WO2023140357A1 - 水性液剤 - Google Patents

水性液剤 Download PDF

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Publication number
WO2023140357A1
WO2023140357A1 PCT/JP2023/001725 JP2023001725W WO2023140357A1 WO 2023140357 A1 WO2023140357 A1 WO 2023140357A1 JP 2023001725 W JP2023001725 W JP 2023001725W WO 2023140357 A1 WO2023140357 A1 WO 2023140357A1
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WO
WIPO (PCT)
Prior art keywords
arbekacin
water
aqueous solution
soluble polymer
salts
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/JP2023/001725
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English (en)
French (fr)
Japanese (ja)
Inventor
夢央 鈴木
祐輝 中村
達也 坂井
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Senju USA Inc
Original Assignee
Senju USA Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Priority to CN202380018185.6A priority Critical patent/CN118613267A/zh
Priority to MX2024009025A priority patent/MX2024009025A/es
Priority to KR1020247024814A priority patent/KR20240134913A/ko
Priority to JP2023554283A priority patent/JP7479744B2/ja
Priority to CA3244189A priority patent/CA3244189A1/en
Priority to EP23743349.5A priority patent/EP4467144A4/en
Application filed by Senju USA Inc filed Critical Senju USA Inc
Publication of WO2023140357A1 publication Critical patent/WO2023140357A1/ja
Priority to JP2024065941A priority patent/JP2024096898A/ja
Priority to US18/659,629 priority patent/US12296015B2/en
Anticipated expiration legal-status Critical
Priority to US19/173,248 priority patent/US20250235541A1/en
Ceased legal-status Critical Current

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present disclosure relates to an aqueous liquid preparation containing arbekacin and/or a salt thereof, and at least one water-soluble polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and polyvinylpyrrolidone, and its application technology.
  • Arbekacin is one of the aminoglycoside antibiotics. Arbekacin sulfate is used for the treatment of pneumonia and sepsis caused by methicillin-resistant Staphylococcus aureus (MRSA) (Patent Document 1). In addition, arbekacin sulfate has been reported to exhibit a wide range of antimicrobial activity against not only Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus, but also Gram-negative bacteria (Non-Patent Document 1).
  • water-soluble polymers such as hydroxypropylmethylcellulose, 2-hydroxypropyl- ⁇ -cyclodextrin, hydroxyethylcellulose, and dextran are commonly used in aqueous solutions, for example, as thickeners or thickeners (Patent Documents 2 and 3).
  • An object of the present disclosure is to provide a formulation technology related to an aqueous solution containing arbekacin and/or a salt thereof, and at least one water-soluble polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and polyvinylpyrrolidone.
  • an aqueous liquid preparation containing arbekacin and/or a salt thereof and at least one water-soluble polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and polyvinylpyrrolidone has excellent mucin adhesiveness, and made further improvements.
  • Item 1-1 An aqueous solution comprising arbekacin and/or a salt thereof and a water-soluble polymer
  • An aqueous liquid preparation wherein the water-soluble polymer comprises at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and polyvinylpyrrolidone.
  • Item 1-2 The aqueous liquid preparation according to Item 1-1, wherein the total concentration of arbekacin and/or salts thereof is 0.05 w/v% to 5.0 w/v%. Section 1-3.
  • Item 1-6 The aqueous liquid preparation according to item 1-1 or 1-2, wherein the total concentration of arbekacin and/or salts thereof is 0.1 w/v% to 3.0 w/v%.
  • aqueous liquid preparation according to any one of Items 1-1 to 1-5, wherein the water-soluble polymer has a concentration of 0.3 w/v% to 2.0 w/v%.
  • Item 1-7 The aqueous liquid preparation according to any one of Items 1-1 to 1-6, wherein the water-soluble polymer has a concentration of 0.8 w/v% to 1.4 w/v%. Item 1-8.
  • An aqueous solution comprising arbekacin and/or a salt thereof and hydroxypropylmethylcellulose,
  • the total concentration of arbekacin and / or salts thereof is 0.1 w / v% to 3.0 w / v%
  • An aqueous solution, wherein the concentration of hydroxypropylmethylcellulose is 0.8 w/v% to 1.4 w/v%.
  • the aqueous liquid preparation according to any one of Items 1-1 to 1-8, wherein the mass ratio of the total content of arbekacin and/or salts thereof to the content of the water-soluble polymer is 1:0.04 to 70. Item 1-10.
  • Item 1-12 The aqueous liquid preparation according to any one of Items 1-1 to 1-11, wherein the aqueous liquid preparation has a pH of 5.0 to 8.0. Item 1-13.
  • the aqueous liquid preparation according to any one of Items 1-1 to 1-12, wherein the aqueous liquid preparation has a viscosity of 5 to 50 mPa ⁇ s.
  • Item 1-14. An aqueous solution comprising arbekacin and/or a salt thereof and hydroxypropylmethylcellulose, The total concentration of arbekacin and/or salts thereof is 0.1 w/v% to 3.0 w/v%, the concentration of hydroxypropylmethylcellulose is 0.3 w/v% to 2.0 w/v%, The mass ratio of the total content of the arbekacin and/or salt thereof and the content of the water-soluble polymer is 1:0.04 to 70, The aqueous solution has a pH of 5.0 to 8.0, An aqueous liquid agent having a viscosity of 5 to 50 mPa ⁇ s.
  • Item 1-15 The aqueous liquid formulation according to any one of Items 1-1 to 1-14, wherein C ⁇ (A+B) is greater than 0.
  • An aqueous solution comprising arbekacin and/or a salt thereof and hydroxypropylmethylcellulose,
  • the total concentration of arbekacin and/or salts thereof is 0.1 w/v% to 3.0 w/v%
  • the concentration of hydroxypropylmethylcellulose is 0.3 w/v% to 2.0 w/v%
  • the mass ratio of the total content of the arbekacin and/or salt thereof and the content of the water-soluble polymer is 1:0.04 to 70
  • the aqueous solution has a pH of 5.0 to 8.0
  • the aqueous liquid agent has a viscosity of 5 to 50 mPa s
  • Viscosity increase value due to arbekacin (mPa s) B: Viscosity increase value due to water-soluble polymer (mPa s)
  • C Viscosity increase value due to arbekacin and water-soluble polymer (mPa s)
  • Item 1-19 The aqueous liquid preparation according to any one of Items 1-1 to 1-18, wherein the rate of decrease in release rate of arbekacin and/or a salt thereof is 5% or more.
  • Item 1-21 The aqueous liquid preparation according to any one of Items 1-1 to 1-19, wherein the rate of decrease in release rate of arbekacin and/or a salt thereof is 25% or more.
  • the aqueous solution according to any one of Items 1-1 to 1-20 which is an ophthalmic solution.
  • Item 1-22 The aqueous liquid preparation according to any one of Items 1-1 to 1-21, which is used for thickening an aqueous liquid preparation containing a water-soluble polymer on the ocular surface.
  • the aqueous liquid preparation according to any one of Items 1-1 to 1-28, wherein the bacterium is Gram-positive or Gram-negative. Item 1-30.
  • the bacterium is at least one selected from methicillin-resistant Staphylococcus aureus, Staphylococcus aureus, Corynebacterium, Pseudomonas aeruginosa, Haemophilus influenzae, Streptococcus pneumoniae, Moraxella, Neisseria gonorrhoeae, Serratia, Streptococcus, anaerobic bacteria, and atypical acid-fast bacterium Streptococcus pneumoniae.
  • the aqueous liquid formulation according to any one of Items 1-1 to 1-29. Item 1-31.
  • An aqueous solution comprising arbekacin and/or a salt thereof and hydroxypropylmethylcellulose, An aqueous solution for the treatment of bacterial external eye infections.
  • An aqueous solution comprising arbekacin and/or a salt thereof and hydroxypropylmethylcellulose, An aqueous solution for the treatment of bacterial external eye infections associated with dry eye.
  • Item 2-1 A method of treating a bacterial external eye infection comprising: A step of administering an aqueous solution containing arbekacin and/or a salt thereof and a water-soluble polymer to a subject in need thereof; A method for treating bacterial external ocular infections, wherein the water-soluble polymer comprises at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and polyvinylpyrrolidone.
  • the water-soluble polymer comprises at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and polyvinylpyrrolidone.
  • a method of treating a bacterial external eye infection comprising: A step of administering an aqueous solution containing arbekacin and/or a salt thereof and a water-soluble polymer to a subject in need thereof; A method of treating bacterial external ocular infections, wherein said water-soluble polymer comprises hydroxypropylmethylcellulose.
