TW202135822A - Aqueous composition - Google Patents

Abstract

The present invention pertains to an aqueous composition containing a janus kinase inhibitor and a biguanide-based preservative.

Description

Water-based composition

The present invention relates to an aqueous composition.

Janus kinase (JAK) is a non-receptor tyrosine kinase that plays an important role in the transmission of immune activation messages in cells. It is expected that drugs with Janus kinase inhibitory activity (hereinafter also referred to as "Janus kinase inhibitor" "Agent") Inhibit the excessive activation of the immune response, thereby improving autoimmune diseases or allergic diseases. As a compound having the inhibitory effect of duplicitous kinases, for example, 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) is known -1,6-diazaspiro[3.4]octane-1-yl]-3-oxopropionitrile (common name: Delgocitinib), 3-{(3S,4R)-4-methan 3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropionitrile (common name: tofacitinib ( Tofacitinib)) etc. (for example, Patent Documents 1 and 2). Prior art literature Patent literature

Patent Document 1: International Publication No. 2017/006968 Patent Document 2: International Publication No. 02/096909

[The problem to be solved by the invention]

Aqueous preparations such as eye drops are required to have certain storage efficiency, but the storage efficiency of aqueous preparations blended with LMK inhibitor as an active ingredient is completely unknown.

The object of the present invention is to provide an aqueous composition with excellent storage efficiency and containing a Kinase inhibitor of dangling. [Technical means to solve the problem]

The inventors of the present invention made efforts to solve the above-mentioned problems. As a result, they found that if a biguanide-based preservative is blended into an aqueous composition containing a LMK kinase inhibitor, the storage efficiency is significantly enhanced. The present invention provides the following inventions based on this knowledge.

[1] An aqueous composition containing Janus kinase inhibitor and biguanide preservative. [2] The aqueous composition as described in [1], wherein the content of LMK inhibitor is 0.001% by mass to 5% by mass based on the total amount of the aqueous composition. [3] The aqueous composition as described in [1] or [2], wherein the LMK kinase inhibitor is degatinib. [4] The aqueous composition according to any one of [1] to [3], wherein the biguanide-based preservative is loxidine or a salt thereof. [5] The aqueous composition as described in any one of [1] to [4] has a pH of 4.0 to 6.5. [6] The aqueous composition as described in any one of [1] to [5], which is used in ophthalmology. [Effects of Invention]

According to the present invention, it is possible to provide an aqueous composition with excellent storage efficiency and containing a mirabilis kinase inhibitor.

Hereinafter, the method for implementing the present invention will be described in detail. However, the present invention is not limited to the following embodiments.

The aqueous composition of the present embodiment contains a lioness kinase inhibitor and a biguanide-based preservative.

環或三唑并吡啶環）作為部分結構之化合物或其鹽，該等可較佳地用作兩面神激酶抑制劑。[Two-sided God Kinase Inhibitor] Two-sided God Kinase Inhibitors can be selected from the two-sided God Kinase 1 (JAK1), Two Sides God Kinase 2 (JAK2), Two Sides God Kinase 3 (JAK3), and Tyrosine Kinase 2 (TYK2) as long as they inhibit At least one kind of medicine from the group consisting of it can be used without particular limitation. As the two-faced kinase inhibitors that are commercially available or under development, for example, the following nitrogen-containing condensed heterocycles (preferably pyrrolopyrimidine ring, pyrrolopyridine ring, imidazopyrrolopyrrolopyridine ring) are known as shown below.

Ring or triazolopyridine ring) as part of the structure of the compound or its salt, and these can be preferably used as dampening kinase inhibitors.

