferred, 1.1% (w/v) is particularly preferred, and 1% (w/v) is most preferred.
A preferred range of the content of sodium chloride can be indicated by a combination of the above upper and lower limits.
　本開示の医薬組成物に含まれ得るグリセリンの含有量は、本開示の医薬組成物の浸透圧等に応じて調整され得るが、例えば０．１～５％（ｗ／ｖ）であり、好ましくは、０．２～４％（ｗ／ｖ）であり、より好ましくは０．３～３．５％（ｗ／ｖ）であり、さらに好ましくは０．４～３％（ｗ／ｖ）であり、特に好ましくは０．５～２．５％（ｗ／ｖ）であり、最も好ましくは１～２％（ｗ／ｖ）である。
　グリセリンの含有量の下限値は、０．１％（ｗ／ｖ）が好ましく、０．２％（ｗ／ｖ）がより好ましく、０．３％（ｗ／ｖ）がさらに好ましく、０．４％（ｗ／ｖ）がさらにより好ましく、０．５％（ｗ／ｖ）が特に好ましく、１％（ｗ／ｖ）が最も好ましい。
　グリセリンの含有量の上限値は、５％（ｗ／ｖ）が好ましく、４％（ｗ／ｖ）がより好ましく、３．５％（ｗ／ｖ）がさらに好ましく、３％（ｗ／ｖ）がさらにより好ましく、２．５％（ｗ／ｖ）が特に好ましく、２％（ｗ／ｖ）が最も好ましい。
　グリセリンの含有量の好ましい範囲は、上記の上限値と下限値の組合せにより示され得る。 The content of glycerin that can be contained in the pharmaceutical composition of the present disclosure can be adjusted depending on the osmotic pressure of the pharmaceutical composition of the present disclosure, and is preferably 0.1 to 5% (w/v), for example. is 0.2 to 4% (w/v), more preferably 0.3 to 3.5% (w/v), and even more preferably 0.4 to 3% (w/v). It is particularly preferably 0.5 to 2.5% (w/v), most preferably 1 to 2% (w/v).
The lower limit of the glycerin content is preferably 0.1% (w/v), more preferably 0.2% (w/v), even more preferably 0.3% (w/v), and 0.4% (w/v). % (w/v) is even more preferred, 0.5% (w/v) is particularly preferred and 1% (w/v) is most preferred.
The upper limit of the glycerin content is preferably 5% (w/v), more preferably 4% (w/v), even more preferably 3.5% (w/v), and 3% (w/v) is even more preferred, 2.5% (w/v) is particularly preferred, and 2% (w/v) is most preferred.
A preferred range of the glycerin content can be indicated by a combination of the above upper and lower limits.
　本開示の医薬組成物には、基剤として水を含有する。その量は特に限定されず、他の成分の量に従って調整して使用することができる。添加される水のグレードは医薬的に許容されるものであれば特に限定されない。例えば精製水が挙げられる。 The pharmaceutical composition of the present disclosure contains water as a base. The amount thereof is not particularly limited and can be adjusted according to the amounts of other components. The grade of water added is not particularly limited as long as it is pharmaceutically acceptable. An example is purified water.
　一つの実施形態において、本開示の医薬組成物は、水以外の基剤をさらに含む。１種単独で用いてもよく、２種以上の基剤を組み合わせて使用してもよい。
　一つの実施形態において、本開示の医薬組成物は、水以外の基剤を含まない。 In one embodiment, the pharmaceutical composition of the present disclosure further comprises a base other than water. One type of base may be used alone, or two or more types of bases may be used in combination.
In one embodiment, the pharmaceutical composition of the present disclosure does not contain a base other than water.
　本開示において、水以外の基剤は、医薬品の添加物として使用可能な基剤であれば特に制限はない。
　水以外の基剤の含有量は、本開示の医薬組成物の浸透圧に応じて調整され得るが、例えば１～５０％（ｗ／ｖ）であり、好ましくは、２～４０％（ｗ／ｖ）であり、より好ましくは３～３０％（ｗ／ｖ）である。２種以上の水以外の基剤が含まれる場合、これら水以外の基剤の含有量は、水以外の基剤の合計の含有量とし得る。 In the present disclosure, the base other than water is not particularly limited as long as it can be used as an additive for pharmaceuticals.
The content of the base other than water can be adjusted depending on the osmotic pressure of the pharmaceutical composition of the present disclosure, but is, for example, 1 to 50% (w/v), preferably 2 to 40% (w/v). v), more preferably 3 to 30% (w/v). When two or more types of bases other than water are included, the content of these bases other than water may be the total content of the bases other than water.
　本開示の医薬組成物のｐＨは特に限定されないが、好ましくは８．０以上であり、さらに好ましくは８．１～９．５であり、より好ましくは８．２～９．３であり、さらに好ましくは８．３～９．３であり、さらにより好ましくは８．４～９．３であり、特に好ましくは８．４～９．１であり、最も好ましくは８．４～９．０である。 The pH of the pharmaceutical composition of the present disclosure is not particularly limited, but is preferably 8.0 or higher, more preferably 8.1 to 9.5, more preferably 8.2 to 9.3, and It is preferably 8.3 to 9.3, even more preferably 8.4 to 9.3, particularly preferably 8.4 to 9.1, and most preferably 8.4 to 9.0. be.
　本開示の医薬組成物のｐＨの調整方法は特に限定されず、例えば、医薬品の添加物として使用可能なｐＨ調整剤を適宜配合することができる。ｐＨ調整剤の例としては、塩酸、水酸化ナトリウム、水酸化カリウム等が挙げられる。ｐＨ調整剤の好ましい例として、塩酸および水酸化ナトリウムが挙げられる。
　本発明の医薬組成物にｐＨ調整剤を配合する場合のｐＨ調整剤の含有量は、ｐＨ調整剤の種類などにより適宜調整することができるが、０．００１～５％（ｗ／ｖ）が好ましく、０．０１～１％（ｗ／ｖ）がより好ましく、０．１～０．５％（ｗ／ｖ）がさらに好ましい。 The method for adjusting the pH of the pharmaceutical composition of the present disclosure is not particularly limited, and for example, a pH adjuster that can be used as an additive for pharmaceuticals can be appropriately blended. Examples of pH adjusters include hydrochloric acid, sodium hydroxide, potassium hydroxide, and the like. Preferred examples of pH adjusters include hydrochloric acid and sodium hydroxide.
When a pH adjuster is added to the pharmaceutical composition of the present invention, the content of the pH adjuster can be adjusted as appropriate depending on the type of pH adjuster, but 0.001 to 5% (w/v) is preferable. It is preferably 0.01 to 1% (w/v), more preferably 0.1 to 0.5% (w/v).
　本開示の医薬組成物の形態については、基剤として水を含有する組成物の形態であれば特に限定されない。ペースト、ムース、ジェル、溶液、乳液、懸濁液、クリームを例示することができる。 The form of the pharmaceutical composition of the present disclosure is not particularly limited as long as it is a composition containing water as a base. Examples include paste, mousse, gel, solution, emulsion, suspension, and cream.
　１つの実施形態において、本開示の医薬組成物の形態は、溶液である。
　本開示において、「溶液」とは、目視で観察したときに、澄明または透明な液体を意味する。ウルソデオキシコール酸は水にほとんど溶けないことが知られるが、医薬組成物のｐＨをアルカリ性にすることで、ウルソデオキシコール酸は溶解し得る。 In one embodiment, the form of the pharmaceutical composition of the present disclosure is a solution.
In this disclosure, "solution" means a clear or transparent liquid when visually observed. Although ursodeoxycholic acid is known to be almost insoluble in water, ursodeoxycholic acid can be dissolved by making the pH of the pharmaceutical composition alkaline.
　本発明の医薬組成物には、必要に応じてさらに他の添加剤を用いることができる。
当該他の添加剤は医薬的に許容される添加剤であれば、特に限定されず、投与経路、剤形等に従って適宜選択され得る。
　当該他の添加物の例としては、例えば、防腐剤、界面活性剤、安定化剤、抗酸化剤、高分子量重合体等が挙げられる。 Other additives may be used in the pharmaceutical composition of the present invention, if necessary.
The other additives are not particularly limited as long as they are pharmaceutically acceptable additives, and may be appropriately selected according to the route of administration, dosage form, etc.
Examples of such other additives include preservatives, surfactants, stabilizers, antioxidants, high molecular weight polymers, and the like.
　防腐剤の含有量は防腐剤の種類などにより適宜調整することができるが、例えば、０．０００１～３．５％（ｗ／ｖ）であり、０．００１～２％（ｗ／ｖ）が好ましく、０．００３～１．５％（ｗ／ｖ）がより好ましく、０．００４～１．２％（ｗ／ｖ）がさらにより好ましく、０．００５～１％（ｗ／ｖ）が特に好ましく、０．００６～０．８％（ｗ／ｖ）が特により好ましく、０．００６７５～０．６％（ｗ／ｖ）が特にさらに好ましく、０．００７５～０．５％（ｗ／ｖ）がさらにより好ましい。防腐剤は１種単独で用いてもよく、２種以上の成分を任意に組み合わせて使用してもよい。２種以上の防腐剤が含まれる場合、これら防腐剤の含有量は、防腐剤の合計の含有量を示す。 The content of the preservative can be adjusted appropriately depending on the type of preservative, etc., but for example, it is 0.0001 to 3.5% (w/v), and 0.001 to 2% (w/v) is Preferably, 0.003 to 1.5% (w/v), more preferably 0.004 to 1.2% (w/v), even more preferably 0.005 to 1% (w/v), particularly Preferably, 0.006 to 0.8% (w/v) is particularly more preferable, 0.00675 to 0.6% (w/v) is particularly more preferable, 0.0075 to 0.5% (w/v) ) is even more preferred. One type of preservative may be used alone, or two or more types of preservatives may be used in any combination. When two or more types of preservatives are included, the content of these preservatives indicates the total content of the preservatives.
　界面活性剤の含有量は界面活性剤の種類などにより適宜調整することができるが、例えば、０．０１～１％（ｗ／ｖ）である。界面活性剤は１種単独で用いてもよく、２種以上の成分を任意に組み合わせて使用してもよい。２種以上の界面活性剤が含まれる場合、これら界面活性剤の含有量は、界面活性剤の合計の含有量を示す。 The content of the surfactant can be adjusted as appropriate depending on the type of surfactant, and is, for example, 0.01 to 1% (w/v). One type of surfactant may be used alone, or two or more types of surfactants may be used in any combination. When two or more types of surfactants are included, the content of these surfactants indicates the total content of the surfactants.
　安定化剤の含有量は安定化剤の種類などにより適宜調整することができるが、例えば、０．００１～１０％（ｗ／ｖ）であり、０．０１～５％（ｗ／ｖ）が好ましく、０．０５～３％（ｗ／ｖ）がより好ましく、０．１～２％（ｗ／ｖ）がさらに好ましい。安定化剤は１種単独で用いてもよく、２種以上の成分を任意に組み合わせて使用してもよい。２種以上の安定化剤が含まれる場合、これら安定化剤の含有量は、安定化剤の合計の含有量を示す。 The content of the stabilizer can be adjusted as appropriate depending on the type of stabilizer, but for example, it is 0.001 to 10% (w/v), and 0.01 to 5% (w/v) is It is preferably 0.05 to 3% (w/v), more preferably 0.1 to 2% (w/v). One type of stabilizer may be used alone, or two or more types of stabilizers may be used in any combination. When two or more types of stabilizers are included, the content of these stabilizers indicates the total content of the stabilizers.
　抗酸化剤の含有量は抗酸化剤の種類などにより適宜調整することができるが、例えば、０．０００１～１％（ｗ／ｖ）であり、０．０００５～０．１％（ｗ／ｖ）が好ましく、０．００１～０．０２％（ｗ／ｖ）がより好ましく、０．００５～０．０１０％（ｗ／ｖ）がさらに好ましい。抗酸化剤は１種単独で用いてもよく、２種以上の成分を任意に組み合わせて使用してもよい。２種以上の抗酸化剤が含まれる場合、これら抗酸化剤の含有量は、抗酸化剤の合計の含有量を示す。 The content of the antioxidant can be adjusted as appropriate depending on the type of antioxidant, but for example, it is 0.0001 to 1% (w/v), and 0.0005 to 0.1% (w/v). ) is preferred, 0.001 to 0.02% (w/v) is more preferred, and 0.005 to 0.010% (w/v) is even more preferred. One type of antioxidant may be used alone, or two or more types of antioxidants may be used in any combination. When two or more types of antioxidants are included, the content of these antioxidants indicates the total content of antioxidants.
　高分子量重合体の含有量は高分子量重合体の種類などにより適宜調整することができるが、０．００１～５％（ｗ／ｖ）が好ましく、０．０１～１％（ｗ／ｖ）がより好ましく、０．１～０．５％（ｗ／ｖ）が最も好ましい。高分子量重合体は１種単独で用いてもよく、２種以上の成分を任意に組み合わせて使用してもよい。２種以上の高分子量重合体が含まれる場合、これら高分子量重合体の含有量は、高分子量重合体の合計の含有量を示す。 The content of the high molecular weight polymer can be adjusted appropriately depending on the type of high molecular weight polymer, etc., but it is preferably 0.001 to 5% (w/v), and 0.01 to 1% (w/v). More preferably, 0.1 to 0.5% (w/v) is most preferred. The high molecular weight polymer may be used alone or in any combination of two or more components. When two or more types of high molecular weight polymers are included, the content of these high molecular weight polymers indicates the total content of high molecular weight polymers.
　防腐剤の例として、
　ベンザルコニウムハロゲン化物（ベンザルコニウム塩化物、ベンザルコニウム臭化物）、ベンゼトニウムハロゲン化物（ベンゼトニウム塩化物、ベンゼトニウム臭化物）、クロルヘキシジン、クロルヘキシジングルコン酸塩、ポリクォータニウム－１、ポリヘキサメチレンビグアナイド；
　ホウ酸またはその塩、ソルビン酸、ソルビン酸カリウム、パラオキシ安息香酸メチル、パラオキシ安息香酸プロピル；および
　クロロブタノールが挙げられる。
　ホウ酸またはその塩には、具体的には、ホウ酸、ホウ酸のアルカリ金属塩（テトラホウ酸カリウム、ホウ酸ナトリウム、ホウ酸カリウム、ホウ砂、メタホウ酸カリウム）、ホウ酸のアルカリ土類金属塩（カルシウム塩、マグネシウム塩）、ホウ酸塩の水和物
が挙げられる。 Examples of preservatives include
Benzalkonium halide (benzalkonium chloride, benzalkonium bromide), benzethonium halide (benzethonium chloride, benzethonium bromide), chlorhexidine, chlorhexidine gluconate, polyquaternium-1, polyhexamethylene biguanide;
Examples include boric acid or its salts, sorbic acid, potassium sorbate, methyl paraoxybenzoate, propyl paraoxybenzoate; and chlorobutanol.