  • a method of treating bacterial conjunctivitis comprising: A step of administering an aqueous solution containing arbekacin and/or a salt thereof and a water-soluble polymer to a subject in need thereof; A method of treating bacterial conjunctivitis, wherein the water-soluble polymer comprises hydroxypropylmethylcellulose.
  • a method of treating a bacterial external eye infection comprising: administering an aqueous solution comprising arbekacin and/or a salt thereof and a water-soluble polymer to the ocular surface of a subject in need thereof;
  • the water-soluble polymer contains at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and polyvinylpyrrolidone,
  • a method of treating bacterial external eye infections Item 2-5.
  • a method of treating bacterial conjunctivitis comprising: administering an aqueous solution comprising arbekacin and/or a salt thereof and hydroxypropylmethylcellulose to the ocular surface of a subject in need thereof; A method of treating bacterial conjunctivitis.
  • Item 2-6a The method of treatment according to any one of Items 2-1 to 2-5, comprising the step of contacting said aqueous solution with mucin.
  • Item 2-7a The treatment method according to any one of items 2-1 to 2-5.
  • the method of treatment according to any one of Items 2-1 to 2-6 comprising the step of thickening the aqueous solution on the ocular surface.
  • Item 2-7b. administering the aqueous solution to the ocular surface of a subject in need thereof; administering to the ocular surface of the subject such that the aqueous solution thickens on the ocular surface;
  • Item 2-8a. The treatment method according to any one of Items 2-1 to 2-7, comprising a step of improving the mucin adhesion of the aqueous liquid preparation.
  • a method of treating a bacterial external eye infection comprising: administering an aqueous solution comprising arbekacin and/or a salt thereof and a water-soluble polymer to the ocular surface of a subject in need thereof; contacting the aqueous solution with the mucin to increase the viscosity of the aqueous solution and improve the adhesiveness of the aqueous solution to the mucin;
  • the water-soluble polymer contains at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and polyvinylpyrrolidone,
  • a method of treating bacterial external eye infections Item 2-9b.
  • a method of treating a bacterial external eye infection comprising: administering an aqueous solution comprising arbekacin and/or a salt thereof and a water-soluble polymer to the ocular surface of a subject in need thereof;
  • the water-soluble polymer contains at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and polyvinylpyrrolidone,
  • the administration is carried out so that the aqueous solution contacts the mucin, thereby increasing the viscosity of the aqueous solution and improving the adhesiveness of the aqueous solution to the mucin.
  • a method of treating bacterial external eye infections Item 2-9c.
  • a method of treating bacterial conjunctivitis comprising: administering an aqueous solution comprising arbekacin and/or a salt thereof and hydroxypropylmethylcellulose to the ocular surface of a subject in need thereof; contacting the aqueous solution with the mucin to increase the viscosity of the aqueous solution and improve the adhesiveness of the aqueous solution to the mucin;
  • a method of treating bacterial conjunctivitis Item 2-9d.
  • a method of treating bacterial conjunctivitis comprising: administering an aqueous solution comprising arbekacin and/or a salt thereof and hydroxypropylmethylcellulose to the ocular surface of a subject in need thereof; The administration is carried out so that the aqueous solution contacts the mucin, thereby increasing the viscosity of the aqueous solution and improving the adhesiveness of the aqueous solution to the mucin.
  • a method of treating bacterial conjunctivitis Item 2-10.
  • a method for improving conjunctival migration of arbekacin and/or a salt thereof comprising: A step of administering an aqueous solution containing arbekacin and/or a salt thereof and a water-soluble polymer to a subject in need thereof; A method for improving conjunctival migration, wherein the water-soluble polymer comprises hydroxypropylmethylcellulose.
  • the water-soluble polymer comprises hydroxypropylmethylcellulose.
  • a method of treating a bacterial external eye infection comprising: A step of administering an aqueous solution containing arbekacin and/or a salt thereof and a water-soluble polymer to a subject in need thereof; the water-soluble polymer comprises hydroxypropylmethylcellulose;
  • the total concentration of arbekacin and/or salts thereof is 0.1 w/v% to 3.0 w/v%, the concentration of hydroxypropylmethylcellulose is 0.3 w/v% to 2.0 w/v%,
  • the mass ratio of the total content of the arbekacin and/or salts thereof and the content of the hydroxypropylmethylcellulose is 1:0.04 to 70,
  • the aqueous solution has a pH of 5.0 to 8.0
  • a method for treating bacterial external ocular infections wherein the aqueous solution has a viscosity of 5 to 50 mPa ⁇ s.
  • Item 2-16 A method of treating a bacterial external eye infection comprising: A step of administering
  • Item 2-17 The method according to any one of Items 2-1 to 2-16, wherein the aqueous solution is an aqueous solution in which C ⁇ (A+B) is greater than 0.
  • the aqueous liquid preparation has a rate of decrease in release rate of arbekacin and/or a salt thereof of 5% or more.
  • a method of treating bacterial conjunctivitis comprising: administering an aqueous solution containing arbekacin and/or a salt thereof and a water-soluble polymer to a subject in need thereof, and contacting the aqueous solution with mucin; the water-soluble polymer comprises hydroxypropylmethylcellulose;
  • the total concentration of arbekacin and/or salts thereof is 0.1 w/v% to 3.0 w/v%, the concentration of hydroxypropylmethylcellulose is 0.3 w/v% to 2.0 w/v%,
  • the mass ratio of the total content of the arbekacin and/or salts thereof and the content of the hydroxypropylmethylcellulose is 1:0.04 to 70,
  • the aqueous solution has a pH of 5.0 to 8.0
  • a method of treating bacterial conjunctivitis comprising: administering an aqueous solution comprising arbekacin and/or a salt thereof and a water-soluble polymer to a subject in need thereof such that the aqueous solution is in contact with mucin; the water-soluble polymer comprises hydroxypropylmethylcellulose;
  • the total concentration of arbekacin and/or salts thereof is 0.1 w/v% to 3.0 w/v%, the concentration of hydroxypropylmethylcellulose is 0.3 w/v% to 2.0 w/v%,
  • the mass ratio of the total content of the arbekacin and/or salts thereof and the content of the hydroxypropylmethylcellulose is 1:0.04 to 70,
  • the aqueous solution has a pH of 5.0 to 8.0,
  • Item 3-1 A method of treating a bacterial external ocular infection associated with dry eye, comprising: A step of administering an aqueous solution containing arbekacin and/or a salt thereof and a water-soluble polymer to a subject in need thereof; A method for treating a bacterial external ocular infection associated with dry eye, wherein the water-soluble polymer comprises at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and polyvinylpyrrolidone.
  • the water-soluble polymer comprises at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and polyvinylpyrrolidone.
  • a method of treating a bacterial external ocular infection associated with dry eye comprising: A step of administering an aqueous solution containing arbekacin and/or a salt thereof and a water-soluble polymer to a subject in need thereof; A method of treating external bacterial ocular infections associated with dry eye, wherein said water-soluble polymer comprises hydroxypropylmethylcellulose. Item 3-3.
  • a method of treating bacterial conjunctivitis with dry eye comprising: A step of administering an aqueous solution containing arbekacin and/or a salt thereof and a water-soluble polymer to a subject in need thereof; A method of treating bacterial conjunctivitis associated with dry eye, wherein said water-soluble polymer comprises hydroxypropylmethylcellulose.
  • Item 3-4 The method of treatment according to any one of Items 3-1 to 3-3, wherein the total concentration of arbekacin and/or salts thereof in the aqueous solution is 0.05 w/v% to 5.0 w/v%. Item 3-5.
  • a method of treating a bacterial external ocular infection associated with dry eye comprising: A step of administering an aqueous solution containing arbekacin and/or a salt thereof and a water-soluble polymer to a subject in need thereof; the water-soluble polymer comprises hydroxypropylmethylcellulose;
  • the total concentration of arbekacin and/or salts thereof is 0.1 w/v% to 3.0 w/v%, the concentration of hydroxypropylmethylcellulose is 0.3 w/v% to 2.0 w/v%,
  • the mass ratio of the total content of the arbekacin and/or salts thereof and the content of the hydroxypropylmethylcellulose is 1:0.04 to 70,
  • the aqueous solution has a pH of 5.0 to 8.0
  • a method for treating bacterial external ocular infections associated with dry eye where
  • Item 3-10 The treatment method according to any one of Items 3-1 to 3-9, wherein the aqueous solution is an aqueous solution in which C ⁇ (A+B) is greater than 0.
  • Item 3-11 The treatment method according to any one of Items 3-1 to 3-10, wherein the aqueous liquid preparation has a rate of decrease in release rate of arbekacin and/or a salt thereof of 5% or more.
  • the method of treatment according to any one of Items 3-1 to 3-11, wherein the aqueous solution is eye drops.