The salt of a compound having a nitrogen-containing condensed heterocyclic ring as a partial structure is not particularly limited, as long as it is medically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such salts include salts with inorganic acids (for example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.), and salts with organic acids (for example, salts with acetic acid, succinic acid, and fumaric acid). , Maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid (mesylic acid), ethanesulfonic acid, p-toluenesulfonic acid, etc.), and salts of inorganic bases (for example, sodium salt) , Potassium salt and other alkali metal salt, calcium salt, magnesium salt and other alkaline earth metal salt, aluminum salt, ammonium salt), salt with organic base (for example, with diethylamine, diethanolamine, meglumine, N, N-dibenzylethylenediamine, etc.), with acidic or basic amino acids (for example, with aspartic acid, glutamic acid, arginine, lysine, ornithine And so on salt) and so on.

德格替尼或其鹽例如可藉由國際公開第2017/006968號、國際公開第2018/117151號所記載之方法製造。(1) Degatinib Degatinib is a well-known compound represented by the following formula, also known as 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d ]Pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropionitrile.

Degatinib or its salt can be produced by the method described in International Publication No. 2017/006968 and International Publication No. 2018/117151, for example.

托法替尼或其鹽例如可藉由國際公開第01/42246號所記載之方法製造。作為托法替尼或其鹽，較佳為檸檬酸托法替尼。(2) Tofacitinib Tofacitinib is a well-known compound represented by the following formula, also known as 3-{(3S,4R)-4-methyl-3-[methyl(7H-pyrrolo[2, 3-d]pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropionitrile.

Tofacitinib or its salt can be produced by the method described in International Publication No. 01/42246, for example. As tofacitinib or a salt thereof, tofacitinib citrate is preferred.

-8-基)-N-(2,2,2-三氟乙基)吡咯啶-1-甲醯胺。

作為尤帕達替尼或其鹽，較佳為酒石酸尤帕達替尼。(3) Upadacitinib Upadacitinib is a well-known compound represented by the following formula, also known as (3S,4R)-3-ethyl-4-(3H-imidazo[1,2 -a]pyrrolo[2,3-e]pyridine

-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide.

As yupatinib or a salt thereof, yupatinib tartrate is preferred.

作為奧拉替尼或其鹽，較佳為馬來酸奧拉替尼。(4) Oclacitinib (Oclacitinib) Oclacitinib is a well-known compound represented by the following formula, also known as N-methyl-1-[trans-4-(methyl-7H-pyrrolo[2,3 -d]pyrimidin-4-ylamino)cyclohexyl]methanesulfonamide.

As olatinib or a salt thereof, olatinib maleate is preferred.

作為皮非替尼或其鹽，較佳為氫溴酸皮非替尼。(5) Pefitinib (Peficitinib) Pefitinib is a well-known compound represented by the following formula, also known as 4-{[(1R,2s, 3S,5s,7s)-5-hydroxyadamantane-2- Group]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide.

As pifitinib or its salt, pifitinib hydrobromide is preferable.

(6) Baricitinib (Baricitinib) Baricitinib is a well-known compound represented by the following formula, also known as {1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azir-3-yl}acetonitrile.

(7) Filgotinib (Filgotinib) Filgotinib is a well-known compound represented by the following formula, also known as N-(5-(4-((1,1-dioxothio)methyl )Phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide.

Among the two-sided god kinase inhibitors, in terms of more significantly exerting the effects produced by the present invention, degatinib, tofacitinib or their citrates are preferred, and degatinib is more preferred .

The water-based composition of this embodiment contains LMK kinase inhibitor as an effective ingredient, and can be used for the treatment of endogenous diseases such as dry eye (xerophthalmia), Dove's syndrome, Stevens-Johnson syndrome and other endogenous diseases. Conjunctival epithelial injury, or corneal and conjunctival epithelial injury caused by exogenous disease, exogenous disease is caused by postoperative, drug-induced, trauma, contact lens wearing, etc.