Specifically, boric acid or its salts include boric acid, alkali metal salts of boric acid (potassium tetraborate, sodium borate, potassium borate, borax, potassium metaborate), alkaline earth metal boric acids, etc. Examples include salts (calcium salts, magnesium salts), and borate hydrates.
　１つの実施形態において、本開示の医薬組成物は、ベンザルコニウム塩化物を、例えば、０．００５～０．０１％（ｗ／ｖ）の含有量で、ホウ酸を、例えば０．３～０．５％（ｗ／ｖ）の含有量で、ホウ砂を、例えば０．３～１．０％（ｗ／ｖ）の含有量で含まない。１つの実施形態において、本開示の医薬組成物は、ベンザルコニウム塩化物、ホウ酸、ホウ砂を含まない。 In one embodiment, the pharmaceutical composition of the present disclosure comprises benzalkonium chloride in a content of, for example, 0.005 to 0.01% (w/v) and boric acid in a content of, for example, 0.3 to 0.01% (w/v). With a content of 0.5% (w/v), it does not contain borax, for example with a content of 0.3-1.0% (w/v). In one embodiment, the pharmaceutical composition of the present disclosure is free of benzalkonium chloride, boric acid, and borax.
　１つの実施形態において、本開示の医薬組成物は下記の防腐剤を、例えば０．０００１～３．５％（ｗ／ｖ）の含有量で含まない。１つの実施形態において、本開示の医薬組成物は下記の防腐剤を含まない。
　ベンザルコニウムハロゲン化物（ベンザルコニウム塩化物、ベンザルコニウム臭化物）、ベンゼトニウムハロゲン化物（ベンゼトニウム塩化物、ベンゼトニウム臭化物）、クロルヘキシジン、クロルヘキシジングルコン酸塩、ポリクォータニウム－１、ポリヘキサメチレンビグアナイド；
　ホウ酸またはその塩（ホウ酸、ホウ酸のアルカリ金属塩（テトラホウ酸カリウム、ホウ酸ナトリウム、ホウ酸カリウム、ホウ砂、メタホウ酸カリウム）、ホウ酸のアルカリ土類金属塩（カルシウム塩、マグネシウム塩）、ホウ酸塩の水和物）、ソルビン酸、ソルビン酸カリウム、パラオキシ安息香酸メチル、パラオキシ安息香酸プロピル；および
　クロロブタノール In one embodiment, the pharmaceutical composition of the present disclosure is free of preservatives described below, for example in a content of 0.0001 to 3.5% (w/v). In one embodiment, the pharmaceutical compositions of the present disclosure are free of preservatives described below.
Benzalkonium halide (benzalkonium chloride, benzalkonium bromide), benzethonium halide (benzethonium chloride, benzethonium bromide), chlorhexidine, chlorhexidine gluconate, polyquaternium-1, polyhexamethylene biguanide;
Boric acid or its salts (boric acid, alkali metal salts of boric acid (potassium tetraborate, sodium borate, potassium borate, borax, potassium metaborate), alkaline earth metal salts of boric acid (calcium salt, magnesium salt) ), borate hydrate), sorbic acid, potassium sorbate, methyl parabenzoate, propyl parabenzoate; and chlorobutanol
　１つの実施形態において、本開示の医薬組成物は防腐剤を、例えば０．０００１～３．５％（ｗ／ｖ）の含有量で含まない。１つの実施形態において、本開示の医薬組成物は防腐剤を含まない。ここで防腐剤とは医薬品の防腐剤として使用可能な防腐剤を意味する。 In one embodiment, the pharmaceutical composition of the present disclosure is free of preservatives, for example in a content of 0.0001-3.5% (w/v). In one embodiment, the pharmaceutical compositions of the present disclosure are free of preservatives. The preservative used herein means a preservative that can be used as a preservative for pharmaceuticals.
　界面活性剤の例として、ポリオキシエチレンヒマシ油、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンソルビタン脂肪酸エステル、ビタミンＥ　ＴＰＧＳ、ポリオキシエチレン脂肪酸エステル、ポリオキシエチレンポリオキシプロピレングリコール、ショ糖脂肪酸エステル等が挙げられる。
　１つの実施形態において、本開示の医薬組成物は界面活性剤を含まない。 Examples of surfactants include polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, vitamin E TPGS, polyoxyethylene fatty acid ester, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid ester, etc. can be mentioned.
In one embodiment, the pharmaceutical compositions of the present disclosure are free of surfactants.
　安定化剤の例として、エデト酸、エデト酸ナトリウム等が挙げられる。
　１つの実施形態において、本開示の医薬組成物は安定化剤を含まない。 Examples of stabilizers include edetic acid, sodium edetate, and the like.
In one embodiment, the pharmaceutical compositions of the present disclosure are free of stabilizers.
　抗酸化剤の例としては、トコフェノール、ジブチルヒドロキシトルエン、ブチルヒドロキシアニソール、エリソルビン酸ナトリウム、没食子酸プロピル、亜硫酸ナトリウム等が挙げられる。
　１つの実施形態において、本開示の医薬組成物は抗酸化剤を含まない。 Examples of antioxidants include tocophenol, dibutylated hydroxytoluene, butylated hydroxyanisole, sodium erythorbate, propyl gallate, sodium sulfite, and the like.
In one embodiment, the pharmaceutical compositions of the present disclosure are free of antioxidants.
　本開示の医薬組成物には、医薬品の添加物として使用可能な高分子量重合体を適宜配合することができる。
　高分子量重合体の例としては、メチルセルロース、エチルセルロース、ヒドロキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシエチルメチルセルロース、ヒドロキシプロピルメチルセルロース（ヒプロメロース）、カルボキシメチルセルロース、カルボキシメチルセルロースナトリウム、ヒドロキシプロピルメチルセルロースアセテートサクシネート、ヒドロキシプロピルメチルセルロースフタレート、カルボキシメチルエチルセルロース、酢酸フタル酸セルロース、ポリビニルピロリドン、ポリビニルアルコール、カルボキシビニルポリマー、ポリエチレングリコール等が挙げられる。
　１つの実施形態において、本開示の医薬組成物は高分子量重合体を含まない。 The pharmaceutical composition of the present disclosure may appropriately contain a high molecular weight polymer that can be used as an additive for pharmaceuticals.
Examples of high molecular weight polymers include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose (hypromellose), carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropyl Examples include methylcellulose phthalate, carboxymethylethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, polyethylene glycol, and the like.
In one embodiment, the pharmaceutical compositions of the present disclosure are free of high molecular weight polymers.
　１つの実施形態において、本開示の医薬組成物は、マルトデキストリン、ヒドロキシプロピル-β-シクロデキストリンなどの水可溶性澱粉転化物を含まない。
　１つの実施形態において、本開示の医薬組成物は、マルトデキストリンを含まない。
　１つの実施形態において、本開示の医薬組成物は、ヒドロキシプロピル-β-シクロデキストリンを含まない。 In one embodiment, the pharmaceutical compositions of the present disclosure are free of water-soluble starch conversion products such as maltodextrin, hydroxypropyl-β-cyclodextrin.
In one embodiment, the pharmaceutical composition of the present disclosure is maltodextrin-free.
In one embodiment, the pharmaceutical composition of the present disclosure does not include hydroxypropyl-β-cyclodextrin.
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．０００１～３％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．０１～３％（ｗ／ｖ）、
　塩化ナトリウム　０．０１～２％（ｗ／ｖ）および／またはグリセリン　０．１～５％（ｗ／ｖ）、および
　水
からなる医薬組成物であって、
　さらに任意にｐＨ調整剤を含んでいてもよく、
　該医薬組成物の浸透圧は５０～４００ｍＯｓｍ／Ｌである。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.0001-3% (w/v),
Trometamol or its salt 0.01-3% (w/v),
A pharmaceutical composition comprising 0.01-2% (w/v) sodium chloride and/or 0.1-5% (w/v) glycerin, and water,
Furthermore, it may optionally contain a pH adjuster,
The osmotic pressure of the pharmaceutical composition is 50 to 400 mOsm/L.
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．０００１～３％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．０１～３％（ｗ／ｖ）、
　塩化ナトリウム　０．０１～２％（ｗ／ｖ）、および
　水
からなる医薬組成物であって、
　さらに任意にｐＨ調整剤を含んでいてもよく、
　該医薬組成物の浸透圧は５０～４００ｍＯｓｍ／Ｌである。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.0001-3% (w/v),
Trometamol or its salt 0.01-3% (w/v),
A pharmaceutical composition comprising 0.01-2% (w/v) sodium chloride and water, the composition comprising:
Furthermore, it may optionally contain a pH adjuster,
The osmotic pressure of the pharmaceutical composition is 50 to 400 mOsm/L.
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．０００１～３％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．０１～３％（ｗ／ｖ）、
　グリセリン　０．１～５％（ｗ／ｖ）、および
　水
からなる医薬組成物であって、
　さらに任意にｐＨ調整剤を含んでいてもよく、
　該医薬組成物の浸透圧は５０～４００ｍＯｓｍ／Ｌである。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.0001-3% (w/v),
Trometamol or its salt 0.01-3% (w/v),
A pharmaceutical composition comprising 0.1 to 5% (w/v) glycerin and water, the composition comprising:
Furthermore, it may optionally contain a pH adjuster,
The osmotic pressure of the pharmaceutical composition is 50 to 400 mOsm/L.
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．０７～０．３５％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．３～０．７％（ｗ／ｖ）、
　塩化ナトリウム　０．２～１．１％（ｗ／ｖ）および／またはグリセリン　０．５～２．５％（ｗ／ｖ）、および
　水
からなる医薬組成物であって、
　さらに任意に塩酸および／または水酸化ナトリウムを含んでいてもよく、
　該医薬組成物の浸透圧は２２０～３３０ｍＯｓｍ／Ｌである。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.07-0.35% (w/v),
Trometamol or its salt 0.3-0.7% (w/v),
A pharmaceutical composition consisting of 0.2-1.1% (w/v) sodium chloride and/or 0.5-2.5% (w/v) glycerin, and water,
Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
The osmotic pressure of the pharmaceutical composition is 220-330 mOsm/L.
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．０７～０．３５％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．３～０．７％（ｗ／ｖ）、
　塩化ナトリウム　０．２～１．１％（ｗ／ｖ）、および
　水
からなる医薬組成物であって、
　さらに任意に塩酸および／または水酸化ナトリウムを含んでいてもよく、
　該医薬組成物の浸透圧は２２０～３３０ｍＯｓｍ／Ｌである。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.07-0.35% (w/v),
Trometamol or its salt 0.3-0.7% (w/v),
A pharmaceutical composition comprising 0.2-1.1% (w/v) sodium chloride and water, the composition comprising:
Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
The osmotic pressure of the pharmaceutical composition is 220-330 mOsm/L.
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．０７～０．３５％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．３～０．７％（ｗ／ｖ）、
　グリセリン　０．５～２．５％（ｗ／ｖ）、および
　水
からなる医薬組成物であって、
　さらに任意に塩酸および／または水酸化ナトリウムを含んでいてもよく、
　該医薬組成物の浸透圧は２２０～３３０ｍＯｓｍ／Ｌである。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.07-0.35% (w/v),
Trometamol or its salt 0.3-0.7% (w/v),
A pharmaceutical composition comprising 0.5-2.5% (w/v) glycerin and water, the composition comprising:
Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
The osmotic pressure of the pharmaceutical composition is 220-330 mOsm/L.
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．０７～０．３５％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．１～２％（ｗ／ｖ）、
　塩化ナトリウム　０．２～１．１％（ｗ／ｖ）および／またはグリセリン　０．５～２．５％（ｗ／ｖ）、および
　水
からなる医薬組成物であって、
　さらに任意に塩酸および／または水酸化ナトリウムを含んでいてもよく、
　該医薬組成物の浸透圧は２２０～３３０ｍＯｓｍ／Ｌである。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.07-0.35% (w/v),
Trometamol or its salt 0.1-2% (w/v),
A pharmaceutical composition consisting of 0.2-1.1% (w/v) sodium chloride and/or 0.5-2.5% (w/v) glycerin, and water,
Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
The osmotic pressure of the pharmaceutical composition is 220-330 mOsm/L.
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．０７～０．６％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．３～０．７％（ｗ／ｖ）、
　塩化ナトリウム　０．２～１．１％（ｗ／ｖ）および／またはグリセリン　０．５～２．５％（ｗ／ｖ）、および
　水
からなる医薬組成物であって、
　さらに任意に塩酸および／または水酸化ナトリウムを含んでいてもよく、
　該医薬組成物の浸透圧は２２０～３３０ｍＯｓｍ／Ｌである。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.07-0.6% (w/v),
Trometamol or its salt 0.3-0.7% (w/v),
A pharmaceutical composition consisting of 0.2-1.1% (w/v) sodium chloride and/or 0.5-2.5% (w/v) glycerin, and water,
Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
The osmotic pressure of the pharmaceutical composition is 220-330 mOsm/L.
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．０７～０．６％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．３～０．７％（ｗ／ｖ）、
　塩化ナトリウム　０．２～１．１％（ｗ／ｖ）、および
　水
からなる医薬組成物であって、
　さらに任意に塩酸および／または水酸化ナトリウムを含んでいてもよく、
　該医薬組成物の浸透圧は２２０～３３０ｍＯｓｍ／Ｌである。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.07-0.6% (w/v),
Trometamol or its salt 0.3-0.7% (w/v),
A pharmaceutical composition comprising 0.2-1.1% (w/v) sodium chloride and water, the composition comprising:
Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
