Aqueous composition

Abstract

The present invention relates to an aqueous composition, which is an aqueous composition containing digotinib or a salt thereof, and which has a pH of 4.0-6.5.

Description

[0001] The present invention is a divisional application of the Chinese patent application with application number 202080088980.9, application date December 25, 2020, and invention name “Aqueous Composition”. This application claims the priority of Japanese Patent Application No. 2019-239599 filed in Japan on December 27, 2019. Technical Field

[0002] The present invention relates to an aqueous composition. Background Art

[0003] Janus kinase (JAK) is a non-receptor tyrosine kinase that plays an important role in the immune activation signal transduction in cells. It is expected that drugs having Janus kinase inhibitory activity can suppress the excessive activation of immune response and improve autoimmune diseases or allergic diseases. Among them, as one of the compounds having Janus kinase inhibitory activity, 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropionitrile (common name: Delgocitinib) is known (for example, Patent Document 1).

[0004] Prior art literature

[0005] Patent Literature

[0006] Patent Document 1: International Publication No. 2017 / 006968 Summary of the invention

[0007] 1. Technical issues to be resolved

[0008] When diabetinib is used as a drug for treating diseases in the field of ophthalmology, ophthalmic preparations containing diabetinib are required to have a certain stability.

[0009] An object of the present invention is to provide an aqueous composition having excellent stability and containing digotinib or a salt thereof as an active ingredient.

[0010] (II) Technical solution

[0011] The inventors of the present application have conducted intensive research to solve the above technical problems and have found that the stability of an aqueous composition containing diastatinib is significantly improved by setting the pH of the aqueous composition within a specific range. The present invention is based on this finding and further provides the following inventions.

[0012] [1] An aqueous composition comprising digotinib or a salt thereof, wherein the pH of the composition is 4.0 to 6.5.

[0013] [2] The aqueous composition according to [1], which is contained in a container, wherein part or all of a portion of the container that comes into contact with the ophthalmic aqueous composition is formed of a polyolefin resin.

[0014] [3] The aqueous composition according to [1] or [2], wherein the content of diatinib or its salt is 0.001% by mass to 5% by mass based on the total amount of the aqueous composition.

[0015] [4] The aqueous composition according to [2] or [3], wherein the polyolefin resin is polyethylene.

[0016] [5] The aqueous composition according to any one of [1] to [4], further comprising a buffer.

[0017] [6] The aqueous composition according to any one of [1] to [5], which is for use in ophthalmology.

[0018] (III) Beneficial effects

[0019] According to the present invention, there can be provided an aqueous composition having excellent stability and containing