Water-based liquid preparation

Abstract

Provided is a drug preparation technology associated with a water-based liquid preparation containing arbekacin and / or a salt thereof. More specifically, the present invention provides a water-based liquid preparation containing arbekacin and / or a salt thereof, hydroxypropyl methylcellulose, and propylene glycol.

Description

Water-based liquid

[0001] The present disclosure relates to an aqueous liquid preparation containing arbekacin and / or a salt thereof, hydroxypropyl methylcellulose, and propylene glycol, and its application technology, etc.

[0002] Arbekacin is known as a type of antibiotic.

[0003] U.S. Patent No. 9,511,143, U.S. Patent No. 7,224,390

[0004] Clin Pharmacol. 2014 Sep 26;6:139-48.

[0005] The present inventors have found that when hydroxypropyl methylcellulose is added to an aqueous liquid preparation containing arbekacin to increase the viscosity, the viscosity tends to decrease over time. After further investigation, they have found that the decrease in viscosity can be suppressed by using propylene glycol.

[0006] The present disclosure encompasses, for example, the subject matter described in the following items. Item 1. An aqueous liquid preparation comprising arbekacin and / or a salt thereof, hydroxypropyl methylcellulose, and propylene glycol. Item 2. The aqueous liquid preparation according to Item 1, wherein the total concentration of the arbekacin and / or a salt thereof is about 0.05 w / v % to about 5.0 w / v % in terms of arbekacin. Item 3. The aqueous liquid preparation according to Item 1 or 2, wherein the concentration of the hydroxypropyl methylcellulose is about 0.2 w / v % to about 3.5 w / v %. Item 4. The aqueous liquid preparation according to any one of Items 1 to 3, wherein the concentration of the propylene glycol is about 0.1 w / v % to about 10 w / v %. Item 5. Item 6. The aqueous liquid preparation according to any one of Items 1 to 4, wherein the total concentration of the arbekacin and / or a salt thereof is about 0.05 w / v % to about 5.0 w / v % in terms of arbekacin, and the concentration of the hydroxypropyl methylcellulose is about 0.2 w / v % to about 3.5 w / v %. Item 7. The aqueous liquid preparation according to any one of Items 1 to 6, wherein the total concentration of the arbekacin and / or a salt thereof is about 0.05 w / v % to about 5.0 w / v % in terms of arbekacin, and the concentration of the propylene glycol is about 0.1 w / v % to about 10 w / v %. Item 8. Item 7. The aqueous liquid preparation according to any one of Items 1 to 7, wherein the total concentration of the arbekacin and / or a salt thereof is about 0.05 w / v % to about 5.0 w / v % in terms of arbekacin, the concentration of the hydroxypropyl methylcellulose is about 0.2 w / v % to about 3.5 w / v %, and the concentration of the propylene glycol is about 0.1 w / v % to about 10 w / v %. Item 9. The aqueous liquid preparation according to any one of Items 1 to 8, wherein the mass ratio of the total content of arbekacin and / or a salt thereof in terms of arbekacin to the content of propylene glycol is 1:about 0.02 to 1:about 200. Item 10. The aqueous liquid preparation according to any one of Items 1 to 9, wherein the mass ratio of the content of hydroxypropyl methylcellulose to the content of propylene glycol is 1:about 0.028 to 1:about 50.Item 11. The aqueous liquid preparation according to any one of Items 1 to 10, wherein the mass ratio of the total content of arbekacin and / or a salt thereof, calculated as arbekacin, to the content of hydroxypropyl methylcellulose is 1:about 0.04 to 1:about 70. Item 12. The aqueous liquid preparation according to any one of Items 1 to 11, wherein the mass ratio of the total content of arbekacin and / or a salt thereof, calculated as arbekacin, to the content of hydroxypropyl methylcellulose and the content of propylene glycol is 1:about 0.04:about 0.02 to 1:about 70:about 200. Item 13. The aqueous liquid preparation according to any one of Items 1 to 12, which is an ophthalmic solution. Item 14. A method for stabilizing the viscosity of an aqueous liquid preparation, comprising the step of preparing an aqueous liquid preparation comprising arbekacin and / or a salt thereof, hydroxypropyl methylcellulose, and propylene glycol.

[0007] The viscosity retention rate after 2 weeks at 50°C is shown.

[0008] Each embodiment included in the present disclosure will be described in further detail below.

[0009] 1. Definitions It should be understood that 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 one of ordinary skill in the art to which this disclosure belongs. In the case of conflict, the present specification (including definitions) will control.