The osmotic pressure of the pharmaceutical composition is 220-330 mOsm/L.
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．０７～０．６％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．３～０．７％（ｗ／ｖ）、
　グリセリン　０．５～２．５％（ｗ／ｖ）、および
　水
からなる医薬組成物であって、
　さらに任意に塩酸および／または水酸化ナトリウムを含んでいてもよく、
　該医薬組成物の浸透圧は２２０～３３０ｍＯｓｍ／Ｌである。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.07-0.6% (w/v),
Trometamol or its salt 0.3-0.7% (w/v),
A pharmaceutical composition comprising 0.5-2.5% (w/v) glycerin and water, the composition comprising:
Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
The osmotic pressure of the pharmaceutical composition is 220-330 mOsm/L.
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．０７～０．６％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．１～２％（ｗ／ｖ）、
　塩化ナトリウム　０．２～１．１％（ｗ／ｖ）および／またはグリセリン　０．５～２．５％（ｗ／ｖ）、および
　水
からなる医薬組成物であって、
　さらに任意に塩酸および／または水酸化ナトリウムを含んでいてもよく、
　該医薬組成物の浸透圧は２２０～３３０ｍＯｓｍ／Ｌである。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.07-0.6% (w/v),
Trometamol or its salt 0.1-2% (w/v),
A pharmaceutical composition consisting of 0.2-1.1% (w/v) sodium chloride and/or 0.5-2.5% (w/v) glycerin, and water,
Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
The osmotic pressure of the pharmaceutical composition is 220-330 mOsm/L.
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．０７～１％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．３～０．７％（ｗ／ｖ）、
　塩化ナトリウム　０．２～１．１％（ｗ／ｖ）および／またはグリセリン　０．５～２．５％（ｗ／ｖ）、および
　水
からなる医薬組成物であって、
　さらに任意に塩酸および／または水酸化ナトリウムを含んでいてもよく、
　該医薬組成物の浸透圧は２２０～３３０ｍＯｓｍ／Ｌである。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.07-1% (w/v),
Trometamol or its salt 0.3-0.7% (w/v),
A pharmaceutical composition consisting of 0.2-1.1% (w/v) sodium chloride and/or 0.5-2.5% (w/v) glycerin, and water,
Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
The osmotic pressure of the pharmaceutical composition is 220-330 mOsm/L.
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．０７～１％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．３～０．７％（ｗ／ｖ）、
　塩化ナトリウム　０．２～１．１％（ｗ／ｖ）、および
　水
からなる医薬組成物であって、
　さらに任意に塩酸および／または水酸化ナトリウムを含んでいてもよく、
　該医薬組成物の浸透圧は２２０～３３０ｍＯｓｍ／Ｌである。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.07-1% (w/v),
Trometamol or its salt 0.3-0.7% (w/v),
A pharmaceutical composition comprising 0.2-1.1% (w/v) sodium chloride and water, the composition comprising:
Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
The osmotic pressure of the pharmaceutical composition is 220-330 mOsm/L.
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．０７～１％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．３～０．７％（ｗ／ｖ）、
　グリセリン　０．５～２．５％（ｗ／ｖ）、および
　水
からなる医薬組成物であって、
　さらに任意に塩酸および／または水酸化ナトリウムを含んでいてもよく、
　該医薬組成物の浸透圧は２２０～３３０ｍＯｓｍ／Ｌである。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.07-1% (w/v),
Trometamol or its salt 0.3-0.7% (w/v),
A pharmaceutical composition comprising 0.5-2.5% (w/v) glycerin and water, the composition comprising:
Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
The osmotic pressure of the pharmaceutical composition is 220-330 mOsm/L.
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．０７～１％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．１～２％（ｗ／ｖ）、
　塩化ナトリウム　０．２～１．１％（ｗ／ｖ）および／またはグリセリン　０．５～２．５％（ｗ／ｖ）、および
　水
からなる医薬組成物であって、
　さらに任意に塩酸および／または水酸化ナトリウムを含んでいてもよく、
　該医薬組成物の浸透圧は２２０～３３０ｍＯｓｍ／Ｌである。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.07-1% (w/v),
Trometamol or its salt 0.1-2% (w/v),
A pharmaceutical composition consisting of 0.2-1.1% (w/v) sodium chloride and/or 0.5-2.5% (w/v) glycerin, and water,
Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
The osmotic pressure of the pharmaceutical composition is 220-330 mOsm/L.
　本開示において、所定の成分「からなる」医薬組成物とは、実質的に他の成分を含まない医薬組成物を意味する。
　所定の成分「からなる」医薬組成物が、さらに任意にｐＨ調整剤を含む場合には、当該所定の成分に加えてｐＨ調整剤が添加され得ることを意味する。 In this disclosure, a pharmaceutical composition "consisting of" a given ingredient refers to a pharmaceutical composition that is substantially free of other ingredients.
When a pharmaceutical composition "consisting" of a given ingredient further optionally contains a pH adjuster, it means that the pH adjuster can be added in addition to the given ingredient.
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．０００１～３％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．３～０．７％（ｗ／ｖ）、
　塩化ナトリウム　０．２～１．１％（ｗ／ｖ）および／またはグリセリン　０．５～２．５％（ｗ／ｖ）、および
　水
を含む医薬組成物であって、
　さらに任意にｐＨ調整剤を含んでいてもよく、
　防腐剤を含まず、
　該医薬組成物の浸透圧は２２０～３３０ｍＯｓｍ／Ｌである（医薬組成物Ａという）。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.0001-3% (w/v),
Trometamol or its salt 0.3-0.7% (w/v),
A pharmaceutical composition comprising 0.2-1.1% (w/v) sodium chloride and/or 0.5-2.5% (w/v) glycerin, and water,
Furthermore, it may optionally contain a pH adjuster,
Contains no preservatives
The osmotic pressure of the pharmaceutical composition is 220 to 330 mOsm/L (referred to as pharmaceutical composition A).
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．０００１～３％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．３～０．７％（ｗ／ｖ）、
　塩化ナトリウム　０．２～１．１％（ｗ／ｖ）、および
　水
を含む医薬組成物であって、
　さらに任意にｐＨ調整剤を含んでいてもよく、
　防腐剤を含まず、
　該医薬組成物の浸透圧は２２０～３３０ｍＯｓｍ／Ｌである（医薬組成物Ｂという）。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.0001-3% (w/v),
Trometamol or its salt 0.3-0.7% (w/v),
A pharmaceutical composition comprising 0.2-1.1% (w/v) sodium chloride and water, the composition comprising:
Furthermore, it may optionally contain a pH adjuster,
Contains no preservatives
The osmotic pressure of the pharmaceutical composition is 220 to 330 mOsm/L (referred to as pharmaceutical composition B).
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．０００１～３％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．３～０．７％（ｗ／ｖ）、
　グリセリン　０．５～２．５％（ｗ／ｖ）、および
　水
を含む医薬組成物であって、
　さらに任意にｐＨ調整剤を含んでいてもよく、
　防腐剤を含まず、
　該医薬組成物の浸透圧は２２０～３３０ｍＯｓｍ／Ｌである（医薬組成物Ｃという）。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.0001-3% (w/v),
Trometamol or its salt 0.3-0.7% (w/v),
A pharmaceutical composition comprising 0.5-2.5% (w/v) glycerin and water, the composition comprising:
Furthermore, it may optionally contain a pH adjuster,
Contains no preservatives
The osmotic pressure of the pharmaceutical composition is 220 to 330 mOsm/L (referred to as pharmaceutical composition C).
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．０００１～３％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．３～０．７％（ｗ／ｖ）、
　塩化ナトリウム　０．２～１．１％（ｗ／ｖ）および／またはグリセリン　０．５～２．５％（ｗ／ｖ）、および
　水
からなる医薬組成物であって、
　さらに任意にｐＨ調整剤を含んでいてもよく、
　該医薬組成物の浸透圧は２２０～３３０ｍＯｓｍ／Ｌである（医薬組成物Ｄという）。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.0001-3% (w/v),
Trometamol or its salt 0.3-0.7% (w/v),
A pharmaceutical composition consisting of 0.2-1.1% (w/v) sodium chloride and/or 0.5-2.5% (w/v) glycerin, and water,
Furthermore, it may optionally contain a pH adjuster,
The osmotic pressure of the pharmaceutical composition is 220 to 330 mOsm/L (referred to as pharmaceutical composition D).
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．０００１～３％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．３～０．７％（ｗ／ｖ）、
　塩化ナトリウム　０．２～１．１％（ｗ／ｖ）、および
　水
からなる医薬組成物であって、
　さらに任意にｐＨ調整剤を含んでいてもよく、
　該医薬組成物の浸透圧は２２０～３３０ｍＯｓｍ／Ｌである（医薬組成物Ｅという）。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.0001-3% (w/v),
Trometamol or its salt 0.3-0.7% (w/v),
A pharmaceutical composition comprising 0.2-1.1% (w/v) sodium chloride and water, the composition comprising:
Furthermore, it may optionally contain a pH adjuster,
The osmotic pressure of the pharmaceutical composition is 220 to 330 mOsm/L (referred to as pharmaceutical composition E).
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．０００１～３％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．３～０．７％（ｗ／ｖ）、
　グリセリン　０．５～２．５％（ｗ／ｖ）、および
　水
からなる医薬組成物であって、
　さらに任意にｐＨ調整剤を含んでいてもよく、
　該医薬組成物の浸透圧は２２０～３３０ｍＯｓｍ／Ｌである（医薬組成物Ｆという）。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.0001-3% (w/v),
Trometamol or its salt 0.3-0.7% (w/v),
A pharmaceutical composition comprising 0.5-2.5% (w/v) glycerin and water, the composition comprising:
Furthermore, it may optionally contain a pH adjuster,
The osmotic pressure of the pharmaceutical composition is 220 to 330 mOsm/L (referred to as pharmaceutical composition F).
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．０００１～３％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．１～２％（ｗ／ｖ）、
　塩化ナトリウム　０．２～１．１％（ｗ／ｖ）および／またはグリセリン　０．５～２．５％（ｗ／ｖ）、および
　水
からなる医薬組成物であって、
　さらに任意にｐＨ調整剤を含んでいてもよく、
　該医薬組成物の浸透圧は２２０～３３０ｍＯｓｍ／Ｌである（医薬組成物Ｇという）。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.0001-3% (w/v),
Trometamol or its salt 0.1-2% (w/v),
A pharmaceutical composition consisting of 0.2-1.1% (w/v) sodium chloride and/or 0.5-2.5% (w/v) glycerin, and water,
Furthermore, it may optionally contain a pH adjuster,
The osmotic pressure of the pharmaceutical composition is 220 to 330 mOsm/L (referred to as pharmaceutical composition G).
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．００１～１％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．４～０．６％（ｗ／ｖ）、
　塩化ナトリウム　０．３～１％（ｗ／ｖ）および／またはグリセリン　１～２％（ｗ／ｖ）、および
　水
を含む医薬組成物であって、
　さらに任意に塩酸および／または水酸化ナトリウムを含んでいてもよく、
　防腐剤を含まず、
　該医薬組成物の浸透圧は２５０～３００ｍＯｓｍ／Ｌである（医薬組成物Ｈという）。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.001-1% (w/v),
Trometamol or its salt 0.4-0.6% (w/v),
A pharmaceutical composition comprising 0.3-1% (w/v) sodium chloride and/or 1-2% (w/v) glycerin, and water,
Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
Contains no preservatives
The osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition H).
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．００１～１％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．４～０．６％（ｗ／ｖ）、
　塩化ナトリウム　０．３～１％（ｗ／ｖ）、および
　水
を含む医薬組成物であって、
　さらに任意に塩酸および／または水酸化ナトリウムを含んでいてもよく、
　防腐剤を含まず、
　該医薬組成物の浸透圧は２５０～３００ｍＯｓｍ／Ｌである（医薬組成物Ｉという）。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.001-1% (w/v),
Trometamol or its salt 0.4-0.6% (w/v),
A pharmaceutical composition comprising 0.3-1% (w/v) sodium chloride and water, the composition comprising:
Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
Contains no preservatives
The osmotic pressure of the pharmaceutical composition is 250-300 mOsm/L (referred to as pharmaceutical composition I).
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．００１～１％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．４～０．６％（ｗ／ｖ）、
　グリセリン　１～２％（ｗ／ｖ）、および
　水
を含む医薬組成物であって、
　さらに任意に塩酸および／または水酸化ナトリウムを含んでいてもよく、
　防腐剤を含まず、
　該医薬組成物の浸透圧は２５０～３００ｍＯｓｍ／Ｌである（医薬組成物Ｊという）。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.001-1% (w/v),
Trometamol or its salt 0.4-0.6% (w/v),
A pharmaceutical composition comprising 1-2% (w/v) glycerin and water, the composition comprising:
Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
Contains no preservatives
The osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition J).
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．００１～１％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．４～０．６％（ｗ／ｖ）、