The content of the LMK inhibitor in the aqueous composition of the present embodiment is not particularly limited, and can be appropriately set according to the type and content of other blending ingredients, the use of the aqueous composition, the form of preparation, and the like. As for the content of the LMK kinase inhibitor, in terms of more remarkably exerting the effects produced by the present invention, and in terms of appropriately expressing the medicinal effect produced by the LMK kinase inhibitor, for example, in terms of the aqueous composition of the present embodiment Based on the total amount, the total content of LMK kinase inhibitor is preferably 0.001% by mass to 5% by mass, more preferably 0.003% by mass to 3% by mass, still more preferably 0.005% by mass to 1% by mass, and still more preferably It is 0.01% by mass to 0.5% by mass, more preferably 0.015% by mass to 0.4% by mass, and still more preferably 0.02% by mass to 0.3% by mass.

作為雙胍系防腐劑，例如可例舉：洛赫西定或其鹽、阿來西定（alexidine）或其鹽、聚己縮胍（polihexanide）或其鹽。[Biguanide-based preservative] The biguanide-based preservative means a compound that contains the biguanide shown below in its molecule and has an antiseptic effect.

Examples of the biguanide-based preservative include loxidine or its salt, alexidine (alexidine) or its salt, and polyhexanide (polihexanide) or its salt.

Loxidine is a well-known compound also known as 1,1'-hexamethylene bis[5-(4-chlorophenyl)biguanide]. Moreover, alexidine is a well-known compound also called 1,1'-hexamethylene bis[5-(2-ethylhexyl) biguanide].

Examples of the salt of loxidine, the salt of alexidine, polyhexanide or its salt include inorganic acid salts, organic acid salts, and sulfonates. Examples of inorganic acid salts include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, boric acid, phosphoric acid, and nitric acid. Examples of organic acid salts include salts with acetic acid, gluconic acid, maleic acid, ascorbic acid, stearic acid, tartaric acid, and citric acid. Examples of the sulfonic acid salt include salts with methanesulfonic acid, isethionic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

As the biguanide-based preservative, in order to more significantly exert the effects produced by the present invention, loxidine or a salt thereof is preferable, and loxidine gluconate is more preferable.

The content of the biguanide-based preservative in the aqueous composition of the present embodiment is not particularly limited, and can be appropriately set according to the type and content of other blending ingredients, the use of the aqueous composition, the formulation form, and the like. As the content of the biguanide-based preservative, from the aspect of wanting to more significantly exert the effects produced by the present invention, for example, based on the total amount of the aqueous composition of the present embodiment, the total content of the biguanide-based preservative is preferably 0.00001% by mass to 2% by mass, more preferably 0.00005% by mass to 1% by mass, and particularly preferably 0.00008% by mass to 0.5% by mass. In addition, 0.00005% by mass to 0.1% by mass and 0.0001% by mass to 0.01% by mass can also be cited as preferable contents.

The content ratio of the biguanide preservative in the aqueous composition of the present embodiment relative to the LMK kinase inhibitor is not particularly limited, and it can be based on the type of LMK kinase inhibitor and the biguanide preservative, the types of other blending components, and The content, the use of the aqueous composition, and the formulation form are appropriately set. As the content ratio of the biguanide-based preservative relative to the LMK inhibitor, the effect produced by the present invention is further improved, for example, compared to the total amount of the LMK inhibitor contained in the eye drops of the present embodiment The content is 1 part by mass, and the total content of the biguanide preservative is preferably 0.00003 parts by mass to 100 parts by mass, more preferably 0.0001 parts by mass to 50 parts by mass. In addition, 0.0001 parts by mass to 5 parts by mass, and 0.0003 parts by mass to 0.5 parts by mass can also be cited as preferable content ratios.

[Buffer] The aqueous composition of this embodiment may further contain a buffer. By further containing a buffering agent in the aqueous composition, the effect produced by the present invention can be more remarkably exerted. The buffer is not particularly limited, as long as it is medically, pharmacologically (pharmaceutically) or physiologically acceptable.

As the buffering agent, for example, a boric acid buffering agent (for example, a combination of boric acid, boric acid and borax, etc.) may be mentioned. A commercially available buffer can be used. A buffer can be used individually by 1 type or in combination of 2 or more types. As the buffer, boric acid is preferred.

