Aqueous liquid preparation

Abstract

To provide a formulation technology relating to an aqueous liquid preparation containing arbekacin and / or a salt thereof, and at least one water-soluble polymer.SOLUTION: There is provided an aqueous liquid preparation containing arbekacin and / or a salt thereof, and a water-soluble polymer, the water-soluble polymer containing at least one selected from the group consisting of hydroxypropyl methylcellulose, hydroxyethylcellulose, methylcellulose, and polyvinylpyrrolidone. The total concentration of the arbekacin and / or a salt thereof is 0.05 w / v% to 5.0 w / v%, preferably 0.1 w / v% to 3.0 w / v%, the water-soluble polymer contains hydroxypropyl methylcellulose, and the concentration of the water-soluble polymer is 0.05 w / v% to 8.8 w / v%, preferably 0.3 w / v% to 2.0 w / v%.SELECTED DRAWING: None

Description

[Technical field]

[0001] 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 an application technology thereof, etc. [Background technology]

[0002] Arbekacin is an aminoglycoside antibiotic. Arbekacin sulfate is used to treat pneumonia and sepsis caused by methicillin-resistant Staphylococcus aureus (MRSA) (Patent Document 1). It has also been reported that arbekacin sulfate exhibits a wide range of antibacterial activity not only against gram-positive bacteria including methicillin-resistant Staphylococcus aureus, but also against gram-negative bacteria (Non-Patent Document 1).

[0003] Furthermore, in aqueous liquid preparations, water-soluble polymers such as hydroxypropylmethylcellulose, 2-hydroxypropyl-β-cyclodextrin, hydroxyethylcellulose, and dextran are generally used as, for example, thickeners or viscosity enhancers (Patent Documents 2 and 3). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] U.S. Patent No. 9,511,143 [Patent Document 2] US Patent Application Publication No. 2020 / 0016176 [Patent Document 3] US Patent Application Publication No. 2007 / 0270378 [Non-patent literature]

[0005] [Non-Patent Document 1] Clin Pharmacol. 2014 Sep 26;6:139-48. [Non-Patent Document 2] PharmRes. 1990 May;7(5):491-5. [Non-Patent Document 3] TFOSDEWS II Report Executive Summary, The Ocular Surface(2017), http: / / dx.doi.org / 10.1016 / j.jtos.2017.08.003 [Non-Patent Document 4] Int.J. Pharm. Sci. Rev. Res. 2014, 24(1), 237-245. [Non-Patent Document 5] New Ophthalmology Vol.22,No.3, 2005, 289-294. [Non-Patent Document 6] AdvClin Exp Med. 2019;28(2):165-169. [Non-Patent Document 7] JColloid Interface Sci. 2003 Jun 1;262(1):130-48. [Non-Patent Document 8] VetOphthalmol. Mar-Apr 2004;7(2):71-7. [Non-Patent Document 9] International Journal of Pharmaceutics, 1989;53(3):219-225 Summary of the Invention [Problem to be solved by the invention]

[0006] An objective of the present disclosure is to provide a formulation technology for an aqueous liquid preparation 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. [Means for solving the problem]

[0007] The present inventors have found that 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 have further improved it.

[0008] The present disclosure includes, for example, the subject matter described in the following sections: Section 1-1. An aqueous liquid preparation comprising arbekacin and / or a salt thereof, and a water-soluble polymer, The aqueous liquid preparation comprises at least one water-soluble polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and polyvinylpyrrolidone. Section 1-2. Item 1-1. The aqueous liquid preparation according to Item 1-1, wherein the total concentration of the arbekacin and / or a salt thereof is 0.05 w / v% to 5.0 w / v%. Section 1-3. The aqueous liquid preparation according to Item 1-1 or 1-2, wherein the total concentration of the arbekacin and / or a salt thereof is 0.1 w / v% to 3.0 w / v%. Section 1-4. The aqueous liquid preparation according to any one of items 1-1 to 1-3, wherein the water-soluble polymer comprises hydroxypropyl methylcellulose. Section 1-5. The aqueous liquid preparation according to any one of Items 1-1 to 1-4, wherein the concentration of the water-soluble polymer is 0.05 w / v % to 8.8 w / v %. Section 1-6. The aqueous liquid preparation according to any one of Items 1-1 to 1-5, wherein the concentration of the water-soluble polymer is 0.3 w / v % to 2.0 w / v %. Section 1-7. The aqueous liquid preparation according to any one of Items 1-1 to 1-6, wherein the concentration of the water-soluble polymer is 0.8 w / v % to 1.4 w / v %. Section 1-8. An aqueous liquid preparation comprising arbekacin and / or a salt thereof, and hydroxypropyl methylcellulose, The total concentration of arbekacin and / or its salt is 0.1 w / v% to 3.0 w / v%, An aqueous liquid preparation having a concentration of hydroxypropyl methylcellulose of 0.8 w / v% to 1.4 w / v%. Section 1-9. The aqueous liquid preparation according to any one of Items 1-1 to 1-8, wherein a mass ratio of the total content of the arbekacin and / or a salt thereof to the content of the water-soluble polymer is 1:0.04 to 1:70. Section 1-10. The aqueous liquid preparation according to any one of Items 1-1 to 1-9, wherein a mass ratio of the total content of the arbekacin and / or a salt thereof to the content of the water-soluble polymer is 1:0.1-20. Section 1-11. The aqueous liquid preparation according to any one of Items 1-1 to 1-10, wherein a mass ratio of the total content of the arbekacin and / or a salt thereof to the content of the water-soluble polymer is 1:0.25 to 1:14. Section 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. Section 1-13. The aqueous liquid preparation according to any one of items 1-1 to 1-12, wherein the viscosity of the aqueous liquid preparation is 5 to 50 mPa·s. Section 1-14. An aqueous liquid preparation comprising arbekacin and / or a salt thereof, and hydroxypropyl methylcellulose, a total concentration of the arbekacin and / or a salt thereof is 0.1 w / v% to 3.0 w / v%, and a concentration of the hydroxypropyl methylcellulose is 0.3 w / v% to 2.0 w / v%, a mass ratio of the total content of the arbekacin and / or a salt thereof to the content of the water-soluble polymer is 1:0.04-70; The pH of the aqueous liquid is 5.0 to 8.0; The viscosity of the aqueous liquid is 5 to 50 mPa·s. Section 1-15. The aqueous liquid preparation according to any one of items 1-1 to 1-14, wherein C-(A+B) is greater than 0. A: Viscosity increase value due to arbekacin (mPa s) B: Viscosity increase due to water-soluble polymer (mPa s) C: Viscosity increase due to arbekacin and water-soluble polymer (mPa s)