　塩化ナトリウム　０．３～１％（ｗ／ｖ）および／またはグリセリン　１～２％（ｗ／ｖ）、および
　水
からなる医薬組成物であって、
　さらに任意に塩酸および／または水酸化ナトリウムを含んでいてもよく、
　該医薬組成物の浸透圧は２５０～３００ｍＯｓｍ／Ｌである（医薬組成物Ｋという）。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.001-1% (w/v),
Trometamol or its salt 0.4-0.6% (w/v),
A pharmaceutical composition consisting of 0.3-1% (w/v) sodium chloride and/or 1-2% (w/v) glycerin, and water,
Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
The osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition K).
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．００１～１％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．４～０．６％（ｗ／ｖ）、
　塩化ナトリウム　０．３～１％（ｗ／ｖ）、および
　水
からなる医薬組成物であって、
　さらに任意に塩酸および／または水酸化ナトリウムを含んでいてもよく、
　該医薬組成物の浸透圧は２５０～３００ｍＯｓｍ／Ｌである（医薬組成物Ｌという）。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.001-1% (w/v),
Trometamol or its salt 0.4-0.6% (w/v),
A pharmaceutical composition comprising 0.3-1% (w/v) sodium chloride and water, the composition comprising:
Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
The osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition L).
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．００１～１％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．４～０．６％（ｗ／ｖ）、
　グリセリン　１～２％（ｗ／ｖ）、および
　水
からなる医薬組成物であって、
　さらに任意に塩酸および／または水酸化ナトリウムを含んでいてもよく、
　該医薬組成物の浸透圧は２５０～３００ｍＯｓｍ／Ｌである（医薬組成物Ｍという）。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.001-1% (w/v),
Trometamol or its salt 0.4-0.6% (w/v),
A pharmaceutical composition comprising 1-2% (w/v) glycerin and water, the composition comprising:
Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
The osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition M).
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．００１～１％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．１～２％（ｗ／ｖ）、
　塩化ナトリウム　０．３～１％（ｗ／ｖ）および／またはグリセリン　１～２％（ｗ／ｖ）、および
　水
を含む医薬組成物であって、
　さらに任意に塩酸および／または水酸化ナトリウムを含んでいてもよく、
　防腐剤を含まず、
　該医薬組成物の浸透圧は２５０～３００ｍＯｓｍ／Ｌである（医薬組成物Ｎという）。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.001-1% (w/v),
Trometamol or its salt 0.1-2% (w/v),
A pharmaceutical composition comprising 0.3-1% (w/v) sodium chloride and/or 1-2% (w/v) glycerin, and water,
Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
Contains no preservatives
The osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition N).
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．１～０．６％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．４～０．６％（ｗ／ｖ）、
　塩化ナトリウム　０．３～１％（ｗ／ｖ）および／またはグリセリン　１～２％（ｗ／ｖ）、および
　水
を含む医薬組成物であって、
　さらに任意に塩酸および／または水酸化ナトリウムを含んでいてもよく、
　防腐剤を含まず、
　該医薬組成物の浸透圧は２５０～３００ｍＯｓｍ／Ｌである（医薬組成物Ｏという）。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.1-0.6% (w/v),
Trometamol or its salt 0.4-0.6% (w/v),
A pharmaceutical composition comprising 0.3-1% (w/v) sodium chloride and/or 1-2% (w/v) glycerin, and water,
Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
Contains no preservatives
The osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition O).
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．１～０．６％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．４～０．６％（ｗ／ｖ）、
　塩化ナトリウム　０．３～１％（ｗ／ｖ）、および
　水
を含む医薬組成物であって、
　さらに任意に塩酸および／または水酸化ナトリウムを含んでいてもよく、
　防腐剤を含まず、
　該医薬組成物の浸透圧は２５０～３００ｍＯｓｍ／Ｌである（医薬組成物Ｐという）。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.1-0.6% (w/v),
Trometamol or its salt 0.4-0.6% (w/v),
A pharmaceutical composition comprising 0.3-1% (w/v) sodium chloride and water, the composition comprising:
Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
Contains no preservatives
The osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition P).
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．１～０．６％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．４～０．６％（ｗ／ｖ）、
　グリセリン　１～２％（ｗ／ｖ）、および
　水
を含む医薬組成物であって、
　さらに任意に塩酸および／または水酸化ナトリウムを含んでいてもよく、
　防腐剤を含まず、
　該医薬組成物の浸透圧は２５０～３００ｍＯｓｍ／Ｌである（医薬組成物Ｑという）。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.1-0.6% (w/v),
Trometamol or its salt 0.4-0.6% (w/v),
A pharmaceutical composition comprising 1-2% (w/v) glycerin and water, the composition comprising:
Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
Contains no preservatives
The osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition Q).
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．１～０．６％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．４～０．６％（ｗ／ｖ）、
　塩化ナトリウム　０．３～１％（ｗ／ｖ）および／またはグリセリン　１～２％（ｗ／ｖ）、および
　水
からなる医薬組成物であって、
　さらに任意に塩酸および／または水酸化ナトリウムを含んでいてもよく、
　該医薬組成物の浸透圧は２５０～３００ｍＯｓｍ／Ｌである（医薬組成物Ｒという）。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.1-0.6% (w/v),
Trometamol or its salt 0.4-0.6% (w/v),
A pharmaceutical composition consisting of 0.3-1% (w/v) sodium chloride and/or 1-2% (w/v) glycerin, and water,
Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
The osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition R).
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．１～０．６％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．４～０．６％（ｗ／ｖ）、
　塩化ナトリウム　０．３～１％（ｗ／ｖ）、および
　水
からなる医薬組成物であって、
　さらに任意に塩酸および／または水酸化ナトリウムを含んでいてもよく、
　該医薬組成物の浸透圧は２５０～３００ｍＯｓｍ／Ｌである（医薬組成物Ｓという）。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.1-0.6% (w/v),
Trometamol or its salt 0.4-0.6% (w/v),
A pharmaceutical composition comprising 0.3-1% (w/v) sodium chloride and water, the composition comprising:
Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
The osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition S).
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．１～０．６％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．４～０．６％（ｗ／ｖ）、
　グリセリン　１～２％（ｗ／ｖ）、および
　水
からなる医薬組成物であって、
　さらに任意に塩酸および／または水酸化ナトリウムを含んでいてもよく、
　該医薬組成物の浸透圧は２５０～３００ｍＯｓｍ／Ｌである（医薬組成物Ｔという）。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.1-0.6% (w/v),
Trometamol or its salt 0.4-0.6% (w/v),
A pharmaceutical composition comprising 1-2% (w/v) glycerin and water, the composition comprising:
Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
The osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition T).
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．１～０．６％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．１～２％（ｗ／ｖ）、
　塩化ナトリウム　０．３～１％（ｗ／ｖ）および／またはグリセリン　１～２％（ｗ／ｖ）、および
　水
からなる医薬組成物であって、
　さらに任意に塩酸および／または水酸化ナトリウムを含んでいてもよく、
　該医薬組成物の浸透圧は２５０～３００ｍＯｓｍ／Ｌである（医薬組成物Ｕという）。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.1-0.6% (w/v),
Trometamol or its salt 0.1-2% (w/v),
A pharmaceutical composition consisting of 0.3-1% (w/v) sodium chloride and/or 1-2% (w/v) glycerin, and water,
Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
The osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition U).
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．０７～０．３５％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．４～０．６％（ｗ／ｖ）、
　塩化ナトリウム　０．３～１％（ｗ／ｖ）および／またはグリセリン　１～２％（ｗ／ｖ）、および
　水
を含む医薬組成物であって、
　さらに任意に塩酸および／または水酸化ナトリウムを含んでいてもよく、
　防腐剤を含まず、
　該医薬組成物の浸透圧は２５０～３００ｍＯｓｍ／Ｌである（医薬組成物Ｖという）。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.07-0.35% (w/v),
Trometamol or its salt 0.4-0.6% (w/v),
A pharmaceutical composition comprising 0.3-1% (w/v) sodium chloride and/or 1-2% (w/v) glycerin, and water,
Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
Contains no preservatives
The osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition V).
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．０７～０．３５％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．４～０．６％（ｗ／ｖ）、
　塩化ナトリウム　０．３～１％（ｗ／ｖ）、および
　水
を含む医薬組成物であって、
　さらに任意に塩酸および／または水酸化ナトリウムを含んでいてもよく、
　防腐剤を含まず、
　該医薬組成物の浸透圧は２５０～３００ｍＯｓｍ／Ｌである（医薬組成物Wという）。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.07-0.35% (w/v),
Trometamol or its salt 0.4-0.6% (w/v),
A pharmaceutical composition comprising 0.3-1% (w/v) sodium chloride and water, the composition comprising:
Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
Contains no preservatives
The osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition W).
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．０７～０．３５％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．４～０．６％（ｗ／ｖ）、
　グリセリン　１～２％（ｗ／ｖ）、および
　水
を含む医薬組成物であって、
　さらに任意に塩酸および／または水酸化ナトリウムを含んでいてもよく、
　防腐剤を含まず、
　該医薬組成物の浸透圧は２５０～３００ｍＯｓｍ／Ｌである（医薬組成物Ｘという）。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.07-0.35% (w/v),
Trometamol or its salt 0.4-0.6% (w/v),
A pharmaceutical composition comprising 1-2% (w/v) glycerin and water, the composition comprising:
Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
Contains no preservatives
The osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition X).
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．０７～０．３５％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．４～０．６％（ｗ／ｖ）、
　塩化ナトリウム　０．３～１％（ｗ／ｖ）および／またはグリセリン　１～２％（ｗ／ｖ）、および
　水
からなる医薬組成物であって、
　さらに任意に塩酸および／または水酸化ナトリウムを含んでいてもよく、
　該医薬組成物の浸透圧は２５０～３００ｍＯｓｍ／Ｌである（医薬組成物Ｙという）。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.07-0.35% (w/v),
Trometamol or its salt 0.4-0.6% (w/v),
A pharmaceutical composition consisting of 0.3-1% (w/v) sodium chloride and/or 1-2% (w/v) glycerin, and water,
Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
The osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition Y).
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．０７～０．３５％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．４～０．６％（ｗ／ｖ）、
　塩化ナトリウム　０．３～１％（ｗ／ｖ）、および
　水
からなる医薬組成物であって、
　さらに任意に塩酸および／または水酸化ナトリウムを含んでいてもよく、
　該医薬組成物の浸透圧は２５０～３００ｍＯｓｍ／Ｌである（医薬組成物Ｚという）。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.07-0.35% (w/v),
Trometamol or its salt 0.4-0.6% (w/v),
A pharmaceutical composition comprising 0.3-1% (w/v) sodium chloride and water, the composition comprising:
Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
The osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition Z).
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．０７～０．３５％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．４～０．６％（ｗ／ｖ）、
　グリセリン　１～２％（ｗ／ｖ）、および
　水
からなる医薬組成物であって、
　さらに任意に塩酸および／または水酸化ナトリウムを含んでいてもよく、
　該医薬組成物の浸透圧は２５０～３００ｍＯｓｍ／Ｌである（医薬組成物ＡＡという）。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.07-0.35% (w/v),
Trometamol or its salt 0.4-0.6% (w/v),
A pharmaceutical composition comprising 1-2% (w/v) glycerin and water, the composition comprising:
Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
The osmotic pressure of the pharmaceutical composition is 250 to 300 mOsm/L (referred to as pharmaceutical composition AA).
　１つの実施形態において、本開示の医薬組成物は、
　ウルソデオキシコール酸またはその塩　０．０７～０．３５％（ｗ／ｖ）、
　トロメタモールまたはその塩　０．１～２％（ｗ／ｖ）、
　塩化ナトリウム　０．３～１％（ｗ／ｖ）および／またはグリセリン　１～２％（ｗ／ｖ）、および
　水
を含む医薬組成物であって、
　さらに任意に塩酸および／または水酸化ナトリウムを含んでいてもよく、
　防腐剤を含まず、
　該医薬組成物の浸透圧は２５０～３００ｍＯｓｍ／Ｌである（医薬組成物ＡＢという）。 In one embodiment, the pharmaceutical composition of the present disclosure comprises:
Ursodeoxycholic acid or its salt 0.07-0.35% (w/v),
Trometamol or its salt 0.1-2% (w/v),