  • a method of treating dry eye comprising: A step of administering an aqueous solution containing arbekacin and/or a salt thereof and a water-soluble polymer to a subject in need thereof; A method of treating dry eye, wherein the water-soluble polymer comprises at least one water-soluble polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and polyvinylpyrrolidone.
  • the water-soluble polymer comprises at least one water-soluble polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and polyvinylpyrrolidone.
  • a method for thickening an aqueous solution containing a water-soluble polymer on an ocular surface comprising: A step of administering an aqueous solution containing arbekacin and/or a salt thereof and a water-soluble polymer to a subject in need thereof; A method, wherein the water-soluble polymer comprises hydroxypropylmethylcellulose.
  • a method for improving mucin adhesion comprising: A step of administering an aqueous solution containing arbekacin and/or a salt thereof and a water-soluble polymer to a subject in need thereof; A method of improving mucin adhesion, wherein said water-soluble polymer comprises hydroxypropylmethylcellulose.
  • a method of stabilizing a tear film comprising: A step of administering an aqueous solution containing arbekacin and/or a salt thereof and a water-soluble polymer to a subject in need thereof; A method of stabilizing a tear film, wherein said water-soluble polymer comprises hydroxypropylmethylcellulose.
  • a method of treating dry eye comprising: A step of administering an aqueous solution containing arbekacin and/or a salt thereof and a water-soluble polymer to a subject in need thereof; A method of treating dry eye, wherein the water-soluble polymer comprises hydroxypropylmethylcellulose.
  • a method of treating dry eye comprising: A step of administering an aqueous solution containing arbekacin and/or a salt thereof and a water-soluble polymer to a subject in need thereof; the water-soluble polymer comprises hydroxypropylmethylcellulose;
  • the total concentration of arbekacin and/or salts thereof is 0.1 w/v% to 3.0 w/v%, the concentration of hydroxypropylmethylcellulose is 0.3 w/v% to 2.0 w/v%,
  • the mass ratio of the total content of the arbekacin and/or salts thereof and the content of the hydroxypropylmethylcellulose is 1:0.04 to 70,
  • the aqueous solution has a pH of 5.0 to 8.0,
  • a method for treating dry eye wherein the aqueous solution has a viscosity of 5 to 50 mPa ⁇ s.
  • Item 4-12 The method according to any one of Items 4-1 to 4-11, wherein the aqueous solution is an aqueous solution in which C ⁇ (A+B) is greater than 0.
  • aqueous liquid formulation refers to a formulation that contains water as a base and exhibits a liquid state.
  • water-soluble polymer refers to a polymer that is soluble in water.
  • Albetcacin is 3 -amino -3 -Deoxy - ⁇ -D -Glucopyranosyl- (1 ⁇ 6) - [2,6 -diamino -2, 3,4,6 -Tetradioxy - ⁇ -D -Ellislo -Hexopyran Sil- (1 ⁇ 4)] - [(1 ⁇ 4)] 2S) -4 -Amino -2 -Hydroxy Tanil] -2 -Deoxy -D -steptamine.
  • “Arbekacin” is a compound known as an aminoglycoside antibiotic and has strong antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA).
  • Arbekacin is also described in JP-A-56-051499 and JP-A-58-134099. It is also listed in each article of the Japanese Pharmacopoeia, 18th Edition. In the present specification, concentrations and amounts of arbekacin and/or salts thereof are concentrations and amounts converted to arbekacin unless otherwise specified.
  • hydroxypropyl methylcellulose is a type of cellulosic polymer and refers to a mixed ether of cellulose methyl and hydroxypropyl. Hydroxypropyl methylcellulose is sometimes referred to as hypromellose. It is sometimes abbreviated as HPMC.
  • hydroxyethyl cellulose is a type of cellulosic polymer and refers to partially O-(2-hydroxyethyl) cellulose. It is sometimes abbreviated as HEC.
  • methyl cellulose is a type of cellulosic polymer and refers to methyl ether of cellulose. It is sometimes abbreviated as MC.
  • polyvinylpyrrolidone is a type of polyvinyl polymer and refers to a linear polymer of 1-vinyl-2-pyrrolidone. Polyvinylpyrrolidone is sometimes called povidone or polyvidone. It is sometimes abbreviated as PVP.
  • the "viscosity" of the aqueous liquid formulation is measured according to "2.1.3. Cone-plate rotary viscometer (cone-plate type viscometer)" of “2. Method 2 Rotational viscometer method” of "2.53 Viscosity measurement method” defined in the general test method of the 18th revision of the Japanese Pharmacopoeia (30°C ⁇ 0.1°C, preheating time: 0 s, rotation speed of 100 rpm, cone-plate rotary viscometer, cone rotor used: 3° ⁇ R17. 65, measurement time: 90 s). Specifically, the viscosity of the aqueous solution is measured using a viscometer TVE-25 (model: TVE-25L) manufactured by Toki Sangyo Co., Ltd.
  • viscosity increase value refers to a value obtained by subtracting the viscosity of the arbekacin and/or water-soluble polymer solution and the viscosity of the mucin solution from the viscosity of the mixed solution of arbekacin and/or water-soluble polymer and mucin, more specifically, the value obtained according to the following formula (Non-Patent Document 2).
  • the viscosity increase value due to arbekacin is obtained according to the following formula.
  • the viscosity increase value due to the water-soluble polymer is obtained according to the following formula.
  • the viscosity increase value due to arbekacin and water-soluble polymer is obtained according to the following formula.
  • thickening means that the aqueous solution of arbekacin containing a water-soluble polymer interacts with mucin to increase the viscosity of the aqueous solution.
  • the “decreasing rate (%) of the release rate of arbekacin and/or a salt thereof” is an index showing the adhesiveness between arbekacin and mucin, and the higher the decreasing rate, the higher the adhesiveness.
  • the “decreasing rate (%) of the release rate of arbekacin and/or its salt” is calculated according to the following formula based on the results of the in vitro dialysis membrane test described below.
  • In vitro dialysis membrane test 1) 500 ⁇ L of a sample (containing arbekacin and/or its salt) is enclosed in a 2 mL glass container, the opening is covered with a dialysis membrane, and the surroundings are fixed (the inside of the glass container is the donor side).
  • Detector Charged particle detector Column: A commercially available product in which a stainless tube having an inner diameter of 4.6 mm and a length of 250 mm is filled with octylsilylated silica gel for liquid chromatography having a thickness of 5 ⁇ m.
  • the "arbekacin solution” is obtained by dissolving the same compound as arbekacin and/or a salt thereof contained in the specimen in the same amount of water.
  • the "arbekacin solution” is an arbekacin sulfate aqueous solution with a 1 w/v % arbekacin equivalent.
  • molecular adhesiveness means the ability to reversibly bind the water-soluble polymer, arbekacin, and mucin to each other in the aqueous solution by mixing an aqueous solution of arbekacin containing a water-soluble polymer with mucin.
  • “improving the conjunctival migration of arbekacin” means that the Cmax of the arbekacin concentration in the conjunctiva when the water-soluble polymer-containing arbekacin aqueous solution is administered is higher than the Cmax of the conjunctival arbekacin concentration when the water-soluble polymer-free arbekacin aqueous solution is administered.
  • Cmax means the maximum drug concentration at the target site after drug administration.
  • bacterial external eye infection refers to a disease caused by infection of the external eye by bacteria.
  • outer eye part refers to organs located around the eyeball, and includes, for example, the conjunctiva, cornea, eyelid, lacrimal gland, and meibomian glands.
  • bacterial keratoconjunctivitis refers to a disease in which inflammation occurs due to bacterial infection of the cornea or conjunctiva.
  • Bacterial keratitis refers to a disease in which inflammation occurs due to bacterial infection of the cornea.
  • Bacterial conjunctivitis refers to a disease in which inflammation occurs due to bacterial infection of the conjunctiva.
  • dry eye refers to a disease diagnosed as “dry eye” according to clinical diagnostic criteria. More specifically, it refers to "a multifactorial ocular surface disease characterized by a breakdown in the health of the tear film, with some subjective ocular symptoms, and in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and sensory nerve abnormalities play an etiological role” (Non-Patent Document 3). "Dry eye” is sometimes referred to as “keratoconjunctivitis sicca.” As used herein, “treatment” means amelioration, alleviation, mitigation, or slowing of progression of a disease or symptom.
  • the term "tear film” refers to a layer that covers the surface of the eye and is composed of three layers: a lipid layer (oil layer), an aqueous layer, and a mucin layer. When the water layer and the mucin layer are mixed into one liquid layer, it refers to the layer covering the surface of the eye composed of two layers, the liquid layer in which water and mucin are mixed, and the oil layer (Non-Patent Document 3).