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[0009] Section 2-1. 1. A method for treating a bacterial external eye infection, comprising: The method includes administering an aqueous liquid preparation containing arbekacin and / or a salt thereof, and a water-soluble polymer to a subject in need thereof, The method for treating an external bacterial eye infection, wherein the water-soluble polymer comprises at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and polyvinylpyrrolidone. Section 2-2. 1. A method for treating a bacterial external eye infection, comprising: The method includes administering an aqueous liquid preparation containing arbekacin and / or a salt thereof, and a water-soluble polymer to a subject in need thereof, The method for treating an external bacterial eye infection, wherein the water-soluble polymer comprises hydroxypropyl methylcellulose. Section 2-3. 1. A method for treating bacterial conjunctivitis, comprising: The method includes administering an aqueous liquid preparation containing arbekacin and / or a salt thereof, and a water-soluble polymer to a subject in need thereof, The method for treating bacterial conjunctivitis, wherein the water-soluble polymer comprises hydroxypropyl methylcellulose. Section 2-4. 1. A method for treating a bacterial external eye infection, comprising: The method comprises administering an aqueous solution containing 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 comprises at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and polyvinylpyrrolidone. How to treat bacterial external eye infections. Section 2-5. 1. A method for treating bacterial conjunctivitis, comprising: Administering an aqueous solution comprising arbekacin and / or a salt thereof and hydroxypropyl methylcellulose to the ocular surface of a subject in need thereof. How to treat bacterial conjunctivitis. Section 2-6a. The method for treatment according to any one of items 2-1 to 2-5, comprising a step of contacting the aqueous liquid preparation with mucin. Section 2-6b. administering the aqueous solution to the ocular surface of a subject in need thereof, administering the aqueous solution to the ocular surface of the subject such that the aqueous solution contacts the mucin. The method for treatment according to any one of items 2-1 to 2-5. Section 2-7a. The method for treatment according to any one of Items 2-1 to 2-6, comprising a step of thickening the aqueous liquid preparation on the ocular surface. Section 2-7b. administering the aqueous solution to the ocular surface of a subject in need thereof, administering the aqueous solution to the ocular surface of the subject so that the aqueous solution thickens on the ocular surface; The method for treatment according to any one of items 2-1 to 2-6. Section 2-8a. The method for treatment according to any one of items 2-1 to 2-7, further comprising a step of improving mucin adhesiveness of the aqueous liquid preparation. Section 2-8b. administering the aqueous solution to the ocular surface of a subject in need thereof, administering the aqueous solution to the subject's ocular surface such that mucin adhesion is enhanced after administration; The method for treatment according to any one of Items 2-1 to 2-7. Section 2-9a. 1. A method for treating a bacterial external eye infection, comprising: The method comprises administering an aqueous solution containing arbekacin and / or a salt thereof and a water-soluble polymer to the ocular surface of a subject in need thereof, the step of contacting the aqueous liquid preparation with mucin to thicken the aqueous liquid preparation and improve the mucin adhesiveness of the aqueous liquid preparation; The water-soluble polymer comprises at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and polyvinylpyrrolidone. How to treat bacterial external eye infections. Section 2-9b. 1. A method for treating a bacterial external eye infection, comprising: The method comprises administering an aqueous solution containing 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 comprises at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and polyvinylpyrrolidone; The administration is carried out in such a way that the aqueous liquid preparation comes into contact with mucin, thereby thickening the aqueous liquid preparation and improving the adhesiveness of the aqueous liquid preparation to mucin. How to treat bacterial external eye infections. Section 2-9c. 1. A method for treating bacterial conjunctivitis, comprising: Administering an aqueous solution comprising arbekacin and / or a salt thereof and hydroxypropyl methylcellulose to the ocular surface of a subject in need thereof; the step of contacting the aqueous liquid preparation with mucin to thicken the aqueous liquid preparation and improve the mucin adhesiveness of the aqueous liquid preparation; How to treat bacterial conjunctivitis. Section 2-9d. 1. A method for treating bacterial conjunctivitis, comprising: Administering an aqueous solution comprising arbekacin and / or a salt thereof and hydroxypropyl methylcellulose to the ocular surface of a subject in need thereof; The administration is carried out in such a way that the aqueous liquid preparation comes into contact with mucin, thereby thickening the aqueous liquid preparation and improving the adhesiveness of the aqueous liquid preparation to mucin. How to treat bacterial conjunctivitis. Section 2-10. A method for improving conjunctival permeability of arbekacin and / or a salt thereof, comprising the steps of: The method includes administering an aqueous liquid preparation containing arbekacin and / or a salt thereof, and a water-soluble polymer to a subject in need thereof, The method for improving conjunctival permeability, wherein the water-soluble polymer comprises hydroxypropyl methylcellulose. Section 2-11. The method according to any one of Items 2-1 to 2-10, wherein the total concentration of arbekacin and / or a salt thereof in the aqueous liquid preparation is 0.05 w / v% to 5.0 w / v%. Section 2-12. The method according to any one of Items 2-1 to 2-11, wherein the concentration of the water-soluble polymer in the aqueous liquid preparation is 0.05 w / v % to 8.8 w / v %. Section 2-13. The method according to any one of Items 2-1 to 2-12, wherein the mass ratio of the total content of the arbekacin and / or a salt thereof to the content of the water-soluble polymer in the aqueous liquid preparation is 1:0.04 to 1:70. Section 2-14. The method according to any one of Items 2-1 to 2-13, wherein the aqueous liquid preparation has a pH of 5.0 to 8.0. Section 2-15. The method according to any one of items 2-1 to 2-14, wherein the aqueous liquid preparation has a viscosity of 5 to 50 mPa·s. Section 2-16. 1. A method for treating a bacterial external eye infection, comprising: The method includes administering an aqueous liquid preparation containing arbekacin and / or a salt thereof, and a water-soluble polymer to a subject in need thereof, the water-soluble polymer comprises hydroxypropyl methylcellulose; a total concentration of the arbekacin and / or a salt thereof is 0.1 w / v% to 3.0 w / v%, and a concentration of the hydroxypropyl methylcellulose is 0.3 w / v% to 2.0 w / v%, a mass ratio of the total content of the arbekacin and / or a salt thereof to the content of the hydroxypropyl methylcellulose is 1:0.04-70; The pH of the aqueous liquid is 5.0 to 8.0; The method for treating an external bacterial eye infection, wherein the viscosity of the aqueous liquid preparation is 5 to 50 mPa·s. Section 2-17. The method according to any one of items 2-1 to 2-16, wherein the aqueous liquid preparation is an aqueous liquid preparation in which C-(A+B) is greater than 0. A: Viscosity increase due to arbekacin (mPa s) B: Viscosity increase due to water-soluble polymer (mPa s) C: Viscosity increase due to arbekacin and water-soluble polymer (mPa s)

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[0010] Section 3-1. 1. A method for treating an external bacterial eye infection associated with dry eye, comprising: The method includes administering an aqueous liquid preparation containing arbekacin and / or a salt thereof, and a water-soluble polymer to a subject in need thereof, The method for treating an external bacterial eye infection accompanied by dry eye, wherein the water-soluble polymer comprises at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and polyvinylpyrrolidone. Section 3-2. 1. A method for treating an external bacterial eye infection associated with dry eye, comprising: The method includes administering an aqueous liquid preparation containing arbekacin and / or a salt thereof, and a water-soluble polymer to a subject in need thereof, The method for treating external bacterial eye infections accompanied by dry eye, wherein the water-soluble polymer comprises hydroxypropyl methylcellulose. Section 3-3. 1. A method for treating bacterial conjunctivitis associated with dry eye, comprising: The method includes administering an aqueous liquid preparation containing arbekacin and / or a salt thereof, and a water-soluble polymer to a subject in need thereof, The method for treating bacterial conjunctivitis accompanied by dry eye, wherein the water-soluble polymer comprises hydroxypropyl methylcellulose. Section 3-4. The method for treatment according to any one of Items 3-1 to 3-3, wherein the total concentration of arbekacin and / or a salt thereof in the aqueous liquid preparation is 0.05 w / v % to 5.0 w / v %. Section 3-5. The method for treatment according to any one of Items 3-1 to 3-4, wherein the concentration of the water-soluble polymer in the aqueous liquid preparation is 0.05 w / v % to 8.8 w / v %. Section 3-6. The method for treatment according to any one of Items 3-1 to 3-5, wherein the mass ratio of the total content of the arbekacin and / or a salt thereof to the content of the water-soluble polymer in the aqueous liquid preparation is 1:0.04 to 1:70. Section 3-7. The method for treatment according to any one of Items 3-1 to 3-6, wherein the aqueous liquid preparation has a pH of 5.0 to 8.0. Section 3-8. The method for treatment according to any one of Items 3-1 to 3-7, wherein the aqueous liquid preparation has a viscosity of 5 to 50 mPa·s. Section 3-9. 1. A method for treating an external bacterial eye infection associated with dry eye, comprising: The method includes administering an aqueous liquid preparation containing arbekacin and / or a salt thereof, and a water-soluble polymer to a subject in need thereof, the water-soluble polymer comprises hydroxypropyl methylcellulose; a total concentration of the arbekacin and / or a salt thereof is 0.1 w / v% to 3.0 w / v%, and a concentration of the hydroxypropyl methylcellulose is 0.3 w / v% to 2.0 w / v%, a mass ratio of the total content of the arbekacin and / or a salt thereof to the content of the hydroxypropyl methylcellulose is 1:0.04-70; The pH of the aqueous liquid is 5.0 to 8.0; The method for treating external bacterial eye infections accompanied by dry eye, wherein the viscosity of the aqueous liquid preparation is 5 to 50 mPa·s. Section 3-10. The treatment method according to any one of items 3-1 to 3-9, wherein the aqueous liquid preparation is an aqueous liquid preparation in which C-(A+B) is greater than 0. A: Viscosity increase due to arbekacin (mPa s) B: Viscosity increase due to water-soluble polymer (mPa s) C: Viscosity increase due to arbekacin and water-soluble polymer (mPa s)

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[0011] Section 4-1. 1. A method for treating dry eye, comprising: The method includes administering an aqueous liquid preparation containing arbekacin and / or a salt thereof, and a water-soluble polymer to a subject in need thereof, The method for 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. Section 4-2. A method for thickening an aqueous liquid preparation containing a water-soluble polymer on an ocular surface, comprising: The method includes administering an aqueous liquid preparation containing arbekacin and / or a salt thereof, and a water-soluble polymer to a subject in need thereof, The method wherein the water-soluble polymer comprises hydroxypropyl methylcellulose. Section 4-3. 1. A method for enhancing mucin adhesiveness, comprising: The method includes administering an aqueous liquid preparation containing arbekacin and / or a salt thereof, and a water-soluble polymer to a subject in need thereof, The method for improving mucin adhesiveness, wherein the water-soluble polymer comprises hydroxypropyl methylcellulose. Section 4-4. 1. A method for stabilizing a tear film, comprising: The method includes administering an aqueous liquid preparation containing arbekacin and / or a salt thereof, and a water-soluble polymer to a subject in need thereof, The method for stabilizing the tear film, wherein the water-soluble polymer comprises hydroxypropyl methylcellulose. Section 4-5. 1. A method for treating dry eye, comprising: The method includes administering an aqueous liquid preparation containing arbekacin and / or a salt thereof, and a water-soluble polymer to a subject in need thereof, The method for treating dry eye, wherein the water-soluble polymer comprises hydroxypropyl methylcellulose. Section 4-6. The method according to any one of Items 4-1 to 4-5, wherein the total concentration of arbekacin and / or a salt thereof in the aqueous liquid preparation is 0.05 w / v% to 5.0 w / v%. Section 4-7. The method according to any one of Items 4-1 to 4-6, wherein the concentration of the water-soluble polymer in the aqueous liquid preparation is 0.05 w / v % to 8.8 w / v %. Section 4-8. The method according to any one of Items 4-1 to 4-7, wherein the mass ratio of the total content of the arbekacin and / or a salt thereof to the content of the water-soluble polymer in the aqueous liquid preparation is 1:0.04 to 1:70. Section 4-9. The method according to any one of items 4-1 to 4-8, wherein the aqueous liquid preparation has a pH of 5.0 to 8.0. Section 4-10. The method according to any one of items 4-1 to 4-9, wherein the aqueous liquid preparation has a viscosity of 5 to 50 mPa·s. Section 4-11. 1. A method for treating dry eye, comprising: The method includes administering an aqueous liquid preparation containing arbekacin and / or a salt thereof, and a water-soluble polymer to a subject in need thereof, the water-soluble polymer comprises hydroxypropyl methylcellulose; a total concentration of the arbekacin and / or a salt thereof is 0.1 w / v% to 3.0 w / v%, and a concentration of the hydroxypropyl methylcellulose is 0.3 w / v% to 2.0 w / v%, a mass ratio of the total content of the arbekacin and / or a salt thereof to the content of the hydroxypropyl methylcellulose is 1:0.04-70; The pH of the aqueous liquid is 5.0 to 8.0; The method for treating dry eye, wherein the viscosity of the aqueous liquid preparation is 5 to 50 mPa·s. Section 4-12. The method according to any one of items 4-1 to 4-11, wherein the aqueous liquid formulation is an aqueous liquid formulation in which C-(A+B) is greater than 0. A: Viscosity increase due to arbekacin (mPa s) B: Viscosity increase due to water-soluble polymer (mPa s) C: Viscosity increase due to arbekacin and water-soluble polymer (mPa s)