A pharmaceutical composition comprising 0.3-1% (w/v) sodium chloride and/or 1-2% (w/v) glycerin, and water,
Furthermore, it may optionally contain hydrochloric acid and/or sodium hydroxide,
Contains no preservatives
The osmotic pressure of the pharmaceutical composition is 250-300 mOsm/L (referred to as pharmaceutical composition AB).
　上記医薬組成物Ａ～ＡＢは、防腐剤を含まないにもかかわらず、先行して開発される防腐剤を含有するマルチドーズ型容器に収容された製品と同等のウルソデオキシコール酸の組織移行性を示すため、先行開発品と医薬として同等な防腐剤不含製品を開発するうえで有用である。上記医薬組成物Ａ～ＡＢは防腐剤を含有しないため、防腐剤を必要としないＰＦＭＤ（Preservative Free Multi Dose）容器または１回使い切りのユニットドーズ型容器（単位容量容器）に充填されるのが望ましい。 Although the above pharmaceutical compositions A to AB do not contain preservatives, the tissue migration properties of ursodeoxycholic acid are equivalent to those of previously developed products contained in multi-dose containers containing preservatives. Therefore, it is useful for developing preservative-free products that are pharmaceutically equivalent to previously developed products. Since the above pharmaceutical compositions A to AB do not contain preservatives, they are preferably filled in PFMD (Preservative Free Multi Dose) containers that do not require preservatives or single-use unit dose containers (unit volume containers). .
　本開示の医薬組成物は、経口または非経口投与することができる。投与経路としては、経口投与、静脈内投与、経皮投与、眼局所投与（例えば、点眼投与、結膜嚢内投与、硝子体内投与、結膜下投与、テノン嚢下投与）などが挙げられ、点眼投与が最も好ましい。 The pharmaceutical composition of the present disclosure can be administered orally or parenterally. Administration routes include oral administration, intravenous administration, transdermal administration, and topical ocular administration (e.g., ophthalmic administration, intraconjunctival sac administration, intravitreal administration, subconjunctival administration, and subtenon's administration). Most preferred.
　本開示の医薬組成物の剤形は、医薬品として使用可能なものであれば特に制限されるものではなく、例えば、点眼剤、眼ゲル剤、注射剤等が挙げられる。本発明の医薬組成物は、特に点眼剤が好ましい。これらは当該技術分野における通常の方法に従って製造することができる。 The dosage form of the pharmaceutical composition of the present disclosure is not particularly limited as long as it can be used as a pharmaceutical, and examples thereof include eye drops, eye gels, injections, and the like. The pharmaceutical composition of the present invention is particularly preferably used as eye drops. These can be manufactured according to conventional methods in the art.
　本開示の医薬組成物は、種々の素材で製造された容器に入れて保存することができる。
　本開示の医薬組成物が点眼剤である場合、その充填容器は特に限定されないが、例えばマルチドーズ型容器、ＰＦＭＤ（Preservative Free Multi Dose）容器または１回使い切りのユニットドーズ型容器（単位容量容器）に充填される。本開示の医薬組成物が防腐剤を含有しない場合には、ユニットドーズ型容器またはＰＦＭＤ容器がより好ましく、ＰＦＭＤ容器がさらに好ましい。なお、容器の素材に特に制限はなく、例えば、ポリエチレン、ポリプロピレン、ポリエチレンテレフタレート、ポリブチレンテレフタレート、ポリプロピレン－ポリエチレンコポリマー、ポリ塩化ビニル、アクリル樹脂、ポリスチレン、ポリ環状オレフィンコポリマー等が挙げられる。さらにポリエチレンは、その密度によって分類され、低密度ポリエチレン（ＬＤＰＥ）、中密度ポリエチレン（ＭＤＰＥ）、高密度ポリエチレン（ＨＤＰＥ）等が挙げられる。 Pharmaceutical compositions of the present disclosure can be stored in containers made of a variety of materials.
When the pharmaceutical composition of the present disclosure is an eye drop, the container for filling it is not particularly limited, but for example, a multi-dose container, a PFMD (Preservative Free Multi Dose) container, or a single-use unit dose container (unit volume container). is filled with. When the pharmaceutical composition of the present disclosure does not contain a preservative, a unit dose container or a PFMD container is more preferred, and a PFMD container is even more preferred. The material of the container is not particularly limited, and examples thereof include polyethylene, polypropylene, polyethylene terephthalate, polybutylene terephthalate, polypropylene-polyethylene copolymer, polyvinyl chloride, acrylic resin, polystyrene, polycyclic olefin copolymer, and the like. Furthermore, polyethylene is classified according to its density, and examples thereof include low density polyethylene (LDPE), medium density polyethylene (MDPE), and high density polyethylene (HDPE).
　本開示において「老視」とは、医師または専門家に用いられる一般的な基準に基づいて老視と判断される症状／疾患を意味する。例えば老視の診断基準として、「両眼検査で近見視力の低下を自覚症状として有しかつ両眼生活視力（日常生活と同じ条件で測定した両眼遠見視力）で４０ｃｍ視力が０．４未満である」（臨床的老視）および／または「自覚症状の有無に関係なく片眼完全矯正下（片眼の矯正視力（少数視力）が１．０以上）で調節力が２．５ジオプター未満である」（医学的老視）が挙げられる。ただし、アコモドメーター等を有さない場合には簡便法として４０ｃｍ視力が０．４未満を用いてもよい。 In the present disclosure, "presbyopia" refers to a symptom/disease that is determined to be presbyopia based on general criteria used by doctors or specialists. For example, the diagnostic criteria for presbyopia is ``a person who has a subjective symptom of decreased near visual acuity in a binocular test, and whose binocular daily visual acuity (binocular distance visual acuity measured under the same conditions as in daily life) has a visual acuity of 40 cm of 0.4. (clinical presbyopia) and/or "accommodative power of 2.5 diopters with one eye fully corrected (corrected visual acuity (minority visual acuity) of one eye of 1.0 or more) regardless of the presence or absence of subjective symptoms" (medical presbyopia). However, if you do not have an acomodometer or the like, you may use a visual acuity of less than 0.4 at 40 cm as a simple method.
　本開示において「水晶体の弾性の低下を伴う眼疾患」とは、眼科分野において水晶体の弾性の低下を伴うと考えられている眼疾患を意味し、例えば老視（例えば加齢による老視）、および薬剤等により誘発された水晶体硬化が挙げられる。 In the present disclosure, "eye disease accompanied by a decrease in the elasticity of the crystalline lens" refers to an eye disease that is considered to be accompanied by a decrease in the elasticity of the crystalline lens in the field of ophthalmology, such as presbyopia (e.g., presbyopia due to aging), and lens hardening induced by drugs and the like.
　本開示において「眼の調節力」とは、遠見時および／または近見時に自動的にピントを合わす眼の機能を意味する。「眼の調節力の低下を伴う眼疾患」とは眼科分野において眼の調節力の低下を伴うと考えられている眼疾患を意味し、例えば老視（例えば加齢による老視）、薬剤等により誘発された水晶体硬化、および長時間の近方視により誘発された調節力低下が挙げられる。 In the present disclosure, "accommodative power of the eye" refers to the ability of the eye to automatically focus when viewing far and/or near. "Eye disease accompanied by a decline in the accommodation power of the eye" means an eye disease that is considered to be accompanied by a decline in the accommodation power of the eye in the field of ophthalmology, such as presbyopia (e.g. presbyopia due to aging), drugs, etc. These include lens stiffness induced by ophthalmopathy, and accommodative loss induced by long-term near vision.
　本開示において、「患者」とは、ヒトのみに限らずその他の動物、例えば、イヌ、ネコ、ウマなども意味する。患者は、好ましくは哺乳動物であり、より好ましくはヒトである。 In the present disclosure, the term "patient" refers not only to humans but also to other animals such as dogs, cats, and horses. The patient is preferably a mammal, more preferably a human.
　本開示において「治療」および「予防」には、疾患を治療することおよび疾患を予防することに加え、疾患の症状を緩和する、疾患の進行を遅らせる、疾患の症状を抑制する、および疾患の症状の改善を誘発することを含み得る。 In this disclosure, "treatment" and "prevention" include not only treating and preventing a disease, but also alleviating the symptoms of a disease, delaying the progression of a disease, suppressing symptoms of a disease, and preventing a disease. May include inducing improvement in symptoms.
　本開示において、「治療および／または予防上の有効量」とは、疾患およびその症状の治療および／または予防効果およびをもたらす量、または疾患およびその症状の進行の遅延をもたらし得る量などを指す。 In the present disclosure, a "therapeutically and/or prophylactically effective amount" refers to an amount that provides a therapeutic and/or preventive effect on a disease and its symptoms, or an amount that can delay the progression of a disease and its symptoms. .
　本開示において、「ウルソデオキシコール酸またはその塩の組織移行性」とは、組織、特に眼組織（例えば、角膜、結膜、ブドウ膜、眼瞼、前房（房水）、毛様体、虹彩、水晶体、硝子体、網膜、脈絡膜等）へのウルソデオキシコール酸またはその塩の移行を意味する。本発明によれば、ウルソデオキシコール酸またはその塩、トロメタモールまたはその塩、および水を含有する医薬組成物において、浸透圧を５０～４００ｍＯｓｍ／Ｌとし、該医薬組成物中のトロメタモールまたはその塩の含有量を０．０１～３％（ｗ／ｖ）とすることにより、ウルソデオキシコール酸またはその塩の組織移行性を向上し得る。ウルソデオキシコール酸またはその塩の組織移行性が向上するとは、例えば、本開示の医薬組成物でない組成物を投与した時と比べてウルソデオキシコール酸またはその塩の組織移行量が増加することを意味し得る。ウルソデオキシコール酸またはその塩の組織移行性は、例えば、本願の試験例１あるいは試験例３の方法により評価され得る。 In the present disclosure, "tissue penetration of ursodeoxycholic acid or its salts" refers to tissues, particularly ocular tissues (e.g., cornea, conjunctiva, uvea, eyelids, anterior chamber (aqueous humor), ciliary body, iris, Refers to the transfer of ursodeoxycholic acid or its salts to the lens, vitreous body, retina, choroid, etc.). According to the present invention, in a pharmaceutical composition containing ursodeoxycholic acid or its salt, trometamol or its salt, and water, the osmotic pressure is set to 50 to 400 mOsm/L, and trometamol or its salt in the pharmaceutical composition is By controlling the content to 0.01 to 3% (w/v), the tissue migration of ursodeoxycholic acid or its salt can be improved. Improving tissue migration of ursodeoxycholic acid or a salt thereof means, for example, that the amount of tissue migration of ursodeoxycholic acid or a salt thereof increases compared to when a composition other than the pharmaceutical composition of the present disclosure is administered. It can mean something. The tissue migration properties of ursodeoxycholic acid or its salts can be evaluated, for example, by the method of Test Example 1 or Test Example 3 of the present application.
　本開示において、「医薬組成物の防腐効力」とは、医薬組成物中に微生物が混入しても微生物が増殖しない、又は、増殖しにくいことであり、医薬組成物の保存効力ともいう。本発明によれば、ウルソデオキシコール酸またはその塩、トロメタモールまたはその塩、および水を含有する医薬組成物において、該医薬組成物中にイオン性等張化剤を加えることにより、該医薬組成物の防腐効力が向上し得る。イオン性等張化剤としては、塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム等が挙げられ、塩化ナトリウムが好ましい。医薬組成物の防腐効力が向上するとは、例えば、ウルソデオキシコール酸またはその塩、トロメタモールまたはその塩、および水を含有する医薬組成物において、イオン性等張化剤を加える前の医薬組成物に比べて、イオン性等張化剤を加えた後の医薬組成物の方が微生物の増殖が抑制されることを意味し得る。医薬組成物の防腐効力は、例えば、日本薬局方などの規格試験のほか、本願の試験例４の方法により評価され得る。試験に用いる微生物は、細菌、酵母、カビ等が挙げられ、特に、Cladosporium Cladosporioidesが好ましい。 In the present disclosure, the "preservative efficacy of a pharmaceutical composition" refers to the fact that microorganisms do not proliferate or are difficult to proliferate even if microorganisms are mixed into the pharmaceutical composition, and is also referred to as the preservative efficacy of the pharmaceutical composition. According to the present invention, in a pharmaceutical composition containing ursodeoxycholic acid or a salt thereof, trometamol or a salt thereof, and water, by adding an ionic tonicity agent to the pharmaceutical composition, the pharmaceutical composition The preservative efficacy of can be improved. Examples of the ionic tonicity agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and the like, with sodium chloride being preferred. Improving the preservative efficacy of a pharmaceutical composition means, for example, in a pharmaceutical composition containing ursodeoxycholic acid or a salt thereof, trometamol or a salt thereof, and water, if the preservative efficacy of the pharmaceutical composition is improved before the ionic tonicity agent is added. In comparison, it may mean that microbial growth is more inhibited in the pharmaceutical composition after adding the ionic tonicity agent. The preservative efficacy of a pharmaceutical composition can be evaluated, for example, by the method of Test Example 4 of the present application, in addition to the standard test such as the Japanese Pharmacopoeia. Microorganisms used in the test include bacteria, yeast, mold, etc., with Cladosporium Cladosporioides being particularly preferred.