[0010] In this specification, unless otherwise specified, the term "about" means ±10% of the following numerical value.

[0011] As used herein, the term "aqueous liquid preparation" refers to a preparation that contains water as a base and is in a liquid form.

[0012] As used herein, "arbekacin" refers to a compound known as an aminoglycoside antibiotic having potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), namely 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 also described in Japanese Patent Application Laid-Open Nos. 56-051499 and 58-134099. It is also listed in the monographs on pharmaceuticals in the 18th edition of the Japanese Pharmacopoeia. Unless otherwise specified, the concentrations of arbekacin and / or its salts used herein are those calculated as arbekacin.

[0013] As used herein, "hydroxypropyl methylcellulose" refers to a type of cellulose polymer, a mixed methyl and hydroxypropyl ether of cellulose. Hydroxypropyl methylcellulose is also called hypromellose and is sometimes abbreviated as HPMC.

[0014] In this specification, the "viscosity" of an aqueous liquid preparation is measured in accordance with "2.1.3. Cone-plate rotational viscometer (cone-plate type viscometer)" in "2. Method 2: Rotational Viscometer Method" in "2.53 Viscosity Measurement Method" defined in the General Testing Methods of the Japanese Pharmacopoeia, 18th Edition (25°C±0.1°C, preheat time: 0 s, rotation speed: 50 rpm, cone-plate rotational viscometer, cone rotor used: 1°34' x R24, measurement time: 90 s). Specifically, the viscosity of the aqueous liquid preparation is measured using a TVE-25 viscometer (model: TVE-25L) manufactured by Toki Sangyo Co., Ltd.

[0015] As used herein, "viscosity stabilization" refers to suppressing a decrease in the viscosity of an aqueous liquid preparation over time. "Viscosity maintenance rate" is an index showing the degree of "viscosity stabilization," with a higher value indicating higher viscosity stability. For example, the viscosity maintenance rate after storage at a predetermined temperature for a predetermined period of time is calculated according to the following formula: Viscosity maintenance rate (%) = Viscosity of aqueous liquid preparation at each storage time (mPa·s) / Viscosity of aqueous liquid preparation at the time of preparation (mPa·s) × 100

[0016] 2. Aqueous Liquid Preparation The aqueous liquid preparation encompassed by the present disclosure comprises arbekacin and / or a salt thereof, hydroxypropyl methylcellulose, and propylene glycol. In this specification, the aqueous liquid preparation may be referred to as the "aqueous liquid preparation of the present disclosure."

[0017] 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).

[0018] The salt of arbekacin is not particularly limited as long as it is pharmaceutically acceptable. Examples thereof include organic acid salts and inorganic acid salts. Examples of organic acid salts include tartrate and acetate. Examples of inorganic acid salts include sulfate and hydrochloride. Arbekacin or a salt thereof may also 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 commercially available as a pharmaceutical product and its safety has been established.

[0019] 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.

[0020] The total concentration of arbekacin and / or a salt thereof in the aqueous liquid preparation of the present disclosure can be, for example, about 0.05 to about 5.0 w / v% in terms of arbekacin. The upper or lower limit of this range may be, for example, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.5, about 2.0, about 2.5, about 3.0, about 3.5, about 4.0, or about 4.5 w / v%. For example, this range is preferably about 0.1 to about 3.0 w / v%.