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[0012] The mucin adhesiveness of the aqueous liquid preparation can be improved, and the conjunctival transferability of the aqueous liquid preparation can be improved. [Brief description of the drawings]

[0013] [Figure 1] The release profile of each sample in the dialysis membrane test is shown ((a) samples 20 to 23 (systems of arbekacin 1%, HPMC 1%, and mucin 1%), (b) samples 24 and 25 (systems of arbekacin 3%, HPMC 1.5%, and mucin 1%), and (c) samples 26 and 27 (systems of arbekacin 0.5%, HPMC 1.5%, and mucin 1%)). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Each embodiment included in the present disclosure will be described in further detail below.

[0015] 1.Definition It should be understood that the terms used herein are used in the sense commonly used in the art unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. In case of conflict, the present specification (including definitions) shall prevail.

[0016] In the present specification, the term "aqueous liquid preparation" refers to a preparation that contains water as a base and is in a liquid form.

[0017] As used herein, the term "water-soluble polymer" refers to a polymer that is soluble in water.

[0018] In the present specification, "arbekacin" refers to 3-amino-3-deoxy-α-D-glucopyranosyl-(1→6)-[2,6-diamino-2,3,4,6-tetradeoxy-α-D-erythro-hexopyranosyl-(1→4)]-1-N-[(2S)-4-amino-2-hydroxybutanoyl]-2-deoxy-D-streptamine. "Arbekacin" is a compound known as an aminoglycoside antibiotic, and has a 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 on pharmaceuticals in the 18th revised Japanese Pharmacopoeia. In the present specification, the concentration and amount of arbekacin and / or its salt are the concentration and amount converted to arbekacin, unless otherwise specified.

[0019] In this specification, "hydroxypropyl methylcellulose" refers to a type of cellulose polymer, a mixed ether of methyl and hydroxypropyl of cellulose. Hydroxypropyl methylcellulose is also called hypromellose. It is also abbreviated as HPMC.

[0020] In this specification, "hydroxyethyl cellulose" refers to a type of cellulose polymer that is partially O-(2-hydroxyethyl)-modified cellulose. It may also be abbreviated as HEC.

[0021] As used herein, "methylcellulose" refers to a type of cellulose polymer, which is a methyl ether of cellulose. It is sometimes abbreviated as MC.

[0022] In this specification, "polyvinylpyrrolidone" refers to a type of polyvinyl polymer, a linear polymer of 1-vinyl-2-pyrrolidone. Polyvinylpyrrolidone is also called povidone or polyvidone. It is also abbreviated as PVP.

[0023] In this specification, the "viscosity" of the aqueous liquid preparation is measured according to "2.53 Viscosity Measurement Method" in "2. Method 2 Rotational Viscometer Method" in "2.1.3. Cone-plate Rotational Viscometer (Cone-plate type viscometer)" in the General Test Method of the Japanese Pharmacopoeia, 18th Edition (30°C ± 0.1°C, preheat time: 0 s, rotation speed 100 rpm, cone-plate rotational viscometer, cone rotor used: 3° × R17.65, measurement time: 90 s). Specifically, the viscosity of the aqueous liquid preparation is measured using a viscometer TVE-25 (model: TVE-25L) manufactured by Toki Sangyo Co., Ltd.

[0024] In this specification, the "viscosity increase value" refers to a value obtained by subtracting the viscosity of an arbekacin and / or water-soluble polymer solution and the viscosity of a mucin solution from the viscosity of a mixed solution of arbekacin and / or water-soluble polymer and mucin, and more specifically, refers to a value calculated according to the following calculation formula (Non-Patent Document 2).

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[0025] As used herein, the term "thickening" refers to an increase in the viscosity of an aqueous liquid preparation of arbekacin containing a water-soluble polymer as a result of the interaction of the aqueous liquid preparation with mucin.

[0026] In the present specification, the "reduction rate (%) of the release rate of arbekacin and / or a salt thereof" is an index showing the adhesiveness between arbekacin and mucin, and a higher reduction rate means a higher adhesiveness. The "reduction rate (%) of the release rate of arbekacin and / or a salt thereof" is calculated according to the following formula based on the results of the in vitro dialysis membrane test described below. In vitro dialysis membrane testing 1) 500 μL of the sample (containing arbekacin and / or its salt) is sealed in a 2 mL glass container, and the opening is covered with a dialysis membrane and the periphery is fixed (the inside of the glass container is the donor side). 2) Attach 1) to a beaker (external liquid side) filled with PBS (15 mL) so that it is at a certain height from the bottom of the beaker, and stir the liquid in the beaker using a stirrer. 3) Sample 1 mL from the external liquid side at any time between 15 and 240 minutes after the start of stirring to use this as the sampling liquid, dilute the sampling liquid appropriately, and measure using liquid chromatography under the following conditions. Detector: Charged particle detector Column: A commercially available product consisting of a stainless steel tube with an inner diameter of 4.6 mm and a length of 250 mm packed with 5 μm octylsilylated silica gel for liquid chromatography. Column temperature: constant temperature around 30℃ Mobile phase: 5 mM heptafluorobutyric acid in water and 5 mM heptafluorobutyric acid in acetonitrile, gradient Flow rate: 1.4mL per minute Drug remaining rate in the donor relative to the theoretical total amount (%) = 100 - (cumulative amount of arbekacin released into the external solution up to the time of sampling (μg) / theoretical total amount of arbekacin contained in the donor (μg) × 100) Release rate (% / min): The absolute value of the slope of the approximate line obtained by plotting the drug remaining rate (%) on the y-axis and the sampling time (min) on the x-axis for each sampling solution using the least squares method Reduction rate of release rate (%): 100-(release rate of sample / release rate of arbekacin solution alone x 100) In addition, the "arbekacin solution" in the release rate decrease rate calculation formula is an aqueous solution of arbekacin and / or its salt containing the same amount of arbekacin as the amount of arbekacin contained in the sample. The "arbekacin solution" is obtained by dissolving the same compound as the arbekacin and / or its salt contained in the sample in the same amount of water. For example, when the sample contains 1 w / v % arbekacin sulfate in terms of arbekacin, the "arbekacin solution" is an aqueous solution of 1 w / v % arbekacin sulfate in terms of arbekacin.

[0027] As used herein, the term "mucin adhesiveness" refers to the ability of an aqueous arbekacin solution containing a water-soluble polymer to interact with and reversibly bind to mucin in an aqueous solution when the aqueous arbekacin solution contains a water-soluble polymer and is mixed with mucin.

[0028] In this specification, "improving the conjunctival permeability of arbekacin" refers to increasing the Cmax of arbekacin concentration in the conjunctiva when an aqueous solution of arbekacin containing a water-soluble polymer is administered compared to the Cmax of arbekacin concentration in the conjunctiva when an aqueous solution of arbekacin containing no water-soluble polymer is administered. Cmax means the maximum drug concentration at the target site after drug administration.

[0029] As used herein, the term "bacterial external eye infection" refers to a disease caused by bacteria infecting the external eye. The term "external eye" refers to the organs located around the eyeball, such as the conjunctiva, cornea, eyelids, lacrimal glands, and meibomian glands.

[0030] As used herein, "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.

[0031] In this specification, "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 the breakdown of the tear film health, which has some subjective ocular symptoms, and in which instability of the tear film, hyperosmolarity, inflammation or injury of the ocular surface, and sensory nerve abnormalities play a pathological role" (Non-Patent Document 3). "Dry eye" is also called "keratoconjunctivitis sicca." In this specification, "treatment" refers to the improvement, relief, alleviation, or slowing down of the progression of a disease or symptom.

[0032] In this specification, the term "tear film" refers to a layer covering the surface of the eye, which is composed of three layers: a lipid layer (oil layer), an aqueous layer, and a mucin layer. When the aqueous layer and the mucin layer are mixed into one liquid layer, the term refers to a layer covering the surface of the eye, which is composed of two layers: a liquid layer of a mixture of water and mucin, and an oil layer (Non-Patent Document 3). As used herein, "tear film stabilization" refers to the stable maintenance of the tear film on the surface of the eye. Tear film breakup time (BUT) refers to the time from when the tear film is formed to when it breaks down. When the tear film becomes unstable, the BUT tends to shorten. As an example, "tear film stabilization" refers to the prolongation of the BUT.

[0033] 2. Water-based liquid The aqueous liquid preparation included in the present disclosure contains arbekacin and / or a salt thereof, and at least one water-soluble polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and polyvinylpyrrolidone. In the present specification, the aqueous liquid preparation may be referred to as the "aqueous liquid preparation of the present disclosure."