　本開示において、「ｐＨの低下を抑制」や「ｐＨを安定化」とは、一定期間の保存によって医薬組成物のｐＨの低下が少ない又は無いことを意味する。例えば、４０℃で１ヵ月保存したときにｐＨの低下が０．１４以下、好ましくは０．１以下、より好ましくは０．０７以下、さらに好ましくは０．０５以下、特に好ましくは０．０２以下である場合が挙げられる。 In the present disclosure, "suppressing the decrease in pH" and "stabilizing the pH" mean that there is little or no decrease in the pH of the pharmaceutical composition after storage for a certain period of time. For example, when stored at 40°C for one month, the pH decrease is 0.14 or less, preferably 0.1 or less, more preferably 0.07 or less, even more preferably 0.05 or less, particularly preferably 0.02 or less. One example is the case where
　本開示の医薬組成物の詳細な説明は、本明細書に開示する方法の態様等、他の態様にも適用され得る。 The detailed description of the pharmaceutical compositions of the present disclosure may also be applied to other embodiments, such as embodiments of the methods disclosed herein.
　以下に製剤例および試験例を示すが、これらは本発明をより良く理解するためのものであり、本発明の範囲を限定するものではない。 Formulation examples and test examples are shown below, but these are for better understanding of the present invention and are not intended to limit the scope of the present invention.
製剤例
　以下に本発明の医薬組成物を用いた代表的な製剤例を示す。なお、下記製剤例において各成分の配合量は組成物１００ｍＬ中の含量である。 Formulation Examples Typical formulation examples using the pharmaceutical composition of the present invention are shown below. In addition, in the following formulation examples, the amount of each component is the content in 100 mL of the composition.
［製剤例１］
　点眼剤・溶液　（１００ｍＬ中）　ｐＨ　８．７
　　ウルソデオキシコール酸　　　　０．１ｇ
　　ベンザルコニウム塩化物　　　　０．０１ｇ
　　ポリソルベート８０　　　　　　０．１ｇ
　　ホウ酸　　　　　　　　　　　　０．５ｇ
　　トロメタモール　　　　　　　　０．５ｇ
　　グリセリン　　　　　　　　　　２．５ｇ
　　希塩酸　　　　　　　　　　　　　　適量
　　水酸化ナトリウム　　　　　　　　　適量
　　精製水　　　　　　　　　　　　　　適量
　　浸透圧　　２２０～３３０ｍＯｓｍ／Ｌ [Formulation example 1]
Eye drops/solution (in 100mL) pH 8.7
Ursodeoxycholic acid 0.1g
Benzalkonium chloride 0.01g
Polysorbate 80 0.1g
Boric acid 0.5g
Trometamol 0.5g
Glycerin 2.5g
Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount) Osmotic pressure 220-330mOsm/L
［製剤例２］
　点眼剤・溶液　（１００ｍＬ中）　ｐＨ　８．７
　　ウルソデオキシコール酸　　　　０．３ｇ
　　トロメタモール　　　　　　　　０．１ｇ
　　塩化ナトリウム　　　　　　　　０．７ｇ
　　希塩酸　　　　　　　　　　　　　　適量
　　水酸化ナトリウム　　　　　　　　　適量
　　精製水　　　　　　　　　　　　　　適量
　　浸透圧　　　２２０～３３０ｍＯｓｍ／Ｌ [Formulation example 2]
Eye drops/solution (in 100mL) pH 8.7
Ursodeoxycholic acid 0.3g
Trometamol 0.1g
Sodium chloride 0.7g
Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount) Osmotic pressure 220-330mOsm/L
［製剤例３］
　点眼剤・溶液　（１００ｍＬ中）　ｐＨ　８．７
　　ウルソデオキシコール酸　　　　０．３ｇ
　　トロメタモール　　　　　　　　０．１ｇ
　　濃グリセリン　　　　　　　　　２．０ｇ
　　希塩酸　　　　　　　　　　　　　　適量
　　水酸化ナトリウム　　　　　　　　　適量
　　精製水　　　　　　　　　　　　　　適量
　　浸透圧　　　２２０～３３０ｍＯｓｍ／Ｌ [Formulation example 3]
Eye drops/solution (in 100mL) pH 8.7
Ursodeoxycholic acid 0.3g
Trometamol 0.1g
Concentrated glycerin 2.0g
Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount) Osmotic pressure 220-330mOsm/L
［製剤例４］
　点眼剤・溶液　（１００ｍＬ中）　ｐＨ　８．４
　　ウルソデオキシコール酸　　　　０．１ｇ
　　トロメタモール　　　　　　　　０．５ｇ
　　塩化ナトリウム　　　　　　　　０．９ｇ
　　希塩酸　　　　　　　　　　　　　　適量
　　水酸化ナトリウム　　　　　　　　　適量
　　精製水　　　　　　　　　　　　　　適量
　　浸透圧　　　２２０～３３０ｍＯｓｍ／Ｌ [Formulation example 4]
Eye drops/solution (in 100mL) pH 8.4
Ursodeoxycholic acid 0.1g
Trometamol 0.5g
Sodium chloride 0.9g
Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount) Osmotic pressure 220-330mOsm/L
［製剤例５］
　点眼剤・溶液　（１００ｍＬ中）　ｐＨ　８．５
　　ウルソデオキシコール酸　　　　０．３ｇ
　　トロメタモール　　　　　　　　０．４ｇ
　　塩化ナトリウム　　　　　　　　０．６ｇ
　　希塩酸　　　　　　　　　　　　　　適量
　　水酸化ナトリウム　　　　　　　　　適量
　　精製水　　　　　　　　　　　　　　適量
　　浸透圧　　　２２０～３３０ｍＯｓｍ／Ｌ [Formulation Example 5]
Eye drops/solution (in 100mL) pH 8.5
Ursodeoxycholic acid 0.3g
Trometamol 0.4g
Sodium chloride 0.6g
Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount) Osmotic pressure 220-330mOsm/L
［製剤例６］
　点眼剤・溶液　（１００ｍＬ中）　ｐＨ　８．６
　　ウルソデオキシコール酸　　　　０．３ｇ
　　トロメタモール　　　　　　　　０．５ｇ
　　グリセリン　　　　　　　　　　１．５ｇ
　　希塩酸　　　　　　　　　　　　　　適量
　　水酸化ナトリウム　　　　　　　　　適量
　　精製水　　　　　　　　　　　　　　適量
　　浸透圧　　　２２０～３３０ｍＯｓｍ／Ｌ [Formulation example 6]
Eye drops/solution (in 100mL) pH 8.6
Ursodeoxycholic acid 0.3g
Trometamol 0.5g
Glycerin 1.5g
Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount) Osmotic pressure 220-330mOsm/L
［製剤例７］
　点眼剤・溶液　（１００ｍＬ中）　ｐＨ　８．６
　　ウルソデオキシコール酸　　　　０．６ｇ
　　トロメタモール　　　　　　　　０．５ｇ
　　塩化ナトリウム　　　　　　　　０．６ｇ
　　希塩酸　　　　　　　　　　　　　　適量
　　水酸化ナトリウム　　　　　　　　　適量
　　精製水　　　　　　　　　　　　　　適量
　　浸透圧　　　２２０～３３０ｍＯｓｍ／Ｌ [Formulation example 7]
Eye drops/solution (in 100mL) pH 8.6
Ursodeoxycholic acid 0.6g
Trometamol 0.5g
Sodium chloride 0.6g
Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount) Osmotic pressure 220-330mOsm/L
［製剤例８］
　点眼剤・溶液　（１００ｍＬ中）　ｐＨ　８．７
　　ウルソデオキシコール酸　　　　０．１ｇ
　　トロメタモール　　　　　　　　０．５ｇ
　　塩化ナトリウム　　　　　　　　０．７ｇ
　　希塩酸　　　　　　　　　　　　　　適量
　　水酸化ナトリウム　　　　　　　　　適量
　　精製水　　　　　　　　　　　　　　適量
　　浸透圧　　　２２０～３３０ｍＯｓｍ／Ｌ [Formulation example 8]
Eye drops/solution (in 100mL) pH 8.7
Ursodeoxycholic acid 0.1g
Trometamol 0.5g
Sodium chloride 0.7g
Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount) Osmotic pressure 220-330mOsm/L
［製剤例９］
　点眼剤・溶液　（１００ｍＬ中）　ｐＨ　８．７
　　ウルソデオキシコール酸　　　　０．６ｇ
　　トロメタモール　　　　　　　　０．５ｇ
　　塩化ナトリウム　　　　　　　　０．７ｇ
　　希塩酸　　　　　　　　　　　　　　適量
　　水酸化ナトリウム　　　　　　　　　適量
　　精製水　　　　　　　　　　　　　　適量
　　浸透圧　　　２２０～３３０ｍＯｓｍ／Ｌ [Formulation Example 9]
Eye drops/solution (in 100mL) pH 8.7
Ursodeoxycholic acid 0.6g
Trometamol 0.5g
Sodium chloride 0.7g
Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount) Osmotic pressure 220-330mOsm/L
［製剤例１０］
　点眼剤・溶液　（１００ｍＬ中）　ｐＨ　８．７
　　ウルソデオキシコール酸　　　　　　１ｇ
　　トロメタモール　　　　　　　　０．４ｇ
　　塩化ナトリウム　　　　　　　　０．６ｇ
　　希塩酸　　　　　　　　　　　　　　適量
　　水酸化ナトリウム　　　　　　　　　適量
　　精製水　　　　　　　　　　　　　　適量
　　浸透圧　　　　　２２０～３３０ｍＯｓｍ／Ｌ [Formulation example 10]
Eye drops/solution (in 100mL) pH 8.7
Ursodeoxycholic acid 1g
Trometamol 0.4g
Sodium chloride 0.6g
Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount) Osmotic pressure 220-330mOsm/L
［製剤例１１］
　点眼剤・溶液　（１００ｍＬ中）　ｐＨ　８．８
　　ウルソデオキシコール酸　　　　　　１ｇ
　　トロメタモール　　　　　　　　０．６ｇ
　　塩化ナトリウム　　　　　　　　０．５ｇ
　　希塩酸　　　　　　　　　　　　　　適量
　　水酸化ナトリウム　　　　　　　　　適量
　　精製水　　　　　　　　　　　　　　適量
　　浸透圧　　　　　２２０～３３０ｍＯｓｍ／Ｌ [Formulation Example 11]
Eye drops/solution (in 100mL) pH 8.8
Ursodeoxycholic acid 1g
Trometamol 0.6g
Sodium chloride 0.5g
Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount) Osmotic pressure 220-330mOsm/L
　ベンザルコニウム塩化物、ポリソルベート８０、ホウ酸、トロメタモール、グリセリンに精製水８０ｍＬを加え撹拌溶解する。さらにウルソデオキシコール酸を添加し撹拌する。水酸化ナトリウム溶液もしくは希塩酸を適量加えｐＨを調整し、これに精製水を適量加えて全量を１００ｍＬとし、上記製剤例１の溶液を調製する。 Add 80 mL of purified water to benzalkonium chloride, polysorbate 80, boric acid, trometamol, and glycerin and dissolve with stirring. Furthermore, ursodeoxycholic acid is added and stirred. The pH is adjusted by adding an appropriate amount of sodium hydroxide solution or diluted hydrochloric acid, and an appropriate amount of purified water is added to make a total volume of 100 mL to prepare the solution of Formulation Example 1 above.
　トロメタモール、及び、塩化ナトリウム又はグリセリンに精製水を加え撹拌溶解する。さらにウルソデオキシコール酸を添加し撹拌する。水酸化ナトリウム溶液もしくは希塩酸を適量加えｐＨを調整し、これに精製水を適量加えて全量を１００ｍＬとし、上記製剤例２～６の溶液を調製する。 Add purified water to trometamol and sodium chloride or glycerin and stir to dissolve. Furthermore, ursodeoxycholic acid is added and stirred. Add an appropriate amount of sodium hydroxide solution or diluted hydrochloric acid to adjust the pH, and add an appropriate amount of purified water to make a total volume of 100 mL to prepare the solutions of Formulation Examples 2 to 6 above.
試験例１．移行性評価試験-１
　本開示の医薬組成物の有効成分の房水への移行性を評価した。 Test example 1. Migration evaluation test-1
The ability of the active ingredient of the pharmaceutical composition of the present disclosure to migrate into aqueous humor was evaluated.
１－１．被験製剤の調製
　ウルソデオキシコール酸試料の調製
　トロメタモール０．２ｇ、塩化ナトリウム１．４ｇ、ウルソデオキシコール酸０．２ｇに精製水を加え撹拌した。水酸化ナトリウム溶液もしくは希塩酸を適量加えｐＨを調整し、これに精製水を適量加えて全量を２００ｍＬとし、実施例１の製剤を調製した。調製後の外観を目視で確認した。また、同様の方法にて、比較例１及び実施例２～６の製剤を調製した。
　トロメタモール０．２ｇ、濃グリセリン４．０ｇ、ウルソデオキシコール酸０．２ｇに精製水を加え撹拌した。水酸化ナトリウム溶液もしくは希塩酸を適量加えｐＨを調整し、これに精製水を適量加えて全量を２００ｍＬとし、実施例７の製剤を調製した。調製後の外観を目視で確認した。また、同様の方法にて、比較例２及び実施例８～１１の製剤を調製した。
　ｐＨの測定
第十七改正 日本薬局方 一般試験法「２．５４ ｐＨ測定法」に準じてｐＨメーターを用いて測定を行った。調製の際に、いずれの被験製剤も急激なｐＨの変化は認められなかったことから、ｐＨ安定性の観点から問題なく緩衝能が付与されていることを確認した。
　浸透圧の測定
　製剤の浸透圧は、被験製剤１ｍＬを使用して、モル凝固点降下法を原理とした自動浸透圧分析装置（ＯＭ－６０６０、アークレイ（株））にて測定した。 1-1. Preparation of test formulation Preparation of ursodeoxycholic acid sample Purified water was added to 0.2 g of trometamol, 1.4 g of sodium chloride, and 0.2 g of ursodeoxycholic acid and stirred. The pH was adjusted by adding an appropriate amount of sodium hydroxide solution or diluted hydrochloric acid, and an appropriate amount of purified water was added to make the total volume 200 mL to prepare the formulation of Example 1. The appearance after preparation was visually confirmed. In addition, formulations of Comparative Example 1 and Examples 2 to 6 were prepared in the same manner.
Purified water was added to 0.2 g of trometamol, 4.0 g of concentrated glycerin, and 0.2 g of ursodeoxycholic acid, and the mixture was stirred. The pH was adjusted by adding an appropriate amount of sodium hydroxide solution or diluted hydrochloric acid, and an appropriate amount of purified water was added to make the total volume 200 mL to prepare the formulation of Example 7. The appearance after preparation was visually confirmed. In addition, formulations of Comparative Example 2 and Examples 8 to 11 were prepared in the same manner.
Measurement of pH Measurement was carried out using a pH meter in accordance with the Japanese Pharmacopoeia, 17th Edition General Test Methods "2.54 pH Measurement Method". During preparation, no rapid changes in pH were observed for any of the test formulations, confirming that buffering capacity was imparted without any problem from the viewpoint of pH stability.
Measurement of Osmotic Pressure The osmotic pressure of the formulation was measured using 1 mL of the test formulation using an automatic osmotic pressure analyzer (OM-6060, manufactured by ARKRAY, Inc.) based on the principle of molar freezing point depression method.
１－２．試験方法
　ウサギ（雄性日本白色種）に各被験試料（実施例１～１１及び比較例１～２）をそれぞれ５０μＬで１回点眼した。点眼２時間後にウサギ眼球へ局所麻酔を施した後、房水を採取した（２～９眼）。高速液体クロマトグラフ・タンデムマススペクトロメーター（ＬＣ－ＭＳ／ＭＳ）を用いて、房水中ウルソデオキシコール酸濃度を測定した。 1-2. Test method 50 μL of each test sample (Examples 1 to 11 and Comparative Examples 1 to 2) was instilled once into the eyes of rabbits (male Japanese white breed). Two hours after instillation, local anesthesia was administered to the rabbit eyeballs, and aqueous humor was collected (eyes 2 to 9). The ursodeoxycholic acid concentration in the aqueous humor was measured using a high performance liquid chromatograph/tandem mass spectrometer (LC-MS/MS).
１－３．試験結果および考察
　試験結果を下表１－１～１－４に示す。
Figure JPOXMLDOC01-appb-T000002