[0021] In the aqueous liquid preparation of the present disclosure, the methoxy group content of the hydroxypropyl methylcellulose is preferably, for example, about 15% to about 32% by mass. The upper or lower limit of this range may be, for example, about 15.5, about 16, about 16.5, about 17, about 17.5, about 18, about 18.5, about 19, about 19.5, about 20, about 20.5, about 21, about 21.5, about 22, about 22.5, about 23, about 23.5, about 24, about 24.5, about 25, about 25.5, about 26, about 26.5, about 27, about 27.5, about 28, about 28.5, about 29, about 29.5, about 30, about 30.5, about 31, or about 31.5% by mass. The range may be, for example, about 16% to 30% by mass. In addition, the content of hydroxypropoxy groups in the hydroxypropyl methylcellulose in the aqueous liquid preparation of the present disclosure is preferably, for example, about 3% by mass to about 35% by mass. The upper or lower limit of this range is, for example, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, about 10, about 10.5, about 11, about 11.5, about 12, about 12.5, about 13, about 13.5, about 14, about 14.5, about 15, about 15.5, about 16, about 16.5, about 17, about 17.5, about 18, about 18.5, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, The content may be about 9.5, about 20, about 20.5, about 21, about 21.5, about 22, about 22.5, about 23, about 23.5, about 24, about 24.5, about 25, about 25.5, about 26, about 26.5, about 27, about 27.5, about 28, about 28.5, about 29, about 29.5, about 30, about 30.5, about 31, about 31.5, about 32, about 32.5, about 33, about 33.5, about 34, or about 34.5% by mass. The range may be, for example, about 4% to 33% by mass. The content of methoxy groups and hydroxypropoxy groups is preferably a combination of the above ranges. It is preferable to have about 15% to about 32% by mass of methoxy groups and about 3% to about 35% by mass of hydroxypropoxy groups.Among these, for example, those containing about 16.5% by mass to about 20.0% by mass of methoxy groups and about 23.0% by mass to about 32.0% by mass of hydroxypropoxy groups, those containing about 19.0% by mass to about 24.0% by mass of methoxy groups and about 4.0% by mass to about 12.0% by mass of hydroxypropoxy groups, those containing about 27.0% by mass to about 30.0% by mass of methoxy groups and about 4.0% by mass to about 7.5% by mass of hydroxypropoxy groups, and those containing about 28.0% by mass to about 30.0% by mass of methoxy groups and about 7.0% by mass to about 12.0% by mass of hydroxypropoxy groups are more preferred. In the 18th Edition of the Japanese Pharmacopoeia, the degree of substitution type of hydroxypropyl methylcellulose is defined as follows depending on the content of methoxy groups and hydroxypropoxy groups: Substitution type 1828 refers to a copolymer having a lower limit of methoxy groups of about 16.5 mass%, an upper limit of methoxy groups of about 20.0 mass%, a lower limit of hydroxypropoxy groups of about 23.0 mass%, and an upper limit of hydroxypropoxy groups of about 32.0 mass% (i.e., a methoxy group content of about 16.5 mass% to about 20.0 mass%, and a hydroxypropoxy group content of about 23.0 mass% to about 32.0 mass%). Substitution type 2208 refers to a copolymer having a lower limit of methoxy groups of about 19.0 mass%, an upper limit of methoxy groups of about 24.0 mass%, a lower limit of hydroxypropoxy groups of about 4.0 mass%, and an upper limit of hydroxypropoxy groups of about 12.0 mass% (i.e., a methoxy group content of about 19.0 mass% to about 24.0 mass%, and a hydroxypropoxy group content of about 4.0 mass% to about 12.0 mass%). Substitution degree type 2906 indicates a copolymer having a lower limit of methoxy groups of approximately 27.0% by mass, an upper limit of methoxy groups of approximately 30.0% by mass, a lower limit of hydroxypropoxy groups of approximately 4.0% by mass, and an upper limit of hydroxypropoxy groups of approximately 7.5% by mass (i.e., the methoxy group content is approximately 27.0% by mass to approximately 30.0% by mass, and the hydroxypropoxy group content is approximately 4.0% by mass to approximately 7.5% by mass).Substitution degree type 2910 refers to a polymer in which the lower limit of the methoxy group is approximately 28.0% by mass, the upper limit of the methoxy group is approximately 30.0% by mass, the lower limit of the hydroxypropoxy group is approximately 7.0% by mass, and the upper limit of the hydroxypropoxy group is approximately 12.0% by mass (i.e., the methoxy group content is approximately 28.0% by mass to approximately 30.0% by mass, and the hydroxypropoxy group content is approximately 7.0% by mass to approximately 12.0% by mass).

[0022] The degree of substitution type of hydroxypropyl methylcellulose in the aqueous liquid preparation of the present disclosure is not particularly limited and may be, for example, any of 1828, 2208, 2906, and 2910. Preferred are types with a degree of substitution of 2208 or 2910.

[0023] The molecular weight of hydroxypropyl methylcellulose is not particularly limited. For example, the weight-average molecular weight may be about 10,000 to about 500,000, preferably about 50,000 to about 500,000, and more preferably about 50,000 to about 300,000. The weight-average molecular weight can be determined by gel permeation chromatography (GPC) using polystyrene as a standard substance.

[0024] The concentration of hydroxypropyl methylcellulose in the aqueous liquid preparation of the present disclosure can be, for example, about 0.2 to about 3.5 w / v%, preferably about 0.3 to about 2.0 w / v%, more preferably about 0.3 to about 1.5 w / v%, even more preferably about 0.8 to about 1.5 w / v%, and particularly preferably about 0.8 to about 1.4 w / v%.