[0034] The salt of arbekacin is not particularly limited as long as it is pharma- ceutically acceptable. For example, organic acid salts or inorganic acid salts are included. Examples of organic acid salts include 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. Among arbekacin or a salt thereof, arbekacin sulfate is preferably used because it is marketed as a pharmaceutical product and its safety has been established.

[0035] In the aqueous liquid preparation of the present disclosure, either arbekacin or a salt thereof may be used alone, or these may be used in combination.

[0036] The total concentration of arbekacin and / or its salt in the aqueous liquid preparation of the present disclosure may 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%. For example, the range may preferably be about 0.1 to 3.0 w / v%.

[0037] Examples of the water-soluble polymers used in the composition of the present disclosure include hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and polyvinylpyrrolidone. These four types of water-soluble polymers may be collectively referred to as the water-soluble polymers of the present disclosure. Among them, hydroxypropylmethylcellulose is particularly preferred from the viewpoint of easy maintenance of viscosity over time. The water-soluble polymers may be used alone or in combination of two or more. The composition of the present disclosure may contain a water-soluble polymer other than the water-soluble polymer of the present disclosure within a range that does not impair the effect.

[0038] The substitution type of hydroxypropyl methylcellulose is defined by the content of methoxy groups and hydroxypropoxy groups (Japanese Pharmacopoeia, 18th Edition). Substitution type 1828 refers to a methoxy group lower limit of 16.5 mass%, a methoxy group upper limit of 20.0 mass%, a hydroxypropoxy group lower limit of 23.0 mass%, and a hydroxypropoxy group upper limit of 32.0 mass%. Substitution type 2208 refers to a methoxy group lower limit of 19.0 mass%, a methoxy group upper limit of 24.0 mass%, a hydroxypropoxy group lower limit of 4.0 mass%, and a hydroxypropoxy group upper limit of 12.0 mass%. Substitution type 2906 refers to a methoxy group lower limit of 27.0 mass%, a methoxy group upper limit of 30.0 mass%, a hydroxypropoxy group lower limit of 4.0 mass%, and a hydroxypropoxy group upper limit of 7.5 mass%. Substitution degree type 2910 indicates that the lower limit of the methoxy group is 28.0 mass %, the upper limit of the methoxy group is 30.0 mass %, the lower limit of the hydroxypropoxy group is 7.0 mass %, and the upper limit of the hydroxypropoxy group is 12.0 mass %.

[0039] The degree of substitution type of hydroxypropyl methylcellulose is not particularly limited, and may be any of 1828, 2208, 2906, and 2910. Preferred are types with a degree of substitution of 2208 or 2910.

[0040] The molecular weight of hydroxypropylmethylcellulose is not particularly limited. For example, the weight average molecular weight is 10,000 to 500,000, preferably 50,000 to 500,000, and more preferably 50,000 to 300,000. For example, the weight average molecular weight can be determined by gel permeation chromatography (GPC) using polystyrene as a standard substance.

[0041] The concentration of hydroxypropyl methylcellulose in the aqueous liquid preparation of the present disclosure may be, for example, about 0.2 to 3.5 w / v%, 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%, and particularly preferably about 0.8 to 1.4 w / v%.

[0042] The molar substitution degree of the hydroxyethoxy group of the hydroxyethyl cellulose (the average number of moles of the hydroxyethoxy group added per anhydrous glucose unit) is not particularly limited, and may be, for example, about 1.5 to 3.0, and preferably about 2.5.

[0043] The molecular weight of hydroxyethyl cellulose is not particularly limited, and may be, for example, from 10,000 to 1,000,000, preferably from 100,000 to 1,000,000, and more preferably from 600,000 to 800,000, in terms of weight average molecular weight.

[0044] The concentration of hydroxyethyl cellulose in the aqueous liquid preparation of the present disclosure may be, for example, about 0.05 to 1 w / v%, or may be, for example, about 0.08 to 0.6 w / v%, about 0.09 to 0.4 w / v%, or about 0.2 to 0.4 w / v%.

[0045] The degree of substitution of methylcellulose (the average number of hydroxyl groups substituted with methoxy groups per anhydrous glucose unit) is not particularly limited, and may be, for example, about 1.5 to 3.0, and preferably about 1.8.

[0046] There are no particular limitations on the molecular weight of methylcellulose, and examples of the molecular weight include a weight average molecular weight of 10,000 to 500,000, preferably 100,000 to 500,000, and more preferably 300,000 to 500,000.

[0047] The concentration of methylcellulose in the aqueous liquid preparation of the present disclosure may be, for example, about 0.1 to 1.8 w / v%, for example, about 0.15 to 1.0 w / v%, about 0.15 to 0.75 w / v%, about 0.4 to 0.75 w / v%, or about 0.4 to 0.7 w / v%.

[0048] The molecular weight of polyvinylpyrrolidone is not particularly limited, and may be, for example, from 2,000 to 1.5 million, preferably from 40,000 to 1.5 million, and more preferably from 1 million to 1.5 million, in terms of weight average molecular weight.

[0049] 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%, or may be about 0.75 to 5.0 w / v%, about 0.75 to 3.8 w / v%, about 2.0 to 3.8 w / v%, or about 2.0 to 3.5 w / v%.

[0050] 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. Examples of such other water-soluble polymers include cellulose-based polymers and synthetic polymers other than the water-soluble polymers of the present disclosure.

[0051] More specifically, examples of the cellulose-based polymer include nonionic cellulose-based polymers, ionic cellulose-based polymers, etc. Examples of the nonionic cellulose-based polymers include ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, etc., and examples of the ionic cellulose-based polymers include carboxymethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, carboxymethyl ethyl cellulose, cellulose acetate phthalate, etc.

[0052] Examples of the synthetic polymer include carboxyvinyl polymer, polyacrylic acid, and polyvinyl alcohol. When the composition of the present disclosure also contains such other water-soluble polymers, it is preferable that 50% by mass or more of the water-soluble polymers contained in the composition are water-soluble polymers of the present disclosure, more preferably 55, 60, 65, 70, 75, 80, 85, 90, or 95% by mass or more of the water-soluble polymers of the present disclosure, and particularly preferably 100% by mass of the water-soluble polymers of the present disclosure.

[0053] 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, about 0.05 w / v% to 8.8 w / v%. The upper or lower limit of the range can be, for example, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 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. 0.4, 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%, about 0.2 to 6 w / v%, or about 0.3 to 5 w / v%. The total concentration of the water-soluble polymer in the aqueous liquid preparation 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 can be, for example, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 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. 0.4, 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%, about 0.2 to 6 w / v%, or about 0.3 to 5 w / v%.

[0054] In the aqueous liquid preparation of the present disclosure, 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. For example, the mass ratio of the total content of arbekacin and / or its salt in arbekacin equivalent to the content of the water-soluble polymer of the present disclosure (the total content of arbekacin and / or its salt in arbekacin equivalent: 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, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96 9, 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. Thus, the mass ratio may be, for example, about 1:0.01 to 110 parts by mass, about 1:0.04 to 70 parts by mass, about 1:0.1 to 20 parts by mass, or about 1:0.25 to 14 parts by mass. In the aqueous liquid preparation of the present disclosure, 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. For example, the mass ratio of the total content of arbekacin and / or its salt in terms of arbekacin to the content of the water-soluble polymer may be about 1:0.01 to 180 parts by mass. The upper or lower limit of the range (0.01 to 180) may be, 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, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 9, 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. Thus, the mass ratio may be, for example, about 1:0.01 to 110 parts by mass, about 1:0.04 to 70 parts by mass, about 1:0.1 to 20 parts by mass, or about 1:0.25 to 14 parts by mass.

[0055] The aqueous liquid preparation of the present disclosure may contain additives such as a buffering agent, an isotonicity agent, a surfactant, an antiseptic or preservative, a cooling agent, a stabilizer, a pH adjuster, and the like, as necessary.

[0056] The buffer is not particularly limited as long as it is pharma- ceutically acceptable, and examples thereof include borate buffer, citrate buffer, phosphate buffer, Tris buffer, tartrate buffer, acetate buffer, amino acid buffer, etc. These buffers may be used alone or in combination of two or more.

[0057] Specific examples of boric acid buffers include boric acid and / or salts thereof. As boric acid, there is no particular limitation as long as it is pharmaceutically acceptable, but examples include orthoboric acid, metaboric acid, tetraboric acid, etc. Among these boric acids, orthoboric acid and tetraboric acid are preferred. These boric acids may be used alone or in combination of two or more. As salts of boric acid, there is no particular limitation as long as it is pharmaceutically acceptable, but examples include 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. In addition, boric acid / or its salts may be in the form of a hydrate, such as borax. As a boric acid buffer, one of boric acid and its salts may be selected and used alone, or two or more may be used in combination. Among boric acid and salts thereof, at least one of boric acid and borax is preferable, and at least one of orthoboric acid and borax is more preferable.

[0058] Specific examples of the citrate buffer include citric acid and / or its salts. The citrate salt is not particularly limited as long as it is pharma- ceutically acceptable, and examples thereof include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt. The citrate salt may be in the form of a solvate such as a hydrate. As the citrate buffer, one of citric acid and its salts may be selected and used alone, or two or more of them may be used in combination. Among citric acid and its salts, preferred are citric acid salts, more preferred are alkali metal salts of citric acid, and particularly preferred is sodium citrate.

[0059] Specific examples of the phosphate buffer include phosphoric acid and / or its salts. The salts of phosphoric acid are not particularly limited as long as they are pharmaceutically acceptable, and include, for example, dialkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate; alkali metal dihydrogen phosphates such as sodium dihydrogen phosphate and potassium dihydrogen phosphate; trialkali metal phosphates such as trisodium phosphate and tripotassium phosphate. The salts of phosphoric acid may be in the form of a solvate such as a hydrate, for example, 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. As the phosphate buffer, one of phosphoric acid and its salts may be selected and used alone, or two or more of them may be used in combination. Among phosphoric acid and its salts, preferably, phosphates, 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.