Figure JPOXMLDOC01-appb-T000003

上記表中、「実施例２に対する比」とは、実施例２の房水移行量（ng/mL）に対する各被験製剤の房水移行量の比である。

Figure JPOXMLDOC01-appb-T000004


Figure JPOXMLDOC01-appb-T000005

上記表中、「実施例８に対する比」とは、実施例８の房水移行量（ng/mL）に対する各被験製剤の房水移行量の比である。
 1-3. Test Results and Discussion The test results are shown in Tables 1-1 to 1-4 below.
Figure JPOXMLDOC01-appb-T000002


Figure JPOXMLDOC01-appb-T000003

In the above table, "ratio to Example 2" is the ratio of the aqueous humor transfer amount of each test preparation to the aqueous humor transfer amount (ng/mL) of Example 2.

Figure JPOXMLDOC01-appb-T000004


Figure JPOXMLDOC01-appb-T000005

In the above table, the "ratio to Example 8" is the ratio of the aqueous humor transfer amount of each test preparation to the aqueous humor transfer amount (ng/mL) of Example 8.
　表１－１及び１－２から明らかなように、等張化剤として塩化ナトリウムを含み、浸透圧が８５～３７１ｍＯｓｍ／Ｌであり、かつ、トロメタモールの含有量が、０．１～２．０％（ｗ／ｖ）である、実施例１～６は優れたウルソデオキシコール酸の組織移行性（房水移行性）を示した。また、表１－３及び１－４から明らかなように、等張化剤としてグリセリンを含み、浸透圧が１０８～３３７ｍＯｓｍ／Ｌであり、かつ、トロメタモールの含有量が、０．１～２．０％（ｗ／ｖ）である、実施例７～１１も優れたウルソデオキシコール酸の組織移行性（房水移行性）を示した。 As is clear from Tables 1-1 and 1-2, it contains sodium chloride as an isotonic agent, has an osmotic pressure of 85 to 371 mOsm/L, and has a trometamol content of 0.1 to 2.0. % (w/v), Examples 1 to 6 showed excellent tissue migration (aqueous humor migration) of ursodeoxycholic acid. Further, as is clear from Tables 1-3 and 1-4, it contains glycerin as an isotonic agent, has an osmotic pressure of 108 to 337 mOsm/L, and has a trometamol content of 0.1 to 2.0 mOsm/L. 0% (w/v), Examples 7 to 11 also showed excellent tissue migration (aqueous humor migration) of ursodeoxycholic acid.
試験例２．薬理試験
　ＵＤＣＡを含む溶液組成物の水晶体の弾性に対する作用を評価した。 Test example 2. Pharmacological Test The effect of a solution composition containing UDCA on the elasticity of the crystalline lens was evaluated.
２－１．被験試料の調製
　試験例１と同様の方法にて、表２に示す基剤及び実施例２０～２２の製剤を調製した。
　試験例１に記載の方法に準じて、ｐＨと浸透圧を測定した。 2-1. Preparation of test samples In the same manner as in Test Example 1, the bases shown in Table 2 and the formulations of Examples 20 to 22 were prepared.
According to the method described in Test Example 1, pH and osmotic pressure were measured.
２－２．試験方法
１）８ヵ月齢のC５７ＢＬ／６Ｊマウスに各被験試料を１日１回、１週間、２．５ μＬ/ｅｙｅずつピペットマンを用いて両眼に点眼した。
２）最終点眼約０．５時間後に、マウスに二酸化炭素を吸引させ安楽殺し、眼球を摘出して、Ｈａｎｋ‘ｓ ｂａｌａｎｃｅｄ ｓａｌｔ ｓｏｌｕｔｉｏｎ（ＨＢＳＳ）でリンスした。
３）視神経近くの強膜をカミソリで切り、水晶体を切開部から摘出し、摘出した水晶体はＨＢＳＳに浸した。
４）水晶体をスライドガラスの上にのせ、オールインワン蛍光顕微鏡ＢＺ－９０００（キーエンス）を用いて水晶体の画像を取り込んだ（画像ａ）。
５）次に、水晶体の上に１枚のカバーガラス（２２ｘ２２ｍｍ）を載せ、重さにより水晶体の厚さが変動した画像を同様に取り込んだ（画像ｂ）。
６）水晶体直径の変化量を下記計算式１（すなわち、画像ｂの水晶体直径から画像ａの水晶体直径を引く）より算出した。ついで、基剤群と比較した各試料群の水晶体弾性向上量を下記計算式２より算出した。なお、平均値は、各群１０眼の平均である。
（計算式１）
　水晶体直径の変化量＝各被験試料の画像ｂの水晶体直径－各被験試料の画像ａの水晶体直径
（計算式２）
　各試料群の水晶体弾性向上量＝各被験試料群の水晶体直径の変化量の平均値－基剤群の水晶体直径の変化量の平均値 2-2. Test method 1) Each test sample was instilled into both eyes of 8-month-old C57BL/6J mice using a pipetteman once a day for 1 week.
2) Approximately 0.5 hours after the final eye instillation, the mouse was euthanized by inhaling carbon dioxide, and the eyeball was removed and rinsed with Hank's balanced salt solution (HBSS).
3) The sclera near the optic nerve was cut with a razor, the crystalline lens was removed from the incision, and the removed crystalline lens was immersed in HBSS.
4) The crystalline lens was placed on a slide glass, and an image of the crystalline lens was captured using an all-in-one fluorescence microscope BZ-9000 (Keyence) (image a).
5) Next, a cover glass (22 x 22 mm) was placed on the crystalline lens, and an image in which the thickness of the crystalline lens varied depending on the weight was similarly captured (image b).
6) The amount of change in lens diameter was calculated using the following formula 1 (ie, subtracting the lens diameter in image a from the lens diameter in image b). Next, the amount of improvement in lens elasticity of each sample group compared to the base group was calculated using the following formula 2. Note that the average value is the average of 10 eyes in each group.
(Formula 1)
Amount of change in crystalline lens diameter = Lens diameter in image b of each test sample - Lens diameter in image a of each test sample (calculation formula 2)
Amount of improvement in lens elasticity for each sample group = Average value of change in lens diameter for each test sample group - Average value of change in lens diameter for base group
２－３．試験結果および考察
　結果を表２に示す。
Figure JPOXMLDOC01-appb-T000006

　表２から明らかなように、ＵＤＣＡ溶液は１日１回、1週間点眼において０．１％、０．３％、１．０％のいずれの濃度においても強力な水晶体弾性改善作用を示した。 2-3. Test Results and Discussion The results are shown in Table 2.
Figure JPOXMLDOC01-appb-T000006

As is clear from Table 2, the UDCA solution showed a strong lens elasticity improving effect at all concentrations of 0.1%, 0.3%, and 1.0% when instilled into the eye once a day for one week.
試験例３．移行性評価試験－２
　「試験例２．薬理試験」における０．１％（ｗ／ｖ）、０．３％（ｗ／ｖ）および１．０％（ｗ／ｖ）ＵＤＣＡ溶液群から採取された水晶体について、ＵＤＣＡの水晶体移行性を評価した。
３－１．試験方法
　「試験例２．薬理試験」において最終点眼約０．５時間後にマウスを屠殺して採取され、水晶体弾性向上量を測定した水晶体を使用し、水晶体中のＵＤＣＡ濃度を高速液体クロマトグラフィー・タンデムマススペクトロメトリー（ＬＣ－ＭＳ／ＭＳ）を用いて測定した。 Test example 3. Migration evaluation test-2
Regarding the lenses collected from the 0.1% (w/v), 0.3% (w/v) and 1.0% (w/v) UDCA solution groups in "Test Example 2. Pharmacological Test", UDCA Lens migration properties were evaluated.
3-1. Test method In "Test Example 2. Pharmacological Test", the mouse was sacrificed and collected approximately 0.5 hours after the final instillation, and the lens elasticity improvement amount was measured.The UDCA concentration in the lens was measured by high performance liquid chromatography and It was measured using tandem mass spectrometry (LC-MS/MS).
３－２．結果と考察
　各溶液における最終点眼約０．５時間後の水晶体中ＵＤＣＡ濃度の平均値を表３に示す。なお、平均値は、１０眼の平均である。
Figure JPOXMLDOC01-appb-T000007

　０．１％（ｗ／ｖ）、０．３％（ｗ／ｖ）および１．０％（ｗ／ｖ）のＵＤＣＡ溶液を、１日１回、１週間点眼した時の水晶体中ＵＤＣＡ濃度は、濃度依存的な上昇を示した。これにより薬理試験において濃度依存的な水晶体弾性改善作用と水晶体中ＵＤＣＡ濃度に相関があることを示した。一般的に点眼により薬物は角膜を透過して房水へ移行し、その後、水晶体に薬効成分を送達するため、優れた水晶体移行性を示した実施例２０-２２は、優れた房水移行性により水晶体中薬物濃度を上昇させたと考えられた。
 3-2. Results and Discussion Table 3 shows the average value of the UDCA concentration in the crystalline lens approximately 0.5 hours after the final instillation of each solution. Note that the average value is the average of 10 eyes.
Figure JPOXMLDOC01-appb-T000007

When 0.1% (w/v), 0.3% (w/v) and 1.0% (w/v) UDCA solutions were instilled into the eye once a day for one week, the UDCA concentration in the lens was , showed a concentration-dependent increase. As a result, pharmacological tests showed that there is a correlation between the concentration-dependent lens elasticity improving effect and the UDCA concentration in the lens. Generally, when a drug is applied to the eye, it passes through the cornea and transfers to the aqueous humor, and then the medicinal ingredient is delivered to the crystalline lens. It was thought that this increased the drug concentration in the crystalline lens.
試験例４．防腐効力評価試験
　本開示の医薬組成物の防腐効力を評価した。 Test example 4. Preservative Efficacy Evaluation Test The preservative efficacy of the pharmaceutical composition of the present disclosure was evaluated.
４－１．被験製剤の調製
　実施例１～１１の調製方法と同様の方法にて、表４に示す実施例１２～１６を調製した。
　試験例１に記載の方法に準じて、ｐＨと浸透圧を測定した。　 4-1. Preparation of test formulations Examples 12 to 16 shown in Table 4 were prepared in the same manner as in Examples 1 to 11.
According to the method described in Test Example 1, pH and osmotic pressure were measured.
４－２．試験方法
　（菌種）
　接種菌として環境中に存在する代表的なカビであるCladosporium Cladosporioidesを使用した。
（試験手順）
　実施例１２～１６をそれぞれ試験管に入れ試験試料とした。各試験試料中の菌液濃度が２×１０6ｃｆｕ／ｍＬとなるように、接種菌液を試験試料に接種した。具体的には、２×１０8ｃｆｕ／ｍＬとなるように接種菌液を調製し、この接種菌液を２×１０6ｃｆｕ／ｍＬとなるように、各試験試料に接種し、均一に混合して試料とした。試験開始時の試料はいずれも澄明であった。これらの試料を遮光下２０～２５℃に保存し、試験菌接種２８日後の各試験試料の外観を観察し、写真を撮影した。 4-2. Test method (bacterial species)
Cladosporium Cladosporioides, a typical mold that exists in the environment, was used as the inoculum.
(Procedure of test)
Examples 12 to 16 were each placed in a test tube as a test sample. The inoculum solution was inoculated into the test samples so that the concentration of the bacterial solution in each test sample was 2×10 6 cfu/mL. Specifically, an inoculum solution was prepared to have a concentration of 2×10 8 cfu/mL, and this inoculum solution was inoculated to each test sample to a concentration of 2×10 6 cfu/mL, and the mixture was uniformly mixed. and used as a sample. All samples were clear at the start of the test. These samples were stored at 20 to 25°C in the dark, and the appearance of each test sample was observed and photographed 28 days after inoculation with the test bacteria.
４－３．試験結果および考察
　試験菌接種２８日後の各試験試料の外観を示す写真を図１に示す。図１に示されるように、等張化剤として塩化ナトリウムを含有する実施例１４は、試験菌接種２８日後でもその外観は澄明なままであり、試験菌の増殖は確認できなかった。一方、等張化剤として濃グリセリンを含有する実施例１２、１３、１５、１６は、いずれも試験菌接種２８日後に、その液中に黒い沈殿物の存在が認められ、試験菌の増殖が確認された。これにより、イオン性等張化剤が眼科組成物の防腐効力を向上できることが示唆された。
Figure JPOXMLDOC01-appb-T000008
4-3. Test Results and Discussion Photographs showing the appearance of each test sample 28 days after inoculation with the test bacteria are shown in FIG. As shown in FIG. 1, in Example 14 containing sodium chloride as an isotonizing agent, the appearance remained clear even 28 days after inoculation of the test bacteria, and no growth of the test bacteria could be confirmed. On the other hand, in Examples 12, 13, 15, and 16 containing concentrated glycerin as an isotonizing agent, the presence of black precipitates was observed in the liquids 28 days after inoculation of the test bacteria, and the growth of the test bacteria was inhibited. confirmed. This suggested that ionic tonicity agents can improve the preservative efficacy of ophthalmic compositions.
Figure JPOXMLDOC01-appb-T000008
試験例５．ｐH安定性試験 Test example 5. pH stability test
５－１．被験製剤の調製
　トロメタモール０．３ｇ、塩化ナトリウム２．１ｇ、ウルソデオキシコール酸０．９ｇに精製水を加え撹拌した。水酸化ナトリウム溶液もしくは希塩酸を適量加えｐＨを調整し、これに精製水を適量加えて全量を３００ｍＬとし、表５－１に示す実施例１７を調製した。実施例１８～１９はトロメタモールの量のみ変更して、同様に調製した。
　試験例１に記載の方法に準じて、ｐＨと浸透圧を測定した。
Figure JPOXMLDOC01-appb-T000009
5-1. Preparation of test formulation Purified water was added to 0.3 g of trometamol, 2.1 g of sodium chloride, and 0.9 g of ursodeoxycholic acid, and the mixture was stirred. An appropriate amount of sodium hydroxide solution or diluted hydrochloric acid was added to adjust the pH, and an appropriate amount of purified water was added to make the total volume 300 mL to prepare Example 17 shown in Table 5-1. Examples 18 to 19 were prepared in the same manner, except for changing the amount of trometamol.
According to the method described in Test Example 1, pH and osmotic pressure were measured.
Figure JPOXMLDOC01-appb-T000009
５－２．試験方法
（安定性試験）
　表５－１に示す製剤をポリエチレン製容器に充填及び施栓し安定性試験サンプルとした。安定性試験の開始時、１ヵ月におけるｐＨを測定した。本安定性試験の１ヵ月保存品は、２５℃４０％ＲＨ及び４０℃２０％ＲＨに1ヵ月間保存したサンプルを評価対象とした。ｐＨの測定は、第十七改正 日本薬局方 一般試験法「２．５４ ｐＨ測定法」に準じてｐＨメーターを用いて測定を行った。 5-2. Test method (stability test)
The formulations shown in Table 5-1 were filled into polyethylene containers and capped to serve as stability test samples. At the beginning of the stability study, pH was measured at 1 month. In this stability test, samples stored for one month at 25°C, 40% RH and 40°C, 20% RH were evaluated. The pH was measured using a pH meter according to the 17th edition Japanese Pharmacopoeia General Test Methods "2.54 pH Measurement Method".
５－３．試験結果および考察
Figure JPOXMLDOC01-appb-T000010

Figure JPOXMLDOC01-appb-T000011

　安定性の試験結果としてｐＨ測定結果を表５-２及び表５-３に示す。試験開始時から１ヵ月までのｐＨ変化は最大で０．０７であり、最も緩衝能の低いトロメタモール０．１％添加時においても十分なｐＨ安定性が確認された。試験開始時から２ヵ月までのｐＨ変化は最大で０．１４であり、最も緩衝能の低いトロメタモール０．１％添加時においては、若干のｐH低下がみられたものの、トロメタモール０．３％は十分なｐＨ安定性が確認された。
 5-3. Test results and discussion
Figure JPOXMLDOC01-appb-T000010

Figure JPOXMLDOC01-appb-T000011

The pH measurement results are shown in Tables 5-2 and 5-3 as stability test results. The maximum pH change from the start of the test to one month was 0.07, and sufficient pH stability was confirmed even when 0.1% of trometamol, which has the lowest buffering capacity, was added. The maximum pH change from the start of the test to 2 months was 0.14, and although a slight decrease in pH was observed when 0.1% trometamol, which has the lowest buffering capacity, was added, 0.3% trometamol Sufficient pH stability was confirmed.
　本開示の医薬組成物はウルソデオキシコール酸またはその塩の組織移行性に優れるため、医薬として有用である。 The pharmaceutical composition of the present disclosure is useful as a medicine because ursodeoxycholic acid or its salt has excellent tissue migration properties.