[0025] The concentration of propylene glycol in the aqueous liquid preparation of the present disclosure can be, for example, about 0.1 to about 10 w / v%, preferably about 0.1 to about 5 w / v%, more preferably about 0.2 to about 4 w / v%, even more preferably about 0.5 to about 3 w / v%, and particularly preferably about 1.0 to about 2.5 w / v%.

[0026] In the aqueous liquid preparation of the present disclosure, the ratio of propylene glycol to arbekacin and / or a salt thereof is not particularly limited. For example, the mass ratio of the total content of arbekacin and / or a salt thereof, calculated as arbekacin, to the content of propylene glycol may be about 1:about 0.02 to about 1:about 200 parts by mass. For example, the mass ratio may be about 1:about 0.05 to about 1:about 100 parts by mass, about 1:about 0.75 to about 1:about 80 parts by mass, about 1:about 0.1 to about 1:about 60 parts by mass, about 1:about 0.1 to about 1:about 30 parts by mass, about 1:about 0.1 to about 1:about 10 parts by mass, about 1:about 0.2 to about 1:about 5 parts by mass, or about 1:about 0.3 to about 1:about 1 part by mass.

[0027] In the aqueous liquid preparation of the present disclosure, the ratio of propylene glycol to hydroxypropyl methylcellulose is not particularly limited. For example, the mass ratio of the hydroxypropyl methylcellulose content to the propylene glycol content can be about 1:about 0.028 to about 1:about 50 parts by mass. For example, it may be about 1:about 0.1 to about 1:about 25 parts by mass, about 1:about 0.2 to about 1:about 20 parts by mass, about 1:about 0.4 to about 1:about 10 parts by mass, or about 1:about 0.85 to about 1:about 2.7 parts by mass.

[0028] In the aqueous liquid preparation of the present disclosure, the ratio of hydroxypropyl methylcellulose to arbekacin and / or a salt thereof is not particularly limited. For example, the mass ratio of the total content of arbekacin and / or a salt thereof, calculated as arbekacin, to the content of hydroxypropyl methylcellulose may be about 1:about 0.04 to 1:about 70 parts by mass. For example, it may be about 1:about 0.1 to 1:about 20 parts by mass, or about 1:about 0.25 to 1:about 14 parts by mass.

[0029] In the aqueous liquid preparation of the present disclosure, the ratio of arbekacin and / or a salt thereof, hydroxypropyl methylcellulose, and propylene glycol is not particularly limited. For example, the mass ratio of the total content of arbekacin and / or a salt thereof in terms of arbekacin, the content of hydroxypropyl methylcellulose, and the content of propylene glycol can be about 1:about 0.04:about 0.02 to 1:about 70:about 200 parts by mass. For example, it may be about 1:about 0.1:about 0.1 to 1:about 50:about 100 parts by mass, or about 1:about 0.5:about 0.5 to 1:about 25:about 50 parts by mass. (That is, in parts by mass, it may be about 1:about 0.04 to about 70:about 0.02 to about 200, or about 1:about 0.5 to about 25:about 0.5 to about 50.)

[0030] The aqueous liquid preparation of the present disclosure may contain additives such as buffers, isotonic agents, thickeners, surfactants, antiseptics or preservatives, cooling agents, stabilizers, pH adjusters, etc., as needed, within the range that does not impair the effects of the aqueous liquid preparation of the present disclosure.

[0031] The buffer is not particularly limited as long as it is pharmaceutically 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.

[0032] Specific examples of boric acid buffers include boric acid and / or salts thereof. Boric acid is not particularly limited as long as it is pharmaceutically acceptable, but examples include orthoboric acid, metaboric acid, and tetraboric acid. 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. Examples of boric acid salts are not particularly limited as long as they are 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; and organic amine salts such as triethylamine, triethanolamine, morpholine, piperazine, and pyrrolidine. Boric acid and / or its salts may also be in the form of a hydrate, such as borax. As the 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 preferred, and at least one of orthoboric acid and borax is more preferred.

[0033] Specific examples of citrate buffers include citric acid and / or salts thereof. The citric acid salts are not particularly limited as long as they are pharmaceutically acceptable, and include, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; etc. The citric acid salt may also be in the form of a solvate such as a hydrate. As the citrate buffer, one selected from citric acid and its salts may be used alone, or two or more may be used in combination. Among citric acid and its salts, preferred are citric acid salts, more preferred are alkali metal citric acid salts, and particularly preferred is sodium citrate.