[0060] A specific example of the tris buffer is trometamol and / or a salt thereof. The salt of trometamol is not particularly limited as long as it is pharma- ceutically acceptable, and examples thereof include organic acid salts such as acetates and inorganic acid salts such as hydrochlorides and sulfonates. As the tris buffer, one of trometamol and its salts may be selected and used alone, or two or more of them may be used in combination. Among trometamol and its salts, trometamol is preferred.

[0061] Specific examples of tartaric acid buffers include tartaric acid and / or its salts. The salts of tartaric acid are not particularly limited as long as they are pharma- ceutically acceptable, and include, for example, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts. The salts of tartaric acid may also be in the form of solvates such as hydrates. As the tartaric acid buffer, one may be selected from tartaric acid and its salts and used alone, or two or more may be used in combination.

[0062] Specific examples of the acetate buffer include acetic acid and / or its salts. The acetate salt is not particularly limited as long as it is pharma- ceutically acceptable, and examples thereof include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and ammonium salt. The acetate salt may be in the form of a solvate such as a hydrate. As the acetate buffer, one of acetic acid and its salts may be selected and used alone, or two or more of them may be used in combination.

[0063] Specific examples of the amino acid buffer include acidic amino acids and / or their salts. Specific examples of the acidic amino acids include aspartic acid and glutamic acid. The salts of acidic amino acids are not particularly limited as long as they are pharmacologic acceptable, and examples of the salts include alkali metal salts such as sodium salts and potassium salts. As the amino acid buffer, one of the acidic amino acids and its salts may be selected and used alone, or two or more of them may be used in combination.

[0064] The concentration of the buffer in the aqueous liquid preparation of the present disclosure may be appropriately set within a range that imparts the desired buffering capacity to the aqueous liquid preparation, and may be, for example, about 0.01 to 3.0 w / v %.

[0065] The isotonicity agent is not particularly limited as long as it is pharma- ceutically acceptable, and examples thereof include polyhydric alcohols such as glycerin, propylene glycol, butylene glycol, and polyethylene glycol; and 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. These isotonicity agents may be used alone or in combination of two or more.

[0066] The surfactant is not particularly limited as long as it is pharma- ceutically acceptable, and examples thereof include 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 lauryldimethylaminoacetate betaine; anionic surfactants such as alkyl sulfates, N-acyltaurine salts, polyoxyethylene alkyl ether phosphates, and polyoxyethylene alkyl ether sulfates; and cationic surfactants such as alkylpyridinium salts and alkylamine salts. These surfactants may be used alone or in combination of two or more.

[0067] The antiseptic or preservative is not particularly limited as long as it is pharma- ceutically acceptable, and examples thereof include 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, etc. These antiseptics or preservatives may be used alone or in combination of two or more.

[0068] The cooling agent is not particularly limited as long as it is pharma- ceutically acceptable, and examples thereof include 1-menthol, borneol, camphor, eucalyptus oil, etc. These cooling agents may be used alone or in combination of two or more.

[0069] The stabilizer is not particularly limited as long as it is pharmaceutically acceptable, but examples thereof include 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, tocopherol, dibutylhydroxytoluene, etc. The salt form is not particularly limited as long as it is pharmaceutically acceptable, but examples thereof include alkali metal salts such as sodium salts and potassium salts. These stabilizers may be used alone or in combination of two or more.

[0070] The pH adjuster is not particularly limited as long as it is pharma- ceutically acceptable, and examples thereof include acids such as hydrochloric acid, acetic acid, boric acid, aminoethylsulfonic acid, epsilon-aminocaproic acid, etc., and alkalis such as sodium hydroxide, potassium hydroxide, borax, triethanolamine, monoethanolamine, sodium bicarbonate, sodium carbonate, etc. These pH adjusters may be used alone or in combination of two or more.

[0071] The concentrations of these additives may be appropriately set depending on the types of additives used and the properties to be imparted to the aqueous liquid preparation.

[0072] The pH of the aqueous liquid preparation of the present disclosure is not particularly limited as long as it is pharma- ceutically acceptable. For example, the pH may be about 5.0 to 8.0. For example, the pH may be about 5.4 to 7.5, about 5.4 to 7.0, or about 5.4 to 6.0.

[0073] The viscosity of the aqueous liquid preparation of the present disclosure is not particularly limited, but may 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.

[0074] The osmotic pressure of the aqueous liquid preparation is a value measured according to the method specified in "2.47 Osmotic Pressure Measurement Method (Osmolarity Measurement Method)" of the "General Test Method" of the 18th Edition 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 may be about 243 to 350 mOsm / kg.

[0075] The osmotic pressure ratio of an aqueous liquid preparation refers to the ratio of the osmotic pressure of the aqueous liquid preparation to the osmotic pressure of physiological saline (0.9 w / v% aqueous sodium chloride 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. For example, when applied to the ocular mucosa, the osmotic pressure ratio is 0.85 to 1.15. From the viewpoint of mitigating eye irritation, the osmotic pressure ratio is preferably 0.9 to 1.1, more preferably 1.0.

[0076] In the aqueous liquid preparation of the present disclosure, it is preferable that the value obtained by subtracting the viscosity increase value due to arbekacin and the viscosity increase value due to the water-soluble polymer solution from the viscosity increase value due to arbekacin and the water-soluble polymer is greater than 0. In other words, it is preferable that the aqueous liquid preparation of the present disclosure has C-(A+B) greater than 0 (C-(A+B)>0). A: Viscosity increase due to arbekacin (mPa s) B: Viscosity increase due to water-soluble polymer (mPa s) C: Viscosity increase due to arbekacin and water-soluble polymer (mPa s) For example, C-(A+B) may be greater than any one of 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, and 0.65. Among these, 0.1 is preferable, 0.3 is more preferable, and 0.5 is even more preferable.

[0077] The aqueous liquid preparation of the present disclosure preferably has a reduction rate of 5% or more in the release rate of arbekacin and / or a salt thereof. For example, the reduction rate of the release rate of arbekacin and / or a salt 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, and 25%. Among these, 5% is preferable, 15% is more preferable, and 25% is even more preferable.

[0078] The formulation form of the aqueous liquid preparation of the present disclosure is not particularly limited, and may be any of an aqueous solution, a suspension, an emulsion, etc. An aqueous solution is preferable.

[0079] The aqueous liquid preparation of the present disclosure may be prepared according to a known preparation method depending on the formulation form, for example, using the method described in the General Rules for Preparations in the Japanese Pharmacopoeia, 18th Edition.

[0080] Specifically, for example, the method for producing an aqueous liquid preparation of the present disclosure includes a step of blending arbekacin and / or a salt thereof with at least one water-soluble polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and polyvinylpyrrolidone in a pharmaceutically acceptable aqueous medium. The term "pharmaceutically acceptable aqueous medium" refers to a pharmaceutically acceptable aqueous medium, and examples thereof include purified water. In addition, the order of blending each component in the blending step is not particularly limited, and the components may be blended in any order, or may be blended simultaneously.

[0081] The aqueous liquid formulation of the present disclosure is prepared into a pharmaceutical composition for various applications, such as ophthalmic, dental, otolaryngological, and dermatological applications, and is used as a topical administration preparation. The aqueous liquid formulation of the present disclosure can be, for example, an ophthalmic, dental, otolaryngological, or dermatological composition. An ophthalmic composition is preferred.

[0082] Specific examples of the ophthalmic composition include eye drops, eye washes, contact lens preparations, injections, etc. Among these, eye drops are preferred.

[0083] Arbekacin and / or a salt thereof contained in the aqueous liquid preparation of the present disclosure exhibits an antibacterial effect against gram-positive and gram-negative bacteria, and therefore the aqueous liquid preparation of the present disclosure can be suitably used for treating, for example, bacterial external eye infections and bacterial keratoconjunctivitis (bacterial conjunctivitis and / or bacterial keratitis), and can be more suitably used for treating bacterial conjunctivitis. Examples of causative bacteria of bacterial external eye infections include gram-positive bacteria and gram-negative bacteria. Examples of gram-positive bacteria that cause bacterial conjunctivitis include the genus Staphylococcus (e.g., methicillin-resistant Staphylococcus aureus, etc.), Streptococcus pneumoniae, and Corynebacterium. Examples of gram-negative bacteria that cause bacterial conjunctivitis include Haemophilus influenzae, Moraxella, and Neisseria gonorrhoeae (Noriko Inada, Clinical Ophthalmology, Vol. 75, No. 11, 2021). Examples of bacteria that cause bacterial keratitis include Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, Moraxella, Serratia spp., Streptococcus pyogenes, Neisseria gonorrhoeae, anaerobic bacteria, and atypical acid-fast bacteria (Guidelines for the Treatment of Infectious Keratitis (2nd ed.), Japan Ophthalmological Society, 2013). The causative bacteria of external bacterial eye infection and bacterial keratoconjunctivitis may be one kind alone or two or more kinds in combination. The causative bacteria of bacterial external eye infections (more specifically, bacterial keratoconjunctivitis) are preferably Staphylococcus genus (e.g., methicillin-resistant Staphylococcus aureus, etc.), Corynebacterium sp., Pseudomonas aeruginosa, Haemophilus influenzae, Streptococcus pneumoniae, Moraxella, Neisseria gonorrhoeae, Serratia spp., or Streptococcus sp., more preferably Staphylococcus genus (e.g., methicillin-resistant Staphylococcus aureus, etc.), Corynebacterium sp., Pseudomonas aeruginosa, Haemophilus influenzae, or Streptococcus pneumoniae, even more preferably Staphylococcus genus (e.g., methicillin-resistant Staphylococcus aureus, etc.), and particularly preferably methicillin-resistant Staphylococcus aureus.