  • “tear film stabilization” means stably retaining the tear film on the surface of the eye. Tear break-up time (BUT) refers to the time from tear film formation to break-up. BUT tends to shorten when the tear film becomes unstable. As an example, “tear film stabilization” refers to prolongation of BUT.
  • Aqueous Liquid Formulation Aqueous liquid formulations encompassed by the present disclosure include arbekacin and/or salts thereof and at least one water-soluble polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and polyvinylpyrrolidone.
  • the aqueous liquid formulation is sometimes referred to as "the aqueous liquid formulation of the present disclosure”.
  • the salt of arbekacin is not particularly limited as long as it is pharmaceutically acceptable.
  • Examples include organic acid salts or inorganic acid salts.
  • Organic acid salts include, for example, tartrates and acetates.
  • examples of inorganic acid salts include sulfates and hydrochlorides.
  • arbekacin or a salt thereof may be in the form of a solvate such as a hydrate.
  • arbekacin or salts thereof arbekacin sulfate is preferably used because it is marketed as a drug and its safety has been established.
  • arbekacin or a salt thereof may be used alone, or they may be used in combination.
  • the total concentration of arbekacin and/or salts thereof in the aqueous liquid preparation of the present disclosure can be, for example, about 0.05 to 5.0 w/v% in terms of arbekacin.
  • the upper or lower limit of the range may be, for example, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, or 4.5 w/v%.
  • the range is preferably about 0.1 to 3.0 w/v%.
  • Hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and polyvinylpyrrolidone are examples of water-soluble polymers used in the composition of the present disclosure. These four types of water-soluble polymers are sometimes collectively referred to as the water-soluble polymer of the present disclosure. Among them, hydroxypropylmethylcellulose is particularly preferable from the viewpoint that the viscosity can be easily maintained over time.
  • the said water-soluble polymer can be used individually by 1 type or in combination of 2 or more types.
  • the composition of the present disclosure may contain a water-soluble polymer other than the water-soluble polymer of the present disclosure as long as the effect is not impaired.
  • the degree of substitution type of hydroxypropylmethylcellulose is defined by the content of methoxy groups and hydroxypropoxy groups (18th revision of the Japanese Pharmacopoeia).
  • Degree of substitution type 1828 refers to having a lower limit of 16.5% by weight of methoxy groups, an upper limit of 20.0% by weight of methoxy groups, a lower limit of 23.0% by weight of hydroxypropoxy groups, and an upper limit of 32.0% by weight of hydroxypropoxy groups.
  • Degree of substitution type 2208 refers to those having a lower limit of 19.0% by weight of methoxy groups, an upper limit of 24.0% by weight of methoxy groups, a lower limit of 4.0% by weight of hydroxypropoxy groups, and an upper limit of 12.0% by weight of hydroxypropoxy groups.
  • Degree of substitution type 2906 refers to those having a lower limit of 27.0% by weight of methoxy groups, an upper limit of 30.0% by weight of methoxy groups, a lower limit of 4.0% by weight of hydroxypropoxy groups, and an upper limit of 7.5% by weight of hydroxypropoxy groups.
  • Degree of substitution type 2910 refers to those having a lower limit of 28.0% by weight of methoxy groups, an upper limit of 30.0% by weight of methoxy groups, a lower limit of 7.0% by weight of hydroxypropoxy groups, and an upper limit of 12.0% by weight of hydroxypropoxy groups.
  • the degree of substitution type of hydroxypropylmethylcellulose is not particularly limited, and may be any of 1828, 2208, 2906 and 2910. 2208 or 2910 degree of substitution types are preferred.
  • the molecular weight of hydroxypropylmethylcellulose is not particularly limited.
  • the weight average molecular weight is 10,000 to 500,000, preferably 50,000 to 500,000, more preferably 50,000 to 300,000.
  • weight average molecular weight can be determined by a gel permeation chromatography (GPC) method using polystyrene as a standard.
  • the concentration of hydroxypropylmethylcellulose in the aqueous liquid preparation of the present disclosure can be, for example, about 0.2 to 3.5 w/v%. It is preferably about 0.3 to 2.0 w/v%, more preferably about 0.3 to 1.5 w/v%, even more preferably about 0.8 to 1.5 w/v%, particularly preferably about 0.8 to 1.4 w/v%.
  • the molar substitution degree of hydroxyethoxy groups of hydroxyethyl cellulose is not particularly limited. For example, about 1.5 to 3.0 can be mentioned. About 2.5 is preferable.
  • the molecular weight of hydroxyethyl cellulose is not particularly limited.
  • the weight average molecular weight is 10,000 to 1,000,000, preferably 100,000 to 1,000,000, more preferably 600,000 to 800,000.
  • the concentration of hydroxyethyl cellulose in the aqueous liquid preparation of the present disclosure can be, for example, about 0.05 to 1 w/v%. For example, it may be about 0.08 to 0.6 w/v%, may be about 0.09 to 0.4 w/v%, or may be about 0.2 to 0.4 w/v%.
  • the degree of substitution of methylcellulose is not particularly limited. For example, about 1.5 to 3.0 can be mentioned. About 1.8 is preferable.
  • the molecular weight of methylcellulose is not particularly limited.
  • the weight average molecular weight is 10,000 to 500,000, preferably 100,000 to 500,000, more preferably 300,000 to 500,000.
  • the concentration of methyl cellulose in the aqueous liquid preparation of the present disclosure can be, for example, about 0.1 to 1.8 w/v%.
  • it may be about 0.15 to 1.0 w/v%, may be about 0.15 to 0.75 w/v%, may be about 0.4 to 0.75 w/v%, or may be about 0.4 to 0.7 w/v%.
  • the molecular weight of polyvinylpyrrolidone is not particularly limited.
  • the weight average molecular weight is 2,000 to 1,500,000, preferably 40,000 to 1,500,000, more preferably 1,000,000 to 1,500,000.
  • the concentration of polyvinylpyrrolidone in the aqueous liquid preparation of the present disclosure can be, for example, about 0.5 to 8.8 w/v%. For example, it may be about 0.75 to 5.0 w/v%, may be about 0.75 to 3.8 w/v%, may be about 2.0 to 3.8 w/v%, or may be about 2.0 to 3.5 w/v%.
  • composition of the present disclosure may contain a water-soluble polymer other than the water-soluble polymer of the present disclosure as long as the effect is not impaired.
  • water-soluble polymers include, for example, cellulosic polymers other than the water-soluble polymers of the present disclosure, synthetic polymers, and the like.
  • examples of the cellulose-based polymer include nonionic cellulose-based polymers, ionic cellulose-based polymers, and the like.
  • Nonionic cellulose polymers include, for example, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, etc.
  • examples of ionic cellulose polymers include carboxymethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, carboxymethyl ethyl cellulose, cellulose acetate phthalate, and the like.
  • the synthetic polymer examples include carboxyvinyl polymer, polyacrylic acid, polyvinyl alcohol, and the like.
  • 50% by mass or more of the water-soluble polymer contained in the composition is preferably the water-soluble polymer of the present disclosure, more preferably 55, 60, 65, 70, 75, 80, 85, 90, or 95% by mass or more is the water-soluble polymer of the present disclosure, and particularly preferably 100% by mass is the water-soluble polymer of the present disclosure.
  • the total concentration of the water-soluble polymer of the present disclosure in the aqueous liquid preparation of the present disclosure can be, for example, approximately 0.05 w/v % to 8.8 w/v %.
  • the upper or lower limit of the range is e.g.
  • the range may be, for example, about 0.1 to 7 w/v%, may be about 0.2 to 6 w/v%, or may be about 0.3 to 5 w/v%.
  • the total concentration of the water-soluble polymer in the aqueous liquid formulation of the present disclosure can be, for example, about 0.05 w/v% to 8.8 w/v%.
  • the upper or lower limit of the range is e.g. ,3.1,3.2,3.3,3.4,3.5,3.6,3.7,3.8,3.9,4,4.1,4.2,4.3,4.4,4.5,4.6,4.7,4.8,4.9,5,5.1,5.2,5.3,5.4,5.5,5.6,5.7,5.8,5.9,6,6.1,6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, or 8.7 w/v%.
  • the range may be, for example, about 0.1 to 7 w/v%, may be about 0.2 to 6 w/v%, or may be about 0.3 to 5 w/v%.
  • the ratio of the water-soluble polymer of the present disclosure to arbekacin and/or its salt is not particularly limited as long as the effect is not impaired.
  • the mass ratio of the total content of arbekacin and/or a salt thereof in terms of arbekacin to the content of the water-soluble polymer of the present disclosure can be about 1:0.01 to 180 parts by mass.