[0034] Specific examples of phosphate buffers include phosphoric acid and / or salts thereof. Phosphate salts 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; and trialkali metal phosphates such as trisodium phosphate and tripotassium phosphate. Phosphate salts may also be in the form of solvates such as hydrates, e.g., disodium hydrogen phosphate may be in the form of a dodecahydrate, and sodium dihydrogen phosphate may be in the form of a dihydrate. Phosphate buffers may be selected from phosphoric acid and salts thereof and used alone or in combination of two or more. Among phosphoric acid and salts thereof, preferred are phosphates, more preferably at least one of dialkali metal hydrogen phosphates and alkali metal dihydrogen phosphates, and particularly preferably at least one of disodium hydrogen phosphate and sodium dihydrogen phosphate.

[0035] Specific examples of Tris buffers include trometamol and / or salts thereof. The salts of trometamol are not particularly limited as long as they are pharmaceutically acceptable, and examples include organic acid salts such as acetate salts; and inorganic acid salts such as hydrochloride and sulfonate salts. As the Tris buffer, one selected from trometamol and its salts may be used alone, or two or more may be used in combination. Among trometamol and its salts, trometamol is preferred.

[0036] 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 pharmaceutically acceptable, and examples include 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 selected from tartaric acid and its salts may be used alone, or two or more may be used in combination.

[0037] Specific examples of acetate buffers include acetic acid and / or salts thereof. The salts of acetic acid are not particularly limited as long as they are pharmaceutically acceptable, and examples include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and ammonium salts. Furthermore, the salts of acetic acid may be in the form of a solvate such as a hydrate. As the acetate buffer, one selected from acetic acid and salts thereof may be used alone, or two or more may be used in combination.

[0038] 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 pharmaceutically acceptable, and examples include alkali metal salts such as sodium salts and potassium salts. As the amino acid buffer, one selected from acidic amino acids and salts thereof may be used alone, or two or more may be used in combination.

[0039] The concentration of the buffer in the aqueous liquid preparation of the present disclosure may be appropriately set within a range that can impart the desired buffering capacity to the aqueous liquid preparation, and can be, for example, about 0.01 to about 3.0 w / v %.

[0040] The isotonicity agent is not particularly limited as long as it is pharmaceutically acceptable and does not impair the effects of the aqueous liquid preparation of the present disclosure, and examples thereof include polyhydric alcohols other than propylene glycol, such as glycerin, butylene glycol, polyethylene glycol, and mannitol; metal salts, such as sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium acetate, potassium acetate, sodium hydrogensulfite, sodium hydrogencarbonate, sodium carbonate, disodium hydrogenphosphate, and sodium dihydrogenphosphate; and the like. These isotonicity agents may be used alone or in combination of two or more.

[0041] The thickener is not particularly limited as long as it is within the scope that does not impair the effect of the aqueous liquid preparation of the present disclosure and is pharmaceutically acceptable, and for example, includes water-soluble polymers such as carboxyvinyl polymer, polyvinylpyrrolidone, polyacrylic acid, polyvinyl alcohol, xanthan gum, sodium chondroitin sulfate, sodium hyaluronate, celluloses other than hydroxypropylmethylcellulose, etc. Specific examples of the celluloses here include hydroxyethylcellulose, methylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, etc. These thickeners can be used alone or in combination of two or more.

[0042] The surfactant is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include nonionic surfactants such as tyloxapol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, octoxynol, etc.; amphoteric surfactants such as alkyldiaminoethylglycine, lauryldimethylaminoacetic acid betaine, etc.; anionic surfactants such as alkyl sulfates, N-acyltaurine salts, polyoxyethylene alkyl ether phosphates, polyoxyethylene alkyl ether sulfates, etc.; cationic surfactants such as alkylpyridinium salts, alkylamine salts, etc. These surfactants may be used alone or in combination of two or more.

[0043] The antiseptic or preservative is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include sorbic acid or a salt thereof, benzoic acid or a salt thereof, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, benzalkonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, chlorhexidine acetate, dehydroacetic acid or a salt thereof, benzethonium chloride, benzyl alcohol, zinc chloride, zinc sulfate, silver nitrate, polyhexanide, alkyldiaminoethylglycine hydrochloride, parachlormetaxylenol, chlorcresol, phenethyl alcohol, polidronium chloride, thimerosal, dibutylhydroxytoluene, etc. These antiseptics or preservatives may be used alone or in combination of two or more.

[0044] The cooling agent is not particularly limited as long as it is pharmaceutically 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.