The content of the buffer in the aqueous composition of the present embodiment is not particularly limited, and can be appropriately set according to the type of the buffer, the type and content of other blending ingredients, the use of the aqueous composition, and the form of the preparation. As for the content of the buffering agent, in terms of more remarkably exerting the effect produced by the present invention, for example, based on the total amount of the aqueous composition, the total content of the buffering agent is preferably 0.01% by mass to 10% by mass, more preferably It is 0.05% by mass to 5% by mass, and more preferably 0.1% by mass to 3% by mass.

The content ratio of the buffer in the aqueous composition of this embodiment to the LMK inhibitor is not particularly limited, and it can be based on the type of LMK kinase inhibitor and buffer, the types and contents of other blending ingredients, and the aqueous composition. The purpose of the substance and the form of the preparation are appropriately set. As the content ratio of the buffer to the LMK inhibitor, from the aspect of further improving the effect produced by the present invention, for example, relative to the total content of LMK inhibitor contained in the aqueous composition of the present embodiment1 Parts by mass, the total content of the buffer is preferably 0.03 parts by mass to 500 parts by mass, more preferably 0.1 parts by mass to 250 parts by mass, and still more preferably 0.3 parts by mass to 150 parts by mass.

[Inorganic Salts] The aqueous composition of this embodiment may further contain inorganic salts. By further containing inorganic salts in the aqueous composition, the effects produced by the present invention can be more remarkably exhibited. The inorganic salt is not particularly limited, as long as it is medically, pharmacologically (pharmaceutically) or physiologically acceptable.

Examples of inorganic salts include chloride salts such as sodium chloride, potassium chloride, calcium chloride, and magnesium chloride. Commercially available inorganic salts can be used. Inorganic salts may be used alone or in combination of two or more kinds. As the inorganic salt, sodium chloride and potassium chloride are preferred.

The content of the inorganic salt in the aqueous composition of the present embodiment is not particularly limited, and can be appropriately set according to the type of inorganic salt, the type and content of other blending ingredients, the use of the aqueous composition, the form of preparation, and the like. As for the content of inorganic salts, in terms of more remarkably exerting the effects produced by the present invention, for example, based on the total amount of the aqueous composition, the total content of inorganic salts is preferably 0.00001% by mass to 3% by mass, It is more preferably 0.0001% by mass to 2% by mass, and still more preferably 0.001% by mass to 1.5% by mass.

The pH of the aqueous composition of the present embodiment is not particularly limited, as long as it is within a medically, pharmacologically (pharmaceutically) or physiologically acceptable range. The pH of the aqueous composition of the present embodiment may be 5.0 to 6.5, for example, and preferably 5.0 to 6.0. Moreover, as the pH of the aqueous composition of this embodiment, it can be 4.0-6.5, 4.0-6.0, or 4.5-6.0, for example.

The aqueous composition of this embodiment can be adjusted to an osmotic pressure ratio within the range allowed by the organism as necessary. The appropriate osmotic pressure ratio can be appropriately set according to the use, formulation form, method of use, etc. of the aqueous composition. For example, it can be set to 0.4 to 5.0, preferably 0.6 to 3.0, more preferably 0.8 to 2.2, and more. Preferably, it is set to 0.8 to 2.0. According to the seventeenth revised edition of the Japanese Pharmacopoeia, the osmotic pressure ratio is set as the ratio of the osmotic pressure of the sample to 286 mOsm (the osmotic pressure of 0.9 w/v% sodium chloride aqueous solution), and the osmotic pressure refers to the osmotic pressure recorded in the Japanese Pharmacopoeia Pressure measurement method (freezing point depression method) for measurement. In addition, the standard solution for osmotic pressure ratio measurement (0.9 w/v% sodium chloride aqueous solution) is made by drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500-650°C for 40-50 minutes, and then placing it in a desiccator ( Naturally cool in silica gel), accurately weigh 0.900 g of the sodium chloride, and then dissolve it in purified water to accurately prepare 100 mL, or use a commercially available standard solution for osmotic pressure ratio measurement (0.9 w/v% chlorinated Sodium aqueous solution).