  • the upper or lower limit of the range (0.01 to 180) is, for example, 0.02, 0.03, 0.04, 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6 , 7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48 , 49, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, or 170.
  • the mass ratio may be, for example, about 1:0.01 to 110 parts by mass, may be about 1:0.04 to 70 parts by mass, may be about 1:0.1 to 20 parts by mass, or may be about 1:0.25 to 14 parts by mass.
  • the ratio of the water-soluble polymer to arbekacin and/or its salt is not particularly limited as long as the effect is not impaired.
  • the mass ratio of the total content of arbekacin and/or salts thereof in terms of arbekacin and the content of the water-soluble polymer can be about 1:0.01 to 180 parts by mass.
  • the upper or lower limit of the range (0.01 to 180) is, for example, 0.02, 0.03, 0.04, 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6 , 7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48 , 49, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, or 170. Therefore, the mass ratio may be, for example, about 1:0.01 to 110 parts by mass, may be about 1:0.04 to 70 parts by mass, may be about 1:0.1 to 20
  • the aqueous liquid formulation of the present disclosure may contain additives such as buffers, tonicity agents, surfactants, antiseptics or preservatives, cooling agents, stabilizers, pH adjusters, etc., if necessary.
  • the buffer is not particularly limited as long as it is pharmaceutically acceptable, and examples include borate buffers, citrate buffers, phosphate buffers, Tris buffers, tartrate buffers, acetate buffers, amino acid buffers, and the like. These buffering agents may be used individually by 1 type, and may be used in combination of 2 or more type.
  • borate buffers include boric acid and/or salts thereof.
  • Boric acid is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include orthoboric acid, metaboric acid, tetraboric acid and the like. Among these boric acids, orthoboric acid and tetraboric acid are preferred. These boric acids may be used singly or in combination of two or more.
  • the salt of boric acid is not particularly limited as long as it is pharmaceutically acceptable, and includes alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts; organic amine salts such as triethylamine, triethanolamine, morpholine, piperazine, and pyrrolidine.
  • boric acid/or its salt may be in the form of a hydrate, such as borax.
  • borate buffer one of boric acid and its salts may be selected and used alone, or two or more thereof may be used in combination.
  • boric acid and salts thereof at least one of boric acid and borax is preferred, and at least one of orthoboric acid and borax is more preferred.
  • Citric acid buffers specifically include citric acid and/or salts thereof.
  • the salt of citric acid is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts.
  • the citric acid salt may be in the form of a solvate such as a hydrate.
  • the citric acid buffer one of citric acid and salts thereof may be selected and used alone, or two or more thereof may be used in combination.
  • citric acid salts are preferred, alkali metal citric acid salts are more preferred, and sodium citrate is particularly preferred.
  • phosphate buffers include phosphoric acid and/or salts thereof.
  • the salt of phosphoric acid is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include dialkali metal hydrogen phosphate such as disodium hydrogen phosphate and dipotassium hydrogen phosphate; alkali metal dihydrogen phosphate such as sodium dihydrogen phosphate and potassium dihydrogen phosphate; and tri-alkali metal phosphate such as trisodium phosphate and tripotassium phosphate.
  • the salt of phosphoric acid may be in the form of a solvate such as a hydrate.
  • disodium hydrogen phosphate in the case of disodium hydrogen phosphate, it may be in the form of a dodecahydrate, and in the case of sodium dihydrogen phosphate, it may be in the form of a dihydrate.
  • phosphate buffer one of phosphoric acid and salts thereof may be selected and used alone, or two or more thereof may be used in combination.
  • phosphoric acids and salts thereof phosphates are preferred, more preferably at least one of dialkali metal hydrogen phosphate and alkali metal dihydrogen phosphate, and particularly preferably at least one of disodium hydrogen phosphate and sodium dihydrogen phosphate.
  • Tris buffers include trometamol and/or salts thereof.
  • the salt of trometamol is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include organic acid salts such as acetate; inorganic acid salts such as hydrochloride and sulfonate.
  • the Tris buffer one of trometamol and salts thereof may be selected and used alone, or two or more thereof may be used in combination. Among trometamol and salts thereof, trometamol is preferred.
  • tartaric acid buffers include tartaric acid and/or salts thereof.
  • Salts of tartaric acid are not particularly limited as long as they are pharmaceutically acceptable, and examples thereof include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts;
  • the salt of tartaric acid may be in the form of a solvate such as a hydrate.
  • the tartaric acid buffer one of tartaric acid and salts thereof may be selected and used alone, or two or more thereof may be used in combination.
  • acetate buffers include acetic acid and/or salts thereof.
  • the salt of acetic acid is not particularly limited as long as it is pharmaceutically acceptable. Examples include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and ammonium salts.
  • the acetic acid salt may be in the form of a solvate such as a hydrate.
  • one of acetic acid and salts thereof may be selected and used alone, or two or more thereof may be used in combination.
  • amino acid buffers include acidic amino acids and/or salts thereof.
  • acidic amino acids include aspartic acid and glutamic acid.
  • Salts of acidic amino acids are not particularly limited as long as they are pharmaceutically acceptable, and examples thereof include alkali metal salts such as sodium salts and potassium salts.
  • the amino acid buffer one selected from acidic amino acids and salts thereof may be used alone, or two or more thereof may be used in combination.
  • the concentration of the buffering agent in the aqueous solution of the present disclosure may be appropriately set within a range in which the desired buffering capacity can be imparted to the aqueous solution, and can be, for example, about 0.01 to 3.0 w/v%.
  • the tonicity agent is not particularly limited as long as it is pharmaceutically acceptable.
  • examples include polyhydric alcohols such as glycerin, propylene glycol, butylene glycol, and polyethylene glycol; metal salts such as sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium acetate, potassium acetate, sodium hydrogen sulfite, sodium hydrogen carbonate, sodium carbonate, disodium hydrogen phosphate, and sodium dihydrogen phosphate.
  • polyhydric alcohols such as glycerin, propylene glycol, butylene glycol, and polyethylene glycol
  • metal salts such as sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium acetate, potassium acetate, sodium hydrogen sulfite, sodium hydrogen carbonate, sodium carbonate, disodium hydrogen phosphate, and sodium dihydrogen phosphate.
  • isotonizing agents may be used singly or in combination of two or more.
  • the surfactant is not particularly limited as long as it is pharmaceutically acceptable, but for example, nonionic surfactants such as tyloxapol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, and octoxynol; amphoteric surfactants such as alkyldiaminoethylglycine and betaine lauryldimethylaminoacetate; and cationic surfactants such as alkylpyridinium salts and alkylamine salts. These surfactants may be used singly or in combination of two or more.
  • nonionic surfactants such as tyloxapol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, and octoxynol
  • amphoteric surfactants such as alkyldiaminoethylglycine and be
  • the antiseptic or preservative is not particularly limited as long as it is pharmaceutically acceptable, but for example, sorbic acid or its salts, benzoic acid or its salts, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, benzalkonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, chlorhexidine acetate, dehydroacetic acid or its salts, benzethonium chloride, benzyl alcohol, zinc chloride, Zinc sulfate, silver nitrate, polyhexanide, alkyldiaminoethylglycine hydrochloride, parachlormetaxylenol, chlorcresol, phenethyl alcohol, polydronium chloride, thimerosal, dibutylhydroxytoluene and the like.
  • These preservatives or preservatives may be used singly or in combination of two or
  • the cooling agent is not particularly limited as long as it is pharmaceutically acceptable, and examples include l-menthol, borneol, camphor, eucalyptus oil, and the like. These cooling agents may be used singly or in combination of two or more.
  • the stabilizer is not particularly limited as long as it is pharmaceutically acceptable.
  • chelating agents such as edetic acid, citric acid, succinic acid, ascorbic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1-hydroxyethane-1,1-diphosphonic acid, polyphosphoric acid, metaphosphoric acid, hexametaphosphoric acid, and salts thereof; sodium thiosulfate, sulfite, monoethanolamine, cyclodextrin, dextran, ascorbic acid, taurine, copherol, dibutylhydroxytoluene, and the like.
  • the salt form is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include alkali metal salts such as sodium salts and potassium salts. These stabilizers may be used singly or in combination of two or more.
  • the pH adjuster is not particularly limited as long as it is pharmaceutically acceptable.
  • examples include acids such as hydrochloric acid, acetic acid, boric acid, aminoethylsulfonic acid, and epsilon-aminocaproic acid; alkalis such as sodium hydroxide, potassium hydroxide, borax, triethanolamine, monoethanolamine, sodium hydrogen carbonate, and sodium carbonate.
  • acids such as hydrochloric acid, acetic acid, boric acid, aminoethylsulfonic acid, and epsilon-aminocaproic acid
  • alkalis such as sodium hydroxide, potassium hydroxide, borax, triethanolamine, monoethanolamine, sodium hydrogen carbonate, and sodium carbonate.