[0045] The stabilizer is not particularly limited as long as it is pharmaceutically acceptable, and 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, and 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.

[0046] The pH adjuster is not particularly limited as long as it is pharmaceutically 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.

[0047] 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.

[0048] The pH of the aqueous liquid preparation of the present disclosure is not particularly limited as long as it is pharmaceutically acceptable. For example, the pH may be about 5.0 to about 8.0. For example, the pH may be about 5.4 to about 7.5, about 5.4 to about 7.0, or about 5.4 to about 6.0.

[0049] The viscosity of the aqueous liquid preparation of the present disclosure is not particularly limited, but may be, for example, about 5.0 to about 100 mPa·s immediately after preparation. For example, it may be about 5 to about 50 mPa·s, about 10 to about 35 mPa·s, or about 20 to about 35 mPa·s.

[0050] The osmotic pressure of the aqueous liquid preparation is a value measured according to the method specified in "2.47 Osmotic Pressure Measurement Method (Osmolality Measurement Method)" of the "General Test Methods" 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 can be about 243 to about 350 mOsm / kg.

[0051] 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 can be about 0.85 to about 1.15. From the viewpoint of alleviating eye irritation, the osmotic pressure ratio is preferably about 0.9 to about 1.1, and more preferably about 1.0.

[0052] 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 preferred.

[0053] The aqueous liquid preparation of the present disclosure may be prepared according to a known preparation method depending on the formulation, and may be prepared, for example, using the method described in the General Rules for Preparations in the 18th Edition of the Japanese Pharmacopoeia.

[0054] 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, hydroxypropyl methylcellulose, and propylene glycol in a pharmaceutically acceptable aqueous medium. The term "pharmaceutically acceptable aqueous medium" refers to a pharmaceutically acceptable aqueous medium, such as purified water. In the blending step, the order in which the components are blended is not particularly limited, and the components may be blended sequentially in any order or simultaneously.

[0055] The aqueous liquid preparation of the present disclosure is prepared into a pharmaceutical composition for various uses, such as ophthalmology, dentistry, otolaryngology, dermatology, etc., and used as a topical administration preparation. The aqueous liquid preparation of the present disclosure can be, for example, a composition for ophthalmology, dentistry, otolaryngology, dermatology, etc. Preferably, an ophthalmological composition is used.

[0056] Specific examples of the ophthalmic composition include eye drops, eye washes, contact lens preparations, injections, etc. Among these, eye drops are preferred.

[0057] Arbekacin and / or its salt contained in the aqueous liquid preparation of the present disclosure exhibit antibacterial effects against Gram-positive and Gram-negative bacteria. Therefore, the aqueous liquid preparation of the present disclosure can be suitably used for treating, for example, bacterial external ocular infections and bacterial keratoconjunctivitis (bacterial conjunctivitis and / or bacterial keratitis), and is more suitably used for treating bacterial conjunctivitis. Examples of bacteria that cause bacterial external ocular infections include Gram-positive bacteria and Gram-negative bacteria. Examples of Gram-positive bacteria that cause bacterial conjunctivitis include Staphylococcus sp. (e.g., methicillin-resistant Staphylococcus aureus, etc.), Streptococcus pneumoniae, and Corynebacterium sp. Examples of Gram-negative bacteria that cause bacterial conjunctivitis include Haemophilus influenzae, Moraxella sp., 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 marcescens, Streptococcus gonococcus, anaerobic bacteria, and atypical acid-fast bacteria (Guidelines for the Treatment of Infectious Keratitis (2nd Edition), Japan Ophthalmological Society, 2013). The bacteria that cause bacterial external eye infections and bacterial keratoconjunctivitis may be one type alone or a combination of two or more types. The causative bacteria of bacterial external eye infections (more specifically, bacterial keratoconjunctivitis) are preferably Staphylococcus genus (e.g., methicillin-resistant Staphylococcus aureus, etc.), Corynebacterium spp., Pseudomonas aeruginosa, Haemophilus influenzae, Streptococcus pneumoniae, Moraxella genus, Neisseria gonorrhoeae, Serratia genus, or Streptococcus genus, more preferably Staphylococcus genus (e.g., methicillin-resistant Staphylococcus aureus, etc.), Corynebacterium spp., 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.