The viscosity of the aqueous composition of this embodiment is not particularly limited, as long as it is within a medically, pharmacologically (pharmaceutically) or physiologically acceptable range. As the viscosity of the water-based composition of this embodiment, for example, the viscosity at 20°C measured with a rotary viscometer (RE550 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor; 1°34'×R24) is preferably 0.5~ 10 mPa·s, more preferably 1 to 5 mPa·s, still more preferably 1 to 3 mPa·s.

The aqueous composition of the present embodiment can be prepared, for example, by adding and mixing the two-faced kinase inhibitor, the biguanide-based preservative, and other ingredients as necessary in the required content. Specifically, for example, the above-mentioned components can be dissolved or suspended using purified water, adjusted to a predetermined pH and osmotic pressure, and sterilized by filtration sterilization or the like, thereby preparing.

The aqueous composition of the present embodiment can adopt various dosage forms according to the purpose, for example, a liquid agent, a gel agent, a semi-solid agent (ointment, etc.) can be exemplified.

The aqueous composition of this embodiment can be used in ophthalmology. In addition, the aqueous composition of the present embodiment can be used as eye drops (also called eye drops or eye drops; also, eye drops include artificial tears, eye drops that can be instilled into the eyes during the wearing of contact lenses ).

When the aqueous composition of the present embodiment is eye drops, the usage and dosage are not particularly limited, as long as it is effective and has fewer side effects, for example, for adults (over 15 years old) and over 7 years old For children, you can exemplify: 4 drops a day and 1 drop or 1-2 drops once a day, 5-6 times a day and 1 drop or 1-2 drops once a day.

The aqueous composition of the present embodiment is preferably provided in a container (also simply referred to as a "polyolefin resin container") that is partly or entirely in contact with the aqueous composition and is made of polyolefin resin. The polyolefin resin container only needs to be a package having a part in contact with the aqueous composition. For example, the container body part containing the aqueous composition, the part containing the ejection part of the container (such as a nozzle, an inner plug), a straw, and a lid can be used. And other composition.

The polyolefin resin may be a polymer obtained by polymerizing a single olefin, or may be a polymer obtained by copolymerizing two or more olefins. These polymers may also contain other polymerizable monomers as constituent components. Specific examples of polyolefin resins include: polyethylene (including low-density polyethylene, medium-density polyethylene, high-density polyethylene, etc.), polypropylene (including in-row polypropylene, opposite-row polypropylene, and hybrid Polypropylene), ethylene-propylene copolymer, polymethylpentene, etc. Among them, polyethylene and polypropylene are preferred, and polyethylene is more preferred. Example

Hereinafter, the present invention will be specifically described based on test examples, but the present invention is not limited to these test examples. Also, unless otherwise stated, the unit of each component in the table is w/v%.

[Test Example 1: Storage Efficiency Test (1)] According to the composition shown in Table 1, an aqueous composition was prepared according to a conventional method. The prepared aqueous compositions were filtered and sterilized by a 0.2 μm membrane filter. After that, the aqueous composition was filled in an eye drop bottle (material: polyethylene, volume: 5 mL), and stored at 50°C for 2 months under light-shielding conditions. According to the preservation efficiency test method stipulated in the seventeenth revised edition of the Japanese Pharmacopoeia, the preservation efficiency of each aqueous composition after storage at 50°C for 2 months was evaluated. Specifically, Pseudomonas aeruginosa was inoculated on the surface of a soybean-casein-digest agar medium, and cultured at 30-35°C for 24 hours. By aseptically collecting and cultivating bacterial cells from platinum ears and suspending them in an appropriate amount of sterile physiological saline to prepare a ^{bacterial suspension containing approximately 1×10 7} CFU/mL of bacteria. After adding this bacterial suspension to each formulation so as to be about 1×10 ⁵ CFU/mL, it was allowed to stand at 20-25°C for 7 days. After that, the bacteria were recovered according to the membrane filter method and placed on the surface of the soybean-casein-digest agar medium at 30-35°C for 2 to 3 days, and then the bacteria per 1 mL of each aqueous composition were measured Count and calculate Log reduction based on this value. The results are shown in Table 1.