  • concentrations of these additives may be appropriately set according to the types of additives used and the properties to be imparted to the aqueous solution.
  • the pH of the aqueous liquid formulation of the present disclosure is not particularly limited as long as it is pharmaceutically acceptable.
  • about pH 5.0 to 8.0 can be mentioned.
  • it may be about 5.4 to 7.5, about 5.4 to 7.0, or about 5.4 to 6.0.
  • the viscosity of the aqueous liquid formulation of the present disclosure is not particularly limited, but can be, for example, about 5.0 to 100 mPa ⁇ s. For example, it may be about 5 to 50 mPa ⁇ s, about 10 to 35 mPa ⁇ s, or about 20 to 35 mPa ⁇ s.
  • the osmotic pressure of an aqueous solution is a value measured according to the method specified in "2.47 Osmotic pressure measurement method (osmolality measurement method)" of "General test methods” of the 18th revision of the Japanese Pharmacopoeia.
  • the osmotic pressure of the aqueous liquid preparation of the present disclosure is not particularly limited as long as it is applicable to the intended use. For example, when applied to the ocular mucosa, the osmotic pressure is about 243 to 350 mOsm/kg.
  • the osmotic pressure ratio of the aqueous solution refers to the ratio of the osmotic pressure of the aqueous solution to the osmotic pressure of the physiological saline (0.9 w/v% sodium chloride aqueous solution).
  • the osmotic pressure ratio of the aqueous liquid preparation of the present disclosure is not particularly limited as long as it is applicable to the intended use.
  • the osmotic pressure ratio ranges from 0.85 to 1.15. From the viewpoint of alleviating eye irritation, it is preferably 0.9 to 1.1, more preferably 1.0.
  • the value obtained by subtracting the viscosity increase value due to arbekacin and the water-soluble polymer solution from the viscosity increase value due to arbekacin and the water-soluble polymer is preferably greater than zero.
  • C ⁇ (A+B) is greater than 0 (C ⁇ (A+B)>0) in the aqueous liquid formulation of the present disclosure.
  • C ⁇ (A+B) may be greater than any of 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65. Among them, 0.1 is preferred, 0.3 is more preferred, and 0.5 is even more preferred.
  • the aqueous liquid preparation of the present disclosure preferably has a rate of decrease in release rate of arbekacin and/or a salt thereof of 5% or more.
  • the reduction in release rate of arbekacin and/or salts thereof may be greater than any of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25%. Among them, 5% is preferred, 15% is more preferred, and 25% is even more preferred.
  • the formulation form of the aqueous solution of the present disclosure is not particularly limited, and may be any of an aqueous solution, a suspension, an emulsion, and the like. An aqueous solution is preferred.
  • aqueous liquid preparation of the present disclosure may be manufactured according to a known preparation method according to its formulation form, for example, it can be manufactured using the method described in the 18th revision of the Japanese Pharmacopoeia General Rules for Formulations.
  • the method for producing an aqueous liquid preparation of the present disclosure includes a step of blending arbekacin and/or a salt thereof and at least one water-soluble polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and polyvinylpyrrolidone into a pharmaceutically acceptable aqueous medium.
  • "Pharmaceutically acceptable aqueous medium” means a pharmaceutically acceptable aqueous medium and includes, for example, purified water.
  • the order of blending each component is not particularly limited, and the components may be blended sequentially in any order, or may be blended simultaneously.
  • the aqueous liquid formulation of the present disclosure is prepared into pharmaceutical compositions for various uses such as ophthalmology, dentistry, otolaryngology, and dermatology, and used as topical administration formulations.
  • the aqueous solutions of the present disclosure can be, for example, ophthalmic, dental, otolaryngological, or dermatological compositions. Ophthalmic compositions are preferred.
  • ophthalmic compositions include eye drops, eye washes, contact lens preparations, injections, and the like. Among these, eye drops are preferred.
  • Arbekacin and/or a salt thereof contained in the aqueous liquid preparation of the present disclosure exerts an antibacterial effect against Gram-positive and Gram-negative bacteria. Therefore, the aqueous liquid preparation of the present disclosure can be suitably used, for example, for the treatment of bacterial external eye infections and bacterial keratoconjunctivitis (bacterial conjunctivitis and/or bacterial keratitis), and can be more suitably used for the treatment of bacterial conjunctivitis. Gram-positive bacteria, Gram-negative bacteria, etc. are mentioned as causative bacteria of a bacterial external eye infection.
  • Gram-positive bacteria that cause bacterial conjunctivitis include, for example, Staphylococci (eg, methicillin-resistant Staphylococcus aureus), Streptococcus pneumoniae, and Corynebacterium.
  • Gram-negative bacteria that cause bacterial conjunctivitis include, for example, Haemophilus influenzae, Moraxella, and Neisseria gonorrhoeae (Noriko Inada, Clinical Ophthalmology, Vol. 75, No. 11, 2021).
  • causative bacteria of bacterial keratitis examples include Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, Moraxella, Serratia, Streptococcus, Neisseria gonorrhoeae, anaerobes, and atypical acid-fast bacteria (Clinical Guidelines for Infectious Keratitis (2nd edition), Japanese Ophthalmological Society, 2013).
  • the causative bacteria of bacterial external eye infection and bacterial keratoconjunctivitis may be one type alone or two or more types in combination.
  • Bacterial external eye infections are preferably caused by Staphylococcus (e.g., methicillin-resistant Staphylococcus aureus), Corynebacterium, Pseudomonas aeruginosa, Haemophilus influenzae, Streptococcus pneumoniae, Moraxella, Neisseria gonorrhoeae, Serratia, or Streptococcus.
  • Staphylococcus e.g., methicillin-resistant Staphylococcus aureus
  • Corynebacterium eudomonas aeruginosa
  • Haemophilus influenzae Streptococcus pneumoniae
  • Moraxella Moraxella
  • Neisseria gonorrhoeae Neisseria gonorrhoeae
  • Serratia Neisseria gonorrhoeae
  • Streptococcus Preferred are Staphylococci (eg, methicillin-resistant
  • Non-Patent Document 4 It is known that nonionic water-soluble polymers such as hydroxypropylmethylcellulose, methylcellulose, and polyvinylpyrrolidone do not have mucin adhesiveness (Non-Patent Document 4). Nevertheless, as shown in the examples below, it was found that the aqueous liquid preparation of the present disclosure interacts with mucin and thickens when these water-soluble polymers and arbekacin and/or salts thereof are used in combination. When the viscosity of the ophthalmic solution increases, it tends to remain on the ocular surface for a long period of time, thereby improving the migration of the drug to target sites such as the cornea and conjunctiva.
  • the aqueous solution of the present disclosure is mixed with mucin to allow the water-soluble polymer, arbekacin and mucin to interact in the aqueous solution.
  • mucins are classified into free mucins and membranous mucins, both of which have carboxyl groups at their ends and are negatively charged.
  • the mucin layer is composed such that the mucins repel each other and the free mucin spreads over the membranous mucin expressed in epithelial cells of the cornea and conjunctiva (Non-Patent Document 5).
  • Non-Patent Document 6 Both free mucin and membrane-type mucin are known to contribute to the stabilization of the tear film.
  • the aqueous liquid preparation of the present disclosure interacts with the free mucin floating in the aqueous layer of the tear film, thereby facilitating retention in tear fluid for a long period of time.
  • the aqueous liquid preparation of the present disclosure adheres to the ocular surface by interacting with membranous mucin that is expressed on the surface of the epithelial cells of the cornea and conjunctiva, and tends to gather near target sites such as the cornea and conjunctiva.
  • the aqueous liquid preparation of the present disclosure when administered by eye drops, it has excellent migration of arbekacin to target sites such as the cornea and conjunctiva due to the effect of thickening on the ocular surface and the effect of adhesion to mucin.
  • the aqueous liquid preparation of the present disclosure has excellent transferability of arbekacin, and therefore has an excellent effect on the treatment of bacterial external ocular infections (more specifically, bacterial keratoconjunctivitis).
  • the aqueous solution of the present disclosure can also thicken the tear film and stabilize the tear film.
  • the aqueous solution of the present disclosure stabilizes the tear film when administered instilled into the eye so that the tear film stays in the cornea for a long period of time and prevents exposure of the eye surface, thus having a protective effect on the eye surface. Therefore, the aqueous liquid preparation of the present disclosure can be suitably used, for example, for tear film stabilization applications.
  • One of the pathological conditions of dry eye is destabilization of the tear film and shortening of BUT, which leads to failure of ocular surface protection and causes superficial punctate keratopathy (SPK). Since the aqueous solution of the present disclosure stabilizes the tear film when administered instilled into the eye, it improves BUT prolongation and SPK, and can be used for dry eye treatment.