[0058] The aqueous liquid preparation of the present disclosure can be administered to, for example, humans and non-human mammals (e.g., rats, mice, rabbits, cows, pigs, dogs, cats, sheep, monkeys, etc.) Examples of humans to which the aqueous liquid preparation of the present disclosure can be administered include patients with bacterial keratoconjunctivitis or suspected of having bacterial keratoconjunctivitis, and humans infected with the above-mentioned bacteria. More specifically, humans infected with or suspected of being infected with Staphylococcus genus (e.g., methicillin-resistant Staphylococcus aureus, etc.), Corynebacterium spp., Pseudomonas aeruginosa, Haemophilus influenzae, Streptococcus pneumoniae, Moraxella spp., Neisseria gonorrhoeae, Serratia spp., or Streptococcus spp. are preferred, humans infected with or suspected of being infected with Staphylococcus genus (e.g., methicillin-resistant Staphylococcus aureus, etc.), Corynebacterium spp., Pseudomonas aeruginosa, Haemophilus influenzae, or Streptococcus pneumoniae are more preferred, humans infected with or suspected of being infected with Staphylococcus genus (e.g., methicillin-resistant Staphylococcus aureus, etc.) are even more preferred, and humans infected with or suspected of being infected with methicillin-resistant Staphylococcus aureus are particularly preferred. Examples of humans to whom the drug is to be administered include dry eye patients or humans suspected of having dry eye; patients with bacterial external ocular infections accompanied by dry eye (more specifically, bacterial keratoconjunctivitis) or humans suspected of having bacterial external ocular infections accompanied by dry eye (more specifically, bacterial keratoconjunctivitis);

[0059] The dosage (intake) of the aqueous liquid preparation of the present disclosure 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 dosage of arbekacin can be about 0.004 to about 1.5 mg / kg body weight per day.

[0060] When the aqueous liquid preparation of the present disclosure is used as an eye drop, it may be instilled in the eye at a rate of several drops (e.g., 1 to 3 drops) once or multiple times (e.g., 2 to 8 times) per day. In one embodiment of the aqueous liquid preparation of the present disclosure, it is instilled in the eye at a rate of one drop twice per day.

[0061] The present disclosure also encompasses a method for stabilizing the viscosity of an aqueous liquid preparation, the method comprising the step of preparing an aqueous liquid preparation containing arbekacin and / or a salt thereof, hydroxypropyl methylcellulose, and propylene glycol. All of the above descriptions apply to the aqueous liquid preparation and its components.

[0062] It should be noted that in this specification, the term "comprising" includes "consisting essentially of" and "consisting of." Furthermore, the present disclosure encompasses any and all combinations of the constituent elements described in this specification.

[0063] Furthermore, the various characteristics (properties, structures, functions, etc.) described in each embodiment of the present disclosure above may be combined in any way to identify the subject matter encompassed by the present disclosure, i.e., the present disclosure encompasses all subject matter consisting of any combination of the combinable characteristics described herein.

[0064] The contents of the present disclosure will be specifically explained using the following experimental examples and examples. However, the present disclosure is not limited to these in any way. In the following, unless otherwise specified, experiments were conducted under atmospheric pressure and room temperature conditions. Furthermore, unless otherwise specified, "%" means "w / v %." Furthermore, the blending amount of each component listed in each table is also expressed as "w / v %" unless otherwise specified.

[0065] Test Example 1 An aqueous liquid preparation was prepared by mixing the components shown in Table 1A.

[0066] The viscosity of the prepared aqueous liquid was measured under the following conditions, and this was taken as the viscosity at the time of preparation. 5 mL of the prepared aqueous liquid was filled into a colorless glass ampoule (5 mL capacity), and after storing it at 50°C for 2, 4, and 8 weeks, the viscosity of the aqueous liquid was measured. Viscosity measurement conditions Measurement device: TVE-25 type viscometer (Toki Sangyo Co., Ltd.) Rotor: 1°34' x R24 Sample amount: 1.1 mL Preheat time: 0 s Measurement time: 90 s Measurement temperature: 25°C ± 0.1°C Rotation speed: 50 rpm

[0067] The viscosity retention rate at each storage time point was calculated using the following formula. The measurement results of viscosity and viscosity retention rate are shown in Table 1B. Viscosity retention rate (%) = Viscosity of aqueous liquid preparation at each storage time point (mPa s) / Viscosity of aqueous liquid preparation at the time of preparation (starting point) (mPa s) × 100

[0068]

[0069] The viscosity retention rate after 2 weeks at 50°C is shown in Figure 1. In Figure 1, A01 is an aqueous liquid preparation containing neither arbekacin nor propylene glycol.