[0084] 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 described below, it has been found that the aqueous liquid preparation of the present disclosure interacts with mucin and thickens when these water-soluble polymers are used in combination with arbekacin and / or its salt. When the viscosity of an eye drop increases, it tends to remain on the ocular surface for a long time, improving the migration of the drug to the target site such as the cornea or conjunctiva. In addition, when the aqueous liquid preparation of the present disclosure is mixed with mucin, the water-soluble polymer, arbekacin, and mucin interact in the aqueous solution. The ability of these to reversibly bind contributes to improving the migration. Mucins are classified into free mucin and membrane mucin, both of which have a carboxyl group at the end and are negatively charged. The mucin layer is formed so that the mucins repel each other and the free mucin spreads over the membrane mucin expressed in the epithelial cells of the cornea and conjunctiva (Non-Patent Document 5). In addition, both free mucin and membrane mucin are known to contribute to the stabilization of the tear film (Non-Patent Document 6). The aqueous liquid preparation of the present disclosure interacts with free mucin floating in the aqueous layer of the tear film, making it more likely to remain in the tear film for a long time. In addition, the aqueous liquid preparation of the present disclosure interacts with membrane mucin expressed to grow on the surface of epithelial cells of the cornea and conjunctiva, making it more likely to adhere to the ocular surface and gather near target sites such as the cornea and conjunctiva. Thus, when administered by eye drop, the aqueous liquid preparation of the present disclosure has excellent migration of arbekacin to target sites such as the cornea and conjunctiva due to the thickening effect on the ocular surface and the adhesion effect to mucin. In addition, the aqueous liquid preparation of the present disclosure has excellent migration of arbekacin, making it more likely to be effective against the treatment of bacterial external eye infections (more specifically, bacterial keratoconjunctivitis).

[0085] In addition, when the mucin layer thickens, the destruction of the tear film on the ocular surface is suppressed and the BUT is extended. In other words, it is known that the tear film is stabilized (Non-Patent Documents 6 and 7). The aqueous liquid preparation of the present disclosure can thicken the tear film as well and stabilize the tear film by interacting with mucin. In addition, when administered by eye drop, the aqueous liquid preparation of the present disclosure stabilizes the tear film, so that the tear film remains on the cornea for a long time and prevents the exposure of the ocular surface, thereby having a protective effect on the ocular surface. For this reason, 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 that the tear film becomes unstable and the BUT is shortened, which causes the protection of the ocular surface to fail, resulting in superficial punctate keratopathy (SPK), etc. When administered by instillation, the aqueous liquid formulation of the present disclosure stabilizes the tear film, thereby improving the extension of the BUT and SPK, and can be used for the treatment of dry eye.

[0086] 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). When administered by eye drop, the aqueous liquid preparation of the present disclosure stabilizes the tear film, protecting the ocular surface with the tear film, making it difficult for foreign enemies such as bacteria to invade, and more effectively exerts the inherent antibacterial activity of tears. In addition, the antibacterial effect of arbekacin is also enhanced by the above-mentioned thickening and adhesiveness improving action, so that the aqueous liquid preparation has excellent effects on the treatment of bacterial external eye infections (more specifically, bacterial keratoconjunctivitis).

[0087] In addition, in dry eye, the protection of the ocular surface by the tear film is broken, and foreign enemies such as bacteria are easily invaded, and the antibacterial activity inherent to tears may also be reduced. If bacterial conjunctivitis occurs in this state, the risk of the causative bacteria passing through the cornea via the ocular surface increases, which may then cause bacterial keratitis. The aqueous solution of the present disclosure has the tear film stabilizing effect in addition to the therapeutic effect of arbekacin on bacterial external eye infections, and therefore can be used particularly for the treatment of bacterial external eye infections accompanied by dry eye.

[0088] The subjects of administration of the aqueous liquid preparation of the present disclosure include, for example, humans and non-human mammals (for example, rats, mice, rabbits, cows, pigs, dogs, cats, sheep, monkeys, etc.). The subjects of administration include, for example, bacterial keratoconjunctivitis patients or people suspected of having bacterial keratoconjunctivitis, and people infected with the above-mentioned bacteria. More specifically, humans infected or suspected of being infected with Staphylococcus genus (e.g., methicillin-resistant Staphylococcus aureus, etc.), Corynebacterium sp., Pseudomonas aeruginosa, Haemophilus influenzae, Streptococcus pneumoniae, Moraxella, Neisseria gonorrhoeae, Serratia spp., or Streptococcus are preferred, humans infected or suspected of being infected with Staphylococcus genus (e.g., methicillin-resistant Staphylococcus aureus, etc.), Corynebacterium sp., Pseudomonas aeruginosa, Haemophilus influenzae, or Streptococcus pneumoniae are more preferred, humans infected or suspected of being infected with Staphylococcus genus (e.g., methicillin-resistant Staphylococcus aureus, etc.) are even more preferred, and humans infected or suspected of being infected with methicillin-resistant Staphylococcus aureus are particularly preferred. Examples of humans to which the composition is administered include humans with unstable tear films, etc. More specifically, examples include dry eye patients or humans suspected of having dry eye, patients with bacterial external eye infections (more specifically, bacterial keratoconjunctivitis) accompanied by dry eye, or humans suspected of having bacterial external eye infections (more specifically, bacterial keratoconjunctivitis) accompanied by dry eye, etc.

[0089] The amount of the aqueous liquid preparation of the present disclosure to be administered (ingested) is not particularly limited and is determined depending on the age, body weight, sex, severity of symptoms, administration method, etc. of the subject to be administered. For example, the amount of arbekacin administered may be about 0.004 to 1.5 mg / kg body weight per day.

[0090] When the aqueous liquid preparation of the present disclosure is used as an eye drop, several drops (e.g., 1 to 3 drops, etc.) may be instilled once or multiple times (e.g., 2 to 8 times, etc.) per day. In one embodiment of the aqueous liquid preparation of the present disclosure, one drop is instilled twice a day.

[0091] 3.Treatment method The present disclosure also encompasses a method for treating a bacterial external eye infection (more specifically, bacterial keratoconjunctivitis), comprising administering to a subject in need thereof an aqueous liquid preparation 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 for treating dry eye, comprising administering to a subject in need thereof an aqueous liquid preparation 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 for treating a bacterial external eye infection (more specifically, bacterial keratoconjunctivitis) accompanied by dry eye, comprising administering to a subject in need thereof an aqueous liquid preparation 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. In the above-mentioned treatment method, the description in the section "2. Aqueous liquid preparation" can be cited.

[0092] 4. Method for thickening aqueous liquid preparations containing water-soluble polymers on the ocular surface The present disclosure also encompasses a method for thickening an aqueous solution containing a water-soluble polymer on the ocular surface, the method 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. In the method for thickening the aqueous liquid preparation containing the above-mentioned water-soluble polymer on the ocular surface, the description in the section "2. Aqueous liquid preparation" can be used.

[0093] 5. Methods for improving mucin adhesion The present disclosure also encompasses a method for improving mucin adhesiveness, comprising administering to a subject in need thereof an aqueous liquid preparation 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. In the above-mentioned method for improving mucin adhesiveness, the description in the section "2. Aqueous liquid preparation" can be used.

[0094] 6. Methods for improving conjunctival transport The present disclosure also encompasses a method for improving conjunctival permeability of arbekacin and / or a salt thereof, comprising administering to a subject in need thereof an aqueous liquid preparation 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. In the above-mentioned method for improving the conjunctival transportability, the description in the section "2. Aqueous liquid preparation" can be cited.

[0095] 7. Tear film stabilization methods The present disclosure also encompasses a method for stabilizing a tear film, comprising administering to a subject in need thereof an aqueous liquid preparation 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. In the above-mentioned stabilization method, the description in the section "2. Aqueous liquid preparation" can be used.

[0096] In addition, in this specification, the term "comprising" includes "consisting essentially of" and "consisting of." In addition, the present disclosure includes any combination of the constituent elements described in this specification.

[0097] In addition, the various characteristics (properties, structures, functions, etc.) described in each embodiment of the present disclosure above may be combined in any way to specify the subject matter included in the present disclosure. In other words, the present disclosure includes all subject matter consisting of all combinations of each combinable characteristic described in this specification. EXAMPLES

[0098] The contents of the present disclosure will be specifically explained using the following test examples. However, the present disclosure is not limited to these in any way. In the following, unless otherwise specified, the experiments are performed under atmospheric pressure and room temperature conditions. Furthermore, unless otherwise specified, "%" means "mass to volume %".

[0099] Test Example 1: Viscosity measurement in the presence of mucin The viscosity of the specimen and mucin solution was measured when they were mixed, with reference to the test method described in the literature (Emad Eldin Hassan and James M. Gallo, A Simple Rheological Method for the in VitroAssessment of Mucin-Polymer Bioadhesive Bond Strength. Pharmaceutical Research, 1990, 7(5): Non-Patent Document 2). In addition, the respective viscosities were compared to consider the interaction between the specimen and mucin.

[0100] Specimen Samples 1 to 11 were prepared by mixing each preliminary dissolving solution to obtain the composition shown in Table 1. In addition, a 6 w / v% mucin solution was prepared by dissolving mucin (derived from porcine stomach, Type II, reagent, Sigma Aldrich) in 0.1 M (mol / L) phosphate buffer to obtain a pH similar to that of tear fluid (neutral) and adjusting the pH to 7.0 with hydrochloric acid or sodium hydroxide.