Claims (29)

  1. 　ウルソデオキシコール酸またはその塩、トロメタモールまたはその塩、および水を含有する医薬組成物であって、
    　該医薬組成物の浸透圧は５０～４００ｍＯｓｍ／Ｌであり、
    　該医薬組成物中のトロメタモールまたはその塩の含有量は、０．０１～３％（ｗ／ｖ）である、医薬組成物。     A pharmaceutical composition comprising ursodeoxycholic acid or a salt thereof, trometamol or a salt thereof, and water,
    The osmotic pressure of the pharmaceutical composition is 50 to 400 mOsm/L,
    A pharmaceutical composition in which the content of trometamol or a salt thereof is 0.01 to 3% (w/v).
  2. 　該医薬組成物中のウルソデオキシコール酸またはその塩の含有量は、０．０００１～３％（ｗ／ｖ）である、請求項１に記載の医薬組成物。 The pharmaceutical composition according to claim 1, wherein the content of ursodeoxycholic acid or its salt in the pharmaceutical composition is 0.0001 to 3% (w/v).
  3. 　該医薬組成物中のウルソデオキシコール酸またはその塩の含有量は、０．１～１％（ｗ／ｖ）である、請求項１または２に記載の医薬組成物。 The pharmaceutical composition according to claim 1 or 2, wherein the content of ursodeoxycholic acid or its salt in the pharmaceutical composition is 0.1 to 1% (w/v).
  4. 　該医薬組成物中のトロメタモールまたはその塩の含有量は、０．１～２％（ｗ／ｖ）である、請求項１～３のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 3, wherein the content of trometamol or its salt in the pharmaceutical composition is 0.1 to 2% (w/v).
  5. 　該医薬組成物中のトロメタモールまたはその塩の含有量は、０．１～１％（ｗ／ｖ）である、請求項１～４のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 4, wherein the content of trometamol or its salt in the pharmaceutical composition is 0.1 to 1% (w/v).
  6. 　該医薬組成物中のトロメタモールまたはその塩の含有量は、０．３～１％（ｗ／ｖ）である、請求項１～５のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 5, wherein the content of trometamol or its salt in the pharmaceutical composition is 0.3 to 1% (w/v).
  7. 　該医薬組成物の浸透圧は８０～３８０ｍＯｓｍ／Ｌである、請求項１～６のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 6, wherein the pharmaceutical composition has an osmotic pressure of 80 to 380 mOsm/L.
  8. 　該医薬組成物の浸透圧は２２０～３３０ｍＯｓｍ／Ｌである、請求項１～７のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmaceutical composition has an osmotic pressure of 220 to 330 mOsm/L.
  9. 　イオン性等張化剤および／または非イオン性等張化剤を含有する、請求項１～８のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 8, containing an ionic tonicity agent and/or a nonionic tonicity agent.
  10. 　該イオン性等張化剤が塩化ナトリウムであり、該非イオン性等張化剤がグリセリンである、請求項９に記載の医薬組成物。 The pharmaceutical composition according to claim 9, wherein the ionic tonicity agent is sodium chloride and the nonionic tonicity agent is glycerin.
  11. 　塩化ナトリウムを含有する、請求項１～１０のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 10, containing sodium chloride.
  12. 　グリセリンを含有する、請求項１～１１のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 11, containing glycerin.
  13. 　ｐＨが８．０以上である、請求項１～１２のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 12, which has a pH of 8.0 or higher.
  14. 　該医薬組成物中の塩化ナトリウムの含有量が、０．０１～２％（ｗ／ｖ）である、請求項１０～１３のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 10 to 13, wherein the content of sodium chloride in the pharmaceutical composition is 0.01 to 2% (w/v).
  15. 　該医薬組成物中のグリセリンの含有量が、０．１～５％（ｗ／ｖ）である、請求項１０～１４のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 10 to 14, wherein the content of glycerin in the pharmaceutical composition is 0.1 to 5% (w/v).
  16. 　ベンザルコニウム塩化物、ホウ酸、およびホウ砂からなる群から選択される少なくとも１つの防腐剤を含まない、請求項１～１５のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 15, which does not contain at least one preservative selected from the group consisting of benzalkonium chloride, boric acid, and borax.
  17. 　防腐剤を含まない、請求項１～１６のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 16, which does not contain a preservative.
  18. 　ウルソデオキシコール酸またはその塩、トロメタモールまたはその塩、塩化ナトリウム、および水を含有する医薬組成物であって、
    　該医薬組成物の浸透圧は２２０～３３０ｍＯｓｍ／Ｌであり、
    　ｐＨが８．０以上であり、
    　該医薬組成物中のウルソデオキシコール酸またはその塩の含有量は、０．１～１％（ｗ／ｖ）であり、
    　該医薬組成物中のトロメタモールまたはその塩の含有量は、０．３～１％（ｗ／ｖ）であり、
    　該医薬組成物中の塩化ナトリウムの含有量が、０．０１～２％（ｗ／ｖ）であって、
    　防腐剤を含まない、医薬組成物。     A pharmaceutical composition comprising ursodeoxycholic acid or a salt thereof, trometamol or a salt thereof, sodium chloride, and water,
    The osmotic pressure of the pharmaceutical composition is 220 to 330 mOsm/L,
    pH is 8.0 or more,
    The content of ursodeoxycholic acid or its salt in the pharmaceutical composition is 0.1 to 1% (w/v),
    The content of trometamol or its salt in the pharmaceutical composition is 0.3 to 1% (w/v),
    The content of sodium chloride in the pharmaceutical composition is 0.01 to 2% (w/v),
    A pharmaceutical composition free of preservatives.
  19. 　溶液である、請求項１～１８のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 18, which is a solution.
  20. 　眼投与用である、請求項１～１９のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 19, which is for ocular administration.
  21. 　点眼剤である、請求項１～２０のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 20, which is an eye drop.
  22. 　老視、水晶体の弾性の低下を伴う眼疾患、または眼の調節力の低下を伴う眼疾患の治療および／または予防のための、請求項１～２１のいずれか一項に記載の医薬組成物。 Pharmaceutical composition according to any one of claims 1 to 21, for the treatment and/or prevention of presbyopia, eye diseases accompanied by a decrease in the elasticity of the crystalline lens, or eye diseases accompanied by a decrease in the accommodation power of the eye. .
  23. 　老視、水晶体の弾性の低下を伴う眼疾患、または眼の調節力の低下を伴う眼疾患の治療および／または予防するのに使用するための、請求項１～２１のいずれか一項に記載の医薬組成物。 According to any one of claims 1 to 21, for use in the treatment and/or prevention of presbyopia, eye diseases associated with a decrease in the elasticity of the crystalline lens, or eye diseases associated with a decrease in the accommodation power of the eye. Pharmaceutical composition.
  24. 　老視、水晶体の弾性の低下を伴う眼疾患、または眼の調節力の低下を伴う眼疾患を治療および／または予防するための薬剤の製造における、請求項１～２１のいずれか一項に記載の医薬組成物の使用。 According to any one of claims 1 to 21, for the manufacture of a medicament for treating and/or preventing presbyopia, an eye disease accompanied by a decrease in the elasticity of the crystalline lens, or an eye disease accompanied by a decrease in the accommodation power of the eye. Use of the pharmaceutical composition.
  25. 　請求項１～２１のいずれか一項に記載の医薬組成物の治療および／または予防上の有効量を患者に投与することを含む、老視、水晶体の弾性の低下を伴う眼疾患、または眼の調節力の低下を伴う眼疾患の治療および／または予防方法。 Presbyopia, eye diseases accompanied by decreased elasticity of the crystalline lens, or eye disease, comprising administering to a patient a therapeutically and/or prophylactically effective amount of the pharmaceutical composition according to any one of claims 1 to 21. A method for treating and/or preventing an eye disease accompanied by a decrease in accommodation power.
  26. 　ウルソデオキシコール酸またはその塩、トロメタモールまたはその塩、および水を含有する医薬組成物において、
    　該医薬組成物の浸透圧を５０～４００ｍＯｓｍ／Ｌとし、
    該医薬組成物中のトロメタモールまたはその塩の含有量を０．０１～３％（ｗ／ｖ）とすることにより、ウルソデオキシコール酸またはその塩の組織移行性を向上する方法。     A pharmaceutical composition containing ursodeoxycholic acid or a salt thereof, trometamol or a salt thereof, and water,
    The osmotic pressure of the pharmaceutical composition is 50 to 400 mOsm/L,
    A method for improving tissue penetration of ursodeoxycholic acid or a salt thereof by controlling the content of trometamol or a salt thereof in the pharmaceutical composition to 0.01 to 3% (w/v).
  27. 　ウルソデオキシコール酸またはその塩、トロメタモールまたはその塩、および水を含有する医薬組成物において、
    該医薬組成物中にイオン性等張化剤を加えることにより、該医薬組成物の防腐効力を向上する方法。     A pharmaceutical composition containing ursodeoxycholic acid or a salt thereof, trometamol or a salt thereof, and water,
    A method of improving the preservative efficacy of a pharmaceutical composition by adding an ionic tonicity agent to the pharmaceutical composition.
  28. 　ウルソデオキシコール酸またはその塩、トロメタモールまたはその塩、および水を含有する医薬組成物において、
    　該医薬組成物の浸透圧を５０～４００ｍＯｓｍ／Ｌとし、
    該医薬組成物中のトロメタモールまたはその塩の含有量を０．１％（ｗ／ｖ）以上とすることにより、該医薬組成物のｐＨの低下を抑制する方法。     A pharmaceutical composition containing ursodeoxycholic acid or a salt thereof, trometamol or a salt thereof, and water,
    The osmotic pressure of the pharmaceutical composition is 50 to 400 mOsm/L,
    A method of suppressing a decrease in pH of the pharmaceutical composition by controlling the content of trometamol or its salt in the pharmaceutical composition to 0.1% (w/v) or more.
  29. 　ウルソデオキシコール酸またはその塩、トロメタモールまたはその塩、および水を含有する医薬組成物において、
    　該医薬組成物の浸透圧を５０～４００ｍＯｓｍ／Ｌとし、
    該医薬組成物中のトロメタモールまたはその塩の含有量を０．１％（ｗ／ｖ）以上とすることにより、該医薬組成物のｐＨを安定化する方法。     A pharmaceutical composition containing ursodeoxycholic acid or a salt thereof, trometamol or a salt thereof, and water,
    The osmotic pressure of the pharmaceutical composition is 50 to 400 mOsm/L,
    A method of stabilizing the pH of the pharmaceutical composition by controlling the content of trometamol or its salt in the pharmaceutical composition to 0.1% (w/v) or more.
PCT/JP2023/028863 2022-08-09 2023-08-08 Aqueous pharmaceutical composition containing udca or salt thereof WO2024034592A1 (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000509013A (en) * 1995-12-27 2000-07-18 サノフィ Injectable pharmaceutical composition comprising ursodeoxycholic acid or tauroursodeoxycholic acid, strong base, and trometamol
JP2014509602A (en) * 2011-03-14 2014-04-21 ドラッグ デリバリー ソリューションズ リミテッド Ophthalmic composition
WO2020129964A1 (en) * 2018-12-18 2020-06-25 参天製薬株式会社 Ursodeoxycholic acid-containing agent for treating or preventing presbyopia
WO2022173043A1 (en) * 2021-02-15 2022-08-18 参天製薬株式会社 Water-based pharmaceutical composition containing ursodeoxycholic acid or salt thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000509013A (en) * 1995-12-27 2000-07-18 サノフィ Injectable pharmaceutical composition comprising ursodeoxycholic acid or tauroursodeoxycholic acid, strong base, and trometamol
JP2014509602A (en) * 2011-03-14 2014-04-21 ドラッグ デリバリー ソリューションズ リミテッド Ophthalmic composition
WO2020129964A1 (en) * 2018-12-18 2020-06-25 参天製薬株式会社 Ursodeoxycholic acid-containing agent for treating or preventing presbyopia
WO2022173043A1 (en) * 2021-02-15 2022-08-18 参天製薬株式会社 Water-based pharmaceutical composition containing ursodeoxycholic acid or salt thereof

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