[0070] As shown in Comparative Examples 2 and 3, when an aqueous liquid preparation containing arbekacin and hypromellose was stored at 50°C, the viscosity retention rate decreased in proportion to the arbekacin concentration. As shown in Examples 1 to 4, when propylene glycol was further added to an aqueous liquid preparation containing arbekacin and hypromellose, the viscosity retention rate improved in proportion to the propylene glycol concentration. It was confirmed that the use of propylene glycol suppressed viscosity reduction and made it possible to maintain a practical viscosity.

[0071] Furthermore, each component was mixed to prepare an aqueous liquid preparation having the composition shown in Table 2A.

[0072] The viscosity of the prepared aqueous solution was measured under the following conditions, and was recorded as the viscosity at the time of preparation. 5 mL of the prepared aqueous solution was filled into a colorless glass ampoule (5 mL volume), and after storing it at 50°C for 8 weeks, the viscosity of the aqueous solution was measured in the same manner as above, and the viscosity retention rate (%) was calculated using the above formula. The results are shown in Table 2B.

[0073]

[0074] In the aqueous liquid preparation containing arbekacin at a relatively high concentration (3 w / v%), when propylene glycol was further added to the aqueous liquid preparation containing arbekacin and hypromellose, the viscosity retention rate improved in proportion to the concentration of propylene glycol, similar to the results of the above study.

[0075] Test Example 2 Aqueous liquid preparations having the compositions shown in Tables 3 to 6 were prepared and evaluated in the same manner as Test Example 1. The compositions of Examples 12 and 14 and Comparative Example 8 were the same as those of Examples A and B and Comparative Example A, respectively.

[0076]

[0077]

[0078]

[0079]

Claims

1. An aqueous liquid preparation comprising arbekacin and / or a salt thereof, hydroxypropyl methylcellulose, and propylene glycol.

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

3. The aqueous liquid preparation according to claim 1, wherein the concentration of the hydroxypropyl methylcellulose is about 0.2% w / v to about 3.5% w / v.

4. The aqueous liquid preparation according to claim 1, wherein the concentration of propylene glycol is about 0.1% w / v to about 10% w / v.

5. The aqueous liquid preparation according to claim 1, wherein the total concentration of the arbekacin and / or its salt is about 0.05 w / v% to about 5.0 w / v% in terms of arbekacin, and the concentration of the hydroxypropyl methylcellulose is about 0.2 w / v% to about 3.5 w / v%.

6. The aqueous liquid preparation according to claim 1, wherein the total concentration of the arbekacin and / or its salt is about 0.05 w / v% to about 5.0 w / v% in terms of arbekacin, and the concentration of the propylene glycol is about 0.1 w / v% to about 10 w / v%.

7. The aqueous liquid preparation according to claim 1, wherein the concentration of said hydroxypropyl methylcellulose is about 0.2% w / v to about 3.5% w / v, and the concentration of said propylene glycol is about 0.1% w / v to about 10% w / v.

8. The aqueous liquid preparation according to claim 1, wherein the total concentration of the arbekacin and / or its salt is about 0.05 w / v% to about 5.0 w / v% calculated as arbekacin, the concentration of the hydroxypropyl methylcellulose is about 0.2 w / v% to about 3.5 w / v%, and the concentration of the propylene glycol is about 0.1 w / v% to about 10 w / v%.

9. The aqueous liquid preparation according to any one of claims 1 to 8, wherein the mass ratio of the total content of arbekacin and / or a salt thereof, calculated as arbekacin, to the content of propylene glycol is from 1:about 0.02 to 1:about 200.

10. An aqueous liquid preparation according to any one of claims 1 to 8, wherein the mass ratio of the content of said hydroxypropyl methylcellulose to the content of said propylene glycol is from 1:about 0.028 to 1:about 50.

11. The aqueous liquid preparation according to any one of claims 1 to 8, wherein the mass ratio of the total content of arbekacin and / or a salt thereof, calculated as arbekacin, to the content of hydroxypropyl methylcellulose is from 1:about 0.04 to 1:about 70.

12. The aqueous liquid preparation according to any one of claims 1 to 8, wherein the mass ratio of the total content of arbekacin and / or a salt thereof in terms of arbekacin, the content of hydroxypropyl methylcellulose, and the content of propylene glycol is 1:about 0.04:about 0.02 to 1:about 70:about 200.

13. The aqueous liquid preparation according to any one of claims 1 to 8, which is an eye drop.

14. A method for stabilizing the viscosity of an aqueous liquid preparation, comprising the step of preparing an aqueous liquid preparation comprising arbekacin and / or a salt thereof, hydroxypropyl methylcellulose, and propylene glycol.

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