[0101] How to prepare the preliminary dissolution solution 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 (JP) compliant, Shin-Etsu Chemical Co., Ltd.) was added and dispersed in heated (approximately 80°C) purified water, cooled to room temperature, and dissolution was confirmed. 1M phosphate buffer: Sodium dihydrogen phosphate hydrate (Japanese Pharmacopoeia compliant, Fujifilm Wako Pure Chemical Industries, Ltd.) was dissolved in purified water and adjusted to pH 7.0 with hydrochloric acid or sodium hydroxide. 0.1M phosphate buffer: 1M phosphate buffer was diluted 1 / 10 with purified water.

[0102] [Table 1]

[0103] Viscosity measurement The viscosity of each solution was measured according to the following conditions for 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).

[0104] Viscosity measurement conditions Measurement equipment: TVE-25 type viscometer (Toki Sangyo Co., Ltd.) Rotor: 1°34'×R24 or 3°×R17.65 (change rotor according to viscosity to be measured) Sample volume: 1.1mL (when using rotor 1°34'×R24) or 0.8mL (when using rotor 3°×R17.65) Preheat time: 120s Measurement time: 90s Measurement temperature: 34℃±0.1℃ Rotation speed: 100 rpm

[0105] calculation formula The viscosity increase value due to the interaction between each specimen and mucin was calculated according to the following formula.

number

[0106] Evaluation of mucin-analyte interactions A: Viscosity increase due to arbekacin (mPa s) B: Viscosity increase due to HPMC (mPa s) C: Viscosity increase due to arbekacin + HPMC (mPa s), defined as When C-(A+B)>0, it was evaluated that an aqueous liquid preparation containing arbekacin and HPMC has a synergistic thickening effect when in contact with a mucin solution. The sample numbers used to calculate A, B, and C for each concentration of arbekacin and HPMC are shown in Table 2.

[0107] [Table 2]

[0108] Regarding the samples used to calculate A, since it is assumed that there is no significant difference in viscosity in a solution of arbekacin alone, regardless of the concentration, the data of sample 7 (3% arbekacin solution) was used uniformly regardless of the arbekacin concentration.

[0109] The results of evaluating the viscosity increase value of each sample and the interaction between each sample and mucin are shown in Table 3.

[0110] [Table 3]

[0111] When a mixture of arbekacin and HPMC was allowed to coexist with mucin, the interaction evaluation formula C-(A+B)>0 was found to result in a synergistic thickening. A synergistic thickening effect was observed in the range of 0.1w / v%-3w / v% arbekacin and 0.8w / v%-2w / v% HPMC. In other words, it was suggested that an interaction with mucin occurred and thickening occurred (improved mucin adhesiveness) only when arbekacin and HPMC coexisted.

[0112] Non-ionic water-soluble polymers other than hydroxypropylmethylcellulose were used to compare their interactions with mucin.

[0113] Specimen Samples 12 to 19 were prepared by mixing each preliminary dissolving solution to obtain the composition shown in Table 4. The concentration of each water-soluble polymer solution was set to have a viscosity similar to that of a 1.4 w / v% solution of hypromellose 2208 (90SH-100SR, Japanese Pharmacopoeia (JP) compliant product, Shin-Etsu Chemical Co., Ltd.). In addition, mucin (derived from porcine stomach, Type II, reagent, Sigma Aldrich) was dissolved in 0.1 M phosphate buffer to obtain a pH similar to that of tear fluid (neutral), and the pH was adjusted to 7.0 with hydrochloric acid or sodium hydroxide to prepare a 6 w / v% mucin solution.

[0114] How to prepare the preliminary dissolution solution 1 w / v % HEC solution: Hydroxyethyl cellulose (Japanese Pharmacopoeia compliant, Ashland, Inc.) was added to and dispersed in heated (approximately 80°C) purified water, and then cooled to room temperature to confirm dissolution. 1.6 w / v % MC solution: Methylcellulose (SM-400, Japanese Pharmacopoeia (JP) compliant product, Shin-Etsu Chemical Co., Ltd.) was added to and dispersed in heated (approximately 80°C) purified water, and then cooled on ice to confirm dissolution. 5 w / v % PVP solution: Polyvinylpyrrolidone (Kollidon 90F, Japanese Pharmacopoeia (JP) compliant product, BASF SE) was dissolved in purified water. 30 w / v % PEG (polyethylene glycol) solution: Macrogol 6000 (Japanese Pharmacopoeia (JP) compliant product, NOF Corporation) was dissolved in purified water. The 10 w / v % arbekacin solution, 1 M phosphate buffer, and 0.1 M phosphate buffer were prepared in the same manner as described above.

[0115] [Table 4]

[0116] The viscosity was measured by the same method and under the same conditions as described above, and the viscosity increase value was calculated.

[0117] Evaluation of mucin-analyte interactions A: Viscosity increase due to arbekacin (mPa s) B: Viscosity increase due to each water-soluble polymer (mPa s) C: Viscosity increase value due to arbekacin + each water-soluble polymer (mPa s) is defined as When C-(A+B)>0, it was evaluated that an aqueous liquid preparation containing arbekacin and each water-soluble polymer has 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.

[0118] [Table 5]

[0119] Regarding the samples used to calculate A, since it is assumed that there is no significant difference in viscosity in a solution of arbekacin alone, regardless of the concentration, the data of sample 7 (3% arbekacin solution) was used uniformly regardless of the arbekacin concentration.

[0120] The evaluation results of the viscosity increase value of each sample and the interaction between each sample and mucin are shown in Table 6.

[0121] [Table 6]

[0122] Test Example 2: In vitro dialysis membrane test In order to investigate the interaction between mucin and an aqueous liquid preparation containing arbekacin and HPMC, an in vitro dialysis membrane test was carried out to confirm the release rate of arbekacin using a dialysis membrane.

[0123] Specimen The required amount of the preliminary dissolving solution shown below was added to a 1.5 mL polypropylene tube and thoroughly pipetted with a micropipette to prepare samples 20 to 27 (Table 7).

[0124] How to prepare the preliminary dissolution solution 25 w / v % and 16 w / v % arbekacin solutions: arbekacin sulfate was added to and dissolved in purified water. 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, and then cooled to room temperature to confirm dissolution. 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 pig stomach, for biochemistry, Fujifilm Wako Pure Chemical Industries, Ltd.) was dissolved in PBS or water.

[0125] [Table 7]

[0126] Test Method 1) 500 μL of the sample was sealed in a 2 mL glass container, the opening was covered with a dialysis membrane, and the periphery was fixed (the inside of the glass container was the donor side). It was confirmed that the glass container and the dialysis membrane were in close contact and no liquid leaked. The dialysis membrane used was a commercially available product with the following specifications: molecular weight cutoff: 12,000 to 14,000, membrane material: regenerated cellulose. 2) 1) was attached to a beaker (external liquid side) filled with PBS (15 mL) so that it was at a constant height from the bottom of the beaker, and the liquid in the beaker was stirred using a stirrer. 3) 1 mL of the external solution was sampled at any time between 15 and 240 minutes after the start of stirring, and the amount of arbekacin was measured according to the method described below. The remaining rate, release rate, and release rate decrease rate of arbekacin were calculated according to the following formula.

[0127] calculation formula Drug remaining rate in the donor relative to the theoretical total amount (%) = 100 - (cumulative amount of arbekacin released into the external solution up to the time of sampling (μg) / theoretical total amount of arbekacin contained in the donor (μg) × 100) Release rate (% / min): The absolute value of the slope of the approximate line obtained by plotting the drug remaining rate (%) on the y-axis and the sampling time (min) on the x-axis for each sampling solution using the least squares method Reduction rate of release rate (%): 100-(release rate of sample / release rate of arbekacin solution alone x 100)

[0128] Measurement of arbekacin amount The sample solution was appropriately diluted and measured by liquid chromatography (Ultimate 3000, Thermo Fisher Scientific Inc.) under the following conditions.

[0129] Test conditions Detector: Charged particle detector Corona Veo RS Column: A commercially available product (Inertsil C8, 5 μm, 4.6 mm × 250 mm, GL Sciences) consisting of a stainless steel tube with an inner diameter of 4.6 mm and a length of 250 mm packed with 5 μm octylsilylated silica gel for liquid chromatography. Column temperature: constant temperature around 30℃ Mobile phase: 5 mM heptafluorobutyric acid in water and 5 mM heptafluorobutyric acid in acetonitrile, gradient Flow rate: 1.4mL per minute

[0130] The remaining rate, release rate, and decrease rate of the release rate of arbekacin at each time point are shown in Table 8. The release profile of each sample is shown in Figure 1.

[0131] [Table 8]

[0132] In the mixed solutions of arbekacin, HPMC and mucin (samples 20, 24 and 26), the release rate was significantly lower than that of the arbekacin solution, with the rate of decrease being 25% or more. On the other hand, in the mixed solution of arbekacin and HPMC (sample 21) and the mixed solution of arbekacin and mucin (sample 22), the rate of decrease in the release rate hardly changed. This result indicates that arbekacin and HPMC do not interact with mucin when mixed alone, but can interact with mucin only when both are included. In other words, it is suggested that the adhesiveness of mucin is improved by arbekacin and HPMC.

[0133] Test Example 3: Evaluation of conjunctival transfer An aqueous solution containing arbekacin was administered once to the eyes of Japanese white rabbits, and the conjunctival concentration of arbekacin was evaluated.

[0134] Specimen Samples 28 and 29 were prepared as shown in Table 9.

[0135] [Table 9]

[0136] Preparation method 1) HPMC was added to and dispersed in heated (approximately 80°C) purified water, and the solution was confirmed by cooling to room temperature. This solution was roughly filtered through a 5 μm membrane filter to obtain concentrated solution A of HPMC. 2) Trometamol, sodium thiosulfate hydrate, and arbekacin sulfate were added to separately prepared purified water and dissolved. Hydrochloric acid or sodium hydroxide was added to this solution to adjust the pH to 7.0, and concentrated solution B was obtained by mixing each component. 3) Concentrated solution B and benzalkonium chloride solution were added to concentrated solution A (used to prepare sample 28) or purified water (used to prepare sample 29) and stirred until homogenous. 4) Hydrochloric acid or sodium hydroxide was added to adjust the pH to 7.0, and purified water was added to the specified volume. 5) The solution in 4) was sterilized by filtration using a 0.22 μm membrane filter to obtain an aqueous solution.

[0137] Matters related to testing systems, etc. animal Species: Rabbit Strain: Japanese white species Gender: Male Weight range upon arrival: approx. 2.00-2.49kg Number of animals used: 15

[0138] Animal testing Test procedure The conjunctival concentration of arbekacin was evaluated after administration of an aqueous solution containing arbekacin to normal Japanese white rabbits (hereinafter referred to as rabbits). Either sample 28 or 29 was administered as a single drop to both eyes of the rabbits. The rabbits were euthanized 0.25, 0.5, and 1 hour after administration, and ocular tissues were collected. Three eyes / sample / time point were used.

[0139] [Table 10]

[0140] Eye drop administration 1) The rabbit was restrained and macroscopic observation was performed to confirm that there was no damage to the anterior segment of the eye. 2) 35 μL of the sample was instilled into the eye using a micropipette, and the subject was forced to blink twice. 3) The restraint was released 30 minutes after administration.

[0141] Euthanasia and ocular tissue collection At 0.25, 0.5, and 1 hour after administration, the animals were euthanized and ocular tissues were collected. 1) The rabbits were restrained and euthanized by administering an overdose of thiopental sodium. 2) The surface of the eye and the inside of the conjunctival sac were washed with saline and then wiped dry. 3) The eyelids were incised and the eyeball, including the conjunctiva, was removed. 4) The conjunctiva and eyeball were collected. 5) The collected samples were frozen and stored in an ultra-low temperature freezer.

[0142] Analysis The conjunctival arbekacin concentration was analyzed in positive ion mode using LC-MS / MS (Q TRAP 5500, AB SCIEX Pte. Ltd.) with kanamycin monosulfate as the internal standard (IS).

[0143] Preparation of solutions 20mM EDTA 0.672 g of disodium dihydrogen ethylenediaminetetraacetate dihydrate was taken and dissolved in 100 mL of water. Dilution Solution Water / 20 mM EDTA / formic acid (1000:2:1, v / v) and acetonitrile / formic acid (1000:1, v / v) were mixed 1:1. IS solution 2 mg of kanamycin monosulfate was weighed out and dissolved in 20 mL of 20% methanol, and then diluted with acetonitrile to a concentration of 3.00 μg / mL.

[0144] Conjunctival homogenate preparation 1) The conjunctiva and water in an amount four times the weight of the added conjunctiva were added to a tube containing 20 3 mm zirconia beads. 2) The conjunctiva was disrupted using a bead homogenizer to prepare a 20% conjunctival homogenate. Disintegration conditions: Disintegration at 6000 rpm for 30 seconds, followed by a 30-second break, for 10 cycles (set temperature: 4°C) 3) 20% conjunctival homogenate was diluted two-fold with water to prepare 10% conjunctival homogenate.

[0145] Blank sample 1) 20 μL of blank 10% conjunctival homogenate was collected. 2) 40 μL of acetonitrile was added. 3) 80 μL of acetonitrile was added and mixed.

[0146] Actual sample 1) 20 μL of 10% conjunctival homogenate was collected. 2) 40 μL of acetonitrile was added. 3) 80 μL of IS solution was added and mixed.

[0147] Pretreatment 1) 400 μL of diluent was added and mixed. 2) Centrifugation was performed at 4°C and 20,000 x g for 10 minutes. 3) The supernatant was injected into the LC-MS / MS.

[0148] Measurement conditions LC conditions Column: InertSustain Amide 3μm UHPLC 2.1 IDx50mm Column temperature: 40℃ Mobile phase: gradient of water / 20 mM EDTA / formic acid (1000:2:1, v / v) and acetonitrile / formic acid (1000:1, v / v) Flow rate: 0.8mL / min

[0149] MS / MS conditions Scan Type: MRM Polarity:Positive Ion Source:Turbo Spray

[0150] [Table 11]

[0151] Evaluation of conjunctival transfer A single dose of 3% arbekacin ophthalmic solution containing HPMC (sample 28) with a viscosity of approximately 15 mPa·s (30°C±0.1°C, preheat time: 0 s, rotation speed: 100 rpm, TVE-25 viscometer, cone rotor used: 3°×R17.65, measurement time: 90 s) was administered to rabbits. Separately, a single dose of 3% arbekacin ophthalmic solution not containing HPMC (sample 29) was administered to rabbits. Tables 12 and 13 show the C of arbekacin concentration in the conjunctiva.max and area under the concentration-time curve (AUC 0-t ) detailed data is shown below. The maximum concentration of arbekacin in the conjunctiva after administration of 3% arbekacin ophthalmic solution containing HPMC (sample 28) (C max ) and the AUC from time 0 to the last measurable time t 0-t The C of arbekacin in the conjunctiva after administration of 3% arbekacin ophthalmic solution without HPMC (sample 29) was 58.5 μg / g and 20.2 μg h / g, respectively. max and AUC 0-t The C values ​​of the HPMC-containing formulation were 17.0 μg / g and 10.5 μg h / g, respectively. max was about 3.4 times higher, and AUC 0-t was approximately 1.9 times higher. This suggests that by incorporating HPMC into arbekacin ophthalmic solution, the residence time of arbekacin ophthalmic solution on the ocular surface is extended, and the concentration of arbekacin in the conjunctiva is increased. In this regard, when comparing the conjunctival transfer of sodium cromoglycate ophthalmic solution containing hydroxypropyl methylcellulose between a non-viscosity formulation and a high-viscosity formulation (580 mPa s), the C max It has been confirmed that the viscosity of the HPMC-containing formulation (sample 28) is 2.1 times higher than that of the formulation described in the above literature (Non-Patent Document 9). max It was confirmed that the penetration rate was increased by 3.4 times, more than expected. By adding HPMC to arbekacin ophthalmic solution, it interacts with mucin, and in addition to having a thickening effect, it also has excellent mucin adhesion, improving the penetration rate.

[0152] [Table 12]

[0153] [Table 13]

Claims

1. An aqueous liquid preparation comprising arbekacin and / or a salt thereof, and a water-soluble polymer, The aqueous liquid preparation comprises at least one water-soluble polymer selected from the group consisting of hydroxyethyl cellulose, methyl cellulose, and polyvinylpyrrolidone.

2. 2. The aqueous liquid preparation according to claim 1, wherein the total concentration of the arbekacin and / or a salt thereof is 0.05 w / v % to 5.0 w / v %.

3. 3. The aqueous liquid preparation according to claim 1, wherein the total concentration of the arbekacin and / or a salt thereof is 0.1 w / v % to 3.0 w / v %.

4. The aqueous liquid preparation according to any one of claims 1 to 3, wherein the concentration of the water-soluble polymer is 0.05 w / v % to 8.8 w / v %.

5. The aqueous liquid preparation according to any one of claims 1 to 4, wherein the concentration of the water-soluble polymer is 0.3 w / v % to 2.0 w / v %.

6. 6. The aqueous liquid preparation according to claim 1, wherein the mass ratio of the total content of the arbekacin and / or a salt thereof to the content of the water-soluble polymer is 1:0.04-70.

7. An aqueous liquid preparation comprising arbekacin and / or a salt thereof, and a water-soluble polymer, the water-soluble polymer comprises at least one selected from the group consisting of hydroxyethyl cellulose, methyl cellulose, and polyvinylpyrrolidone; The aqueous liquid preparation has a total concentration of the arbekacin and / or a salt thereof of 0.1 w / v % to 3.0 w / v %, a concentration of the water-soluble polymer of 0.3 w / v % to 2.0 w / v %, and a mass ratio of the total content of the arbekacin and / or a salt thereof to the content of the water-soluble polymer of 1:0.04 to 1:

70.

8. The aqueous liquid preparation according to any one of claims 1 to 7, wherein the viscosity of the aqueous liquid preparation is 5 to 50 mPa·s.

9. The aqueous liquid preparation according to any one of claims 1 to 8, wherein C-(A+B) is greater than 0. A: Viscosity increase value due to arbekacin (mPa s) B: Viscosity increase value due to water-soluble polymer (mPa s) C: Viscosity increase value (mPa s) due to arbekacin and water-soluble polymer [Equation 1]

10. The aqueous liquid preparation according to any one of claims 1 to 9, which is an eye drop.

11. The aqueous liquid preparation according to any one of claims 1 to 10, which is used to improve the conjunctival permeability of arbekacin.

12. The aqueous liquid preparation according to any one of claims 1 to 11, which is for treating bacterial external ocular infections.

13. The aqueous liquid preparation according to any one of claims 1 to 12, which is for stabilizing the tear film.

14. The aqueous liquid preparation according to any one of claims 1 to 13, which is for treating bacterial external ocular infections accompanied by dry eye.

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