[Test Example 2: Evaluation of the stability of loxidine gluconate] Each aqueous composition prepared in Test Example 1 was filtered and sterilized with a 0.2 μm membrane filter. After that, the aqueous composition was filled in an eye drop bottle (material: polyethylene, volume: 5 mL), and stored at 50°C for 2 months under light-shielding conditions. The content of loxidine gluconate in each aqueous composition immediately after preparation and each aqueous composition stored at 50°C for 2 months was quantitatively determined by HPLC (the measurement conditions are described below), and the following The above (Equation 1) and (Equation 2) calculate the reduction and improvement rate of loxidine gluconate concentration. The results are shown in Table 1. (Formula 1) Decreased concentration of lohxidine gluconate (mg/100 mL) = concentration of lohxidine gluconate immediately after manufacture-concentration of loxidine gluconate after storage at 50°C for 2 months (Formula 2) Decrease and improvement rate of loxidine gluconate concentration (%) = {(Decrease concentration of Comparative Example 2-Decrease concentration of each example)/Decrease Concentration of Comparative Example 2}×100 (Measurement conditions of HPLC) Detector: UV spectrophotometer (measurement wavelength: 254 nm) Column: Inertsil ODS-2 (inner diameter 4.6 mm, length 150 mm, particle size 5 μm) Column temperature: a certain temperature near 40℃ Mobile phase: Dissolve 1.50 g of sodium lauryl sulfate in 1000 mL of acetonitrile/dilute acetic acid (100) (1→60) mixed solution (7:3) Flow rate: 0.9 mL/min

[Table 1] Comparative example 1 Comparative example 2 Example 1 Example 2 Degatinib 0.3 - 0.02 0.3 Loxidine gluconate - 0.00094 0.00094 0.00094 Boric acid 0.5 0.5 0.5 0.5 Sodium chloride 0.4 0.4 0.4 0.4 Potassium Chloride 0.1 0.1 0.1 0.1 Hydrochloric acid/sodium hydroxide Right amount Right amount Right amount Right amount purified water remaining remaining remaining remaining pH 5.5 5.5 5.5 5.5 Preservation efficiency (Log reduction) 1.7 3.3 5.5 5.5 Concentration reduction and improvement rate of loxidine gluconate (%) - - 32.57 53.99

In Comparative Example 1 where the aqueous composition containing degatinib was not blended with loxidine gluconate, the preservation efficiency was extremely weak. On the other hand, it can be confirmed that in Examples 1 and 2 in which lohexidine gluconate is blended in an aqueous composition containing degatinib, compared to Comparative Example 1, or only lohexidine gluconate is blended Set comparative example 2, the preservation efficiency is significantly enhanced. In addition, depending on the concentration of degatinib, the reduction of loxidine gluconate was improved (Examples 1 and 2), and it was confirmed that degatinib increased the stability of loxidine gluconate.