  • SPK superficial punctate keratopathy
  • Non-Patent Document 8 The tear film is known to protect the ocular surface from bacteria, and the antibacterial activity of mucin has also attracted attention (Non-Patent Document 8). Since the aqueous solution of the present disclosure stabilizes the tear film when administered instilled into the eye, the tear film protects the ocular surface, making it difficult for external enemies such as bacteria to enter, and the antibacterial activity inherent in tear fluid is more effectively exhibited. In addition, the antibacterial effect of arbekacin is enhanced due to the above-described thickening and adhesiveness-improving effects, and thus has excellent effects on the treatment of bacterial external eye infections (more specifically, bacterial keratoconjunctivitis).
  • the aqueous solution of the present disclosure has a tear film stabilizing effect of the aqueous solution of the present disclosure in addition to the therapeutic effect of arbekacin on bacterial external eye infections, it can be used particularly for the treatment of bacterial external eye infections associated with dry eye.
  • Subjects for administration of the aqueous liquid formulation of the present disclosure include, for example, humans and mammals other than humans (eg, rats, mice, rabbits, cows, pigs, dogs, cats, sheep, monkeys, etc.).
  • Humans to be administered include, for example, patients with bacterial keratoconjunctivitis, humans suspected of having bacterial keratoconjunctivitis, and humans infected with the bacteria described above.
  • humans infected with or suspected of being infected with Staphylococci e.g., methicillin-resistant Staphylococcus aureus, etc.
  • Staphylococci e.g., methicillin-resistant Staphylococcus aureus, etc.
  • Corynebacterium, Pseudomonas aeruginosa, Haemophilus influenzae, Streptococcus pneumoniae, Moraxella, Neisseria gonorrhoeae, Serratia, or Streptococcus are preferred, and humans infected or infected with Staphylococci (e.g., methicillin-resistant Staphylococcus aureus, etc.), Corynebacterium, Pseudomonas aeruginosa, Haemophilus influenzae, or Streptococcus pneumoniae.
  • Staphylococci e.g., methicillin-resistant Staphylococcus aureus
  • Humans suspected of being infected with Staphylococcus are more preferred, humans infected with or suspected of being infected with Staphylococcus spp.
  • Humans to be administered include, for example, humans with an unstable tear film. More specifically, dry eye patients, or humans suspected of having dry eye; patients with bacterial external eye infection associated with dry eye (more specifically, bacterial keratoconjunctivitis) or people suspected of having bacterial external eye infection associated with dry eye (more specifically, bacterial keratoconjunctivitis) are exemplified.
  • the administration (ingestion) amount of the aqueous liquid preparation of the present disclosure is not particularly limited, and is determined according to the age, body weight, sex, severity of symptoms, administration method, etc. of the subject to be administered.
  • the dosage of arbekacin can be about 0.004 to 1.5 mg/kg body weight per day.
  • one drop (eg, 1 to 3 drops, etc.) may be instilled once or multiple times (eg, 2 to 8 times, etc.) per day. In one aspect of the aqueous solution of the present disclosure, one drop is instilled twice a day.
  • the present disclosure also includes a method of treating a bacterial external ocular infection (more specifically, bacterial keratoconjunctivitis), comprising administering to a subject in need thereof an aqueous solution comprising arbekacin and/or a salt thereof and at least one water-soluble polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and polyvinylpyrrolidone.
  • the present disclosure also encompasses a method of treating dry eye comprising administering to a subject in need thereof an aqueous solution comprising arbekacin and/or a salt thereof and at least one water-soluble polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and polyvinylpyrrolidone.
  • the present disclosure also encompasses a method of treating external bacterial ocular infections associated with dry eye (more specifically, bacterial keratoconjunctivitis), comprising administering to a subject in need thereof an aqueous solution comprising arbekacin and/or a salt thereof and at least one water-soluble polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and polyvinylpyrrolidone.
  • aqueous liquid preparation can be used.
  • the present disclosure also includes a method for thickening an aqueous solution containing a water-soluble polymer on the ocular surface, comprising administering an aqueous solution containing arbekacin and/or a salt thereof and at least one water-soluble polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and polyvinylpyrrolidone to a subject in need thereof.
  • the description in the column "2. Aqueous solution" can be used.
  • the present disclosure also includes methods for improving mucin adhesion , comprising administering to a subject in need thereof an aqueous solution comprising arbekacin and/or salts thereof and at least one water-soluble polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and polyvinylpyrrolidone.
  • aqueous liquid preparation can be used.
  • the present disclosure also includes a method for improving conjunctival transport of arbekacin and/or a salt thereof, comprising administering to a subject in need thereof an aqueous solution containing arbekacin and/or a salt thereof and at least one water-soluble polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and polyvinylpyrrolidone.
  • aqueous liquid formulation can be used.
  • the present disclosure also encompasses methods of stabilizing the tear film comprising administering to a subject in need thereof an aqueous solution comprising arbekacin and/or salts thereof and at least one water-soluble polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and polyvinylpyrrolidone.
  • aqueous solution comprising arbekacin and/or salts thereof and at least one water-soluble polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and polyvinylpyrrolidone.
  • Test Example 1 Viscosity measurement in the presence of mucin The viscosity was measured when a sample and a mucin solution were mixed with reference to the test method described in EmadEldin Hassan and James M. Gallo, A Simple Rheological Method for the in VitroAssessment of Mucin-Polymer Bioadhesive Bond Strength. In addition, the interaction between the sample and mucin was considered by comparing the respective viscosities.
  • Specimens 1 to 11 were prepared by mixing each pre-dissolved solution so as to have the composition shown in Table 1 of the specimen .
  • mucin derived from porcine stomach, Type II, reagent, Sigma Aldrich
  • 0.1 M (mol/L) phosphate buffer so that the pH was the same as that of tears (neutral), and the pH was adjusted to 7.0 with hydrochloric acid or sodium hydroxide to prepare a 6 w/v% mucin solution.
  • Preliminary solution preparation method 25 w/v %, 16 w/v % or 10 w/v % arbekacin solution: Arbekacin sulfate was dissolved in purified water. 2.5 w/v% HPMC solution: Hypromellose 2208 (90SH-100SR, Japanese Pharmacopoeia (Japanese Pharmacopoeia) compliant product, Shin-Etsu Chemical Co., Ltd.) was added and dispersed in heated (approximately 80°C) purified water, and dissolution was confirmed by cooling to room temperature.
  • 1M phosphate buffer Sodium dihydrogen phosphate hydrate (Japan Pharmacopoeia compliant product, Fujifilm Wako Pure Chemical Industries, Ltd.) was dissolved in purified water, and the pH was adjusted to 7.0 with hydrochloric acid or sodium hydroxide.
  • 0.1 M phosphate buffer 1 M phosphate buffer was diluted 1/10 with purified water.
  • Viscosity measurement A mixed solution of each sample (1 mL) and 6 w/v% mucin solution (1 mL), a mixed solution of each sample (1 mL) and 0.1 M phosphate buffer (1 mL), and a mixed solution of 0.1 M phosphate buffer (1 mL) and 6 w/v% mucin solution (1 mL) were measured for viscosity according to the following conditions.
  • Viscosity measurement conditions Measurement device: TVE-25 viscometer (Toki Sangyo Co., Ltd.) Rotor: 1°34' x R24 or 3° x R17.65 (change the rotor depending on the viscosity to be measured) Sample volume: 1.1 mL (when using rotor 1°34' x R24) or 0.8 mL (when using rotor 3° x R17.65) Preheat time: 120s Measurement time: 90s Measurement temperature: 34°C ⁇ 0.1°C Rotation speed: 100rpm
  • B Viscosity increase value by HPMC (mPa s)
  • C Defined as the viscosity increase value (mPa s) due to arbekacin + HPMC, When C ⁇ (A+B)>0, the aqueous solution containing arbekacin and HPMC was evaluated to have a synergistic thickening effect when in contact with the mucin solution.
  • Table 2 shows the sample numbers used to calculate A, B and C for each concentration of arbekacin and HPMC.
  • Table 3 shows the results of evaluating the viscosity increase value of each sample and the interaction between each sample and mucin.
  • Specimens 12 to 19 were prepared by mixing each preliminary dissolution liquid so as to have the composition shown in Table 4 of the specimen .
  • Hypromellose 2208 (90SH-100SR, Japanese Pharmacopoeia (Japanese Pharmacopoeia) compliant product, Shin-Etsu Chemical Co., Ltd.)
  • the concentration of each water-soluble polymer solution was set so as to have a viscosity similar to that of a 1.4 w/v% solution.
  • mucin derived from porcine stomach, Type II, reagent, Sigma Aldrich
  • 0.1 M phosphate buffer so that the pH was the same as that of tear fluid (neutral)
  • the pH was adjusted to 7.0 with hydrochloric acid or sodium hydroxide to prepare a 6 w/v% mucin solution.
  • Preparation method of preliminary dissolution solution 1 w/v% HEC solution: Hydroxyethyl cellulose (Japanese Pharmacopoeia (Japanese Pharmacopoeia) compliant product, Ashland, Inc.) was added and dispersed in heated (approximately 80°C) purified water, cooled to room temperature, and dissolution was confirmed.
  • 1.6 w/v% MC solution Methyl cellulose (SM-400, Japanese Pharmacopoeia (Japanese Pharmacopoeia) compliant product, Shin-Etsu Chemical Co., Ltd.) was added to purified water heated (approximately 80°C) and dispersed, followed by ice cooling to confirm dissolution.
  • PVP solution Polyvinylpyrrolidone (Kollidon 90F, Japanese Pharmacopoeia (JP) compliant product, BASF SE) was dissolved in purified water.
  • a 10 w/v % arbekacin solution, 1 M phosphate buffer and 0.1 M phosphate buffer were prepared in the same manner as described above.
  • the viscosity was measured using the same method and conditions as those described above, and the viscosity increase value was calculated.
  • Viscosity increase value due to arbekacin (mPa s) B: Viscosity increase value due to each water-soluble polymer (mPa s)
  • C Defined as viscosity increase value (mPa s) due to arbekacin + each water-soluble polymer, When C ⁇ (A+B)>0, it was evaluated that an aqueous solution containing arbekacin and each water-soluble polymer had a synergistic thickening effect when in contact with a mucin solution.
  • Table 5 shows the sample numbers used to calculate A, B and C for each concentration of arbekacin and each water-soluble polymer.
  • Table 6 shows the results of evaluating the viscosity increase value of each sample and the interaction between each sample and mucin.
  • Test Example 2 In Vitro Dialysis Membrane Test For the purpose of investigating the interaction between an aqueous solution containing arbekacin and HPMC and mucin, an in vitro dialysis membrane test was carried out using a dialysis membrane to confirm the release rate of arbekacin.
  • Specimens 20 to 27 were obtained by adding the required amount of the pre-dissolution solution shown below to a 1.5 mL polypropylene tube and sufficiently pipetting with a micropipette.
  • arbekacin sulfate was added to purified water and dissolved.
  • 2.5 w/v % HPMC solution Hypromellose 2208 (90SH-100SR, Japanese Pharmacopoeia compliant product, Shin-Etsu Chemical Co., Ltd.) was added and dispersed in heated (approximately 80°C) purified water, cooled to room temperature, and dissolution was confirmed.
  • Phosphate buffered saline (PBS), pH 7.4: PBS Tablet (reagent, Takara Bio Inc.) was added to purified water and dissolved.
  • 2.5 w/v % and 5 w/v % mucin solutions Mucin (derived from porcine stomach, for biochemistry, Fuji Film Wako Pure Chemical Industries, Ltd.) was dissolved in PBS or water.
  • Test method 1 500 ⁇ L of a specimen was enclosed in a 2 mL glass container, the opening was covered with a dialysis membrane, and the surroundings were fixed (the inside of the glass container is the donor side). It was confirmed that the glass container and the dialysis membrane were in close contact with each other and did not leak.
  • the dialysis membrane a commercially available product with the following specifications was used. Fractional molecular weight: 12000-14000, membrane material: regenerated cellulose. 2) 1) was attached to a beaker (external liquid side) filled with PBS (15 mL) so as to have a constant height from the bottom of the beaker, and the liquid in the beaker was stirred using a stirrer.
  • Drug residual rate (%) in the donor relative to the theoretical total amount 100 - (cumulative amount of arbekacin released into the external solution by the time of sampling ( ⁇ g)/theoretical total amount of arbekacin contained in the donor side ( ⁇ g) ⁇ 100)
  • Test Condition Detector Charged particle detector Corona Veo RS Column: Commercial product (Inertsil C8, 5 ⁇ m, 4.6 mm ⁇ 250 mm, GL Sciences) in which a stainless steel tube with an inner diameter of 4.6 mm and a length of 250 mm is filled with 5 ⁇ m of octylsilylated silica gel for liquid chromatography.
  • Column temperature Constant temperature around 30°C
  • Mobile phase Gradient with 5 mM heptafluorobutyric acid aqueous solution and 5 mM heptafluorobutyric acid acetonitrile solution
  • Flow rate 1.4 mL per minute
  • Table 8 shows the residual rate of arbekacin, the release rate, and the decrease rate of the release rate at each time point. Also, the release profile of each analyte is shown in FIG.
  • Test Example 3 Evaluation of Conjunctival Transfer An aqueous solution containing arbekacin was administered to Japanese white rabbits in a single eye drop, and the concentration of arbekacin in the conjunctiva was evaluated.
  • HPMC HPMC was added to purified water heated (approximately 80° C.) and dispersed, cooled to room temperature, and dissolution was confirmed. This liquid was coarsely filtered through a 5 ⁇ m membrane filter to obtain a concentrate A of HPMC.
  • Trometamol, sodium thiosulfate hydrate and arbekacin sulfate were added and dissolved in separately prepared purified water.
  • Hydrochloric acid or sodium hydroxide was added to this liquid to adjust the pH to 7.0, and a concentrated liquid B was obtained by mixing each component.
  • Concentrate B and benzalkonium chloride solution were added to concentrate A (used for preparation of specimen 28) or purified water (used for preparation of specimen 29) and stirred until uniform.
  • Eye drop administration 1) The rabbit was restrained, and it was confirmed by visual observation that there was no disorder in the anterior segment of the eye. 2) Using a micropipette, 35 ⁇ L of the sample was instilled into the eye, and the subject was forced to blink twice. 3) The restraint was released 30 minutes after administration.
  • Kanamycin monosulfate was used as the internal standard (IS), and the concentration of arbekacin in the conjunctiva was analyzed using LC-MS/MS (Q TRAP 5500, AB SCIEX Pte. Ltd.) in positive ion mode.
  • Solution preparation 20 mM EDTA 0.672 g of disodium dihydrogendihydrogen ethylenediaminetetraacetate dihydrate was collected. Then 100 mL of water was added and dissolved. Diluent water/20 mM EDTA/formic acid (1000:2:1, v/v) and acetonitrile/formic acid (1000:1, v/v) were mixed 1:1. 2 mg of IS solution kanamycin monosulfate was weighed and dissolved in 20 mL of 20% methanol. It was then diluted with acetonitrile to 3.00 ⁇ g/mL.
  • Blank Samples 1 20 ⁇ L of blank 10% conjunctiva homogenate was taken. 2) 40 ⁇ L of acetonitrile was added. 3) 80 ⁇ L of acetonitrile was added and mixed.
  • Pretreatment 1 400 ⁇ L of dilution liquid was added and mixed. 2) Centrifuged at 4°C and 20000 xg for 10 minutes. 3) The supernatant was injected into the LC-MS/MS.
  • a single dose of HPMC-containing 3% arbekacin ophthalmic solution (specimen 28) having an evaluation viscosity of about 15 mPa s (30° C. ⁇ 0.1° C., preheating time: 0 s, rotation speed of 100 rpm, TVE-25 viscometer, cone rotor used: 3° ⁇ R17.65, measurement time: 90 s) was administered to rabbits.
  • a single eye drop of HPMC-free 3% arbekacin ophthalmic solution (Sample 29) was administered to rabbits.
  • Tables 12 and 13 provide detailed data for C max and area under the concentration-time curve (AUC 0-t ) for arbekacin concentrations in the conjunctiva.
  • the maximum conjunctival arbekacin concentration (C max ) and AUC 0-t from time 0 to final measurable time t after administration of HPMC-containing 3% arbekacin ophthalmic solution (specimen 28) were 58.5 ⁇ g/g and 20.2 ⁇ g ⁇ h/g, respectively.
  • the C max and AUC 0-t of the arbekacin concentration in the conjunctiva after administration of HPMC-free 3% arbekacin ophthalmic solution were 17.0 ⁇ g/g and 10.5 ⁇ g ⁇ h/g, respectively.
  • the HPMC-containing formulation showed about 3.4-fold higher C max and about 1.9-fold higher AUC 0-t than the HPMC-free formulation. This suggests that adding HPMC to the arbekacin ophthalmic solution prolongs the retention time of the arbekacin ophthalmic solution on the ocular surface and increases the concentration of arbekacin in the conjunctiva.

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