[Test Example 3: Preservation Efficiency Test (2)] According to the composition shown in Table 2, an aqueous composition was prepared according to a conventional method. The prepared aqueous compositions were filtered and sterilized by a 0.2 μm membrane filter, and the preservation efficiency of each aqueous composition was evaluated according to the preservation efficiency test method stipulated in the seventeenth revised edition of the Japanese Pharmacopoeia. Specifically, Pseudomonas aeruginosa was inoculated on the surface of a soybean-casein-digest agar medium, and cultured at 30-35°C for 24 hours. By aseptically collecting and cultivating bacterial cells from platinum ears and suspending them in an appropriate amount of sterilized physiological saline, a ^{bacterial suspension containing approximately 3×10 7} CFU/mL of bacteria was prepared. After adding this bacterial suspension to each formulation so as to become approximately 3×10 ⁵ CFU/mL, it was allowed to stand at 20 to 25° C. for 7 days. After that, the bacteria were recovered according to the membrane filter method and placed on the surface of the soybean-casein-digest agar medium at 30-35°C for 1 day, and then the number of bacteria per 1 mL of each aqueous composition was measured. And calculate the Log reduction based on this value. The results are shown in Table 2.

[Table 2] Test example 1 Test example 2 Test example 3 Test example 4 Degatinib - 0.3 - 0.02 Loxidine gluconate 0.00094 0.00094 - - Polyhexanide Hydrochloride - - 0.00002 0.00002 Boric acid 0.5 0.5 0.5 0.5 Sodium chloride 0.4 0.4 0.4 0.4 Potassium Chloride 0.1 0.1 0.1 0.1 hydrochloric acid Right amount Right amount Right amount Right amount Sodium hydroxide Right amount Right amount Right amount Right amount purified water remaining remaining remaining remaining pH 4.5 4.5 5.5 5.5 Preservation efficiency (Log reduction) 2.7 3.6 2.5 3.2

[Test Example 4: Preservation Efficiency Test (3)] According to the composition shown in Table 3, an aqueous composition was prepared according to a conventional method. The prepared aqueous compositions were filtered and sterilized by a 0.2 μm membrane filter. After that, the aqueous composition was filled in an eye drop bottle (material: polyethylene, volume: 5 mL), and stored at 60° C. for 3 weeks under light-shielding conditions. The preservation efficiency of each aqueous composition was evaluated according to the preservation efficiency test method stipulated in the seventeenth revised edition of the Japanese Pharmacopoeia. Specifically, Pseudomonas aeruginosa was inoculated on the surface of a soybean-casein-digest agar medium, and cultured at 30-35°C for 24 hours. By aseptically collecting and cultivating bacterial cells from platinum ears and suspending them in an appropriate amount of sterilized physiological saline, a ^{bacterial suspension containing approximately 3×10 7} CFU/mL of bacteria was prepared. After adding this bacterial suspension to each formulation so as to become approximately 3×10 ⁵ CFU/mL, it was allowed to stand at 20 to 25°C for 14 days. After that, the bacteria were recovered according to the membrane filter method and placed on the surface of the soybean-casein-digest agar medium at 30-35°C for 1 day, and then the number of bacteria per 1 mL of each aqueous composition was measured. And calculate the Log reduction based on this value. The results are shown in Table 3.

[table 3] Test Example 5 Test Example 6 Tofacitinib - 0.01 Polyhexanide Hydrochloride 0.00002 0.00002 Boric acid 0.5 0.5 Sodium chloride 0.4 0.4 Potassium Chloride 0.1 0.1 hydrochloric acid Right amount Right amount Sodium hydroxide Right amount Right amount purified water remaining remaining pH 5.5 5.0 Preservation efficiency (Log reduction) 0.9 1.6

without

without

Claims (5)

A water-based composition for ophthalmology, which contains Janus kinase inhibitor and biguanide preservative. For example, the water-based ophthalmic composition of claim 1, wherein the content of the LMK kinase inhibitor is 0.001% to 5% by mass based on the total amount of the water-based ophthalmic composition. Such as the water-based ophthalmic composition of claim 1 or 2, wherein the LMK kinase inhibitor is Delgocitinib. The ophthalmic aqueous composition according to any one of claims 1 to 3, wherein the biguanide-based preservative is loxidine or a salt thereof. The ophthalmic aqueous composition according to any one of claims 1 to 4 has a pH of 4.0 to 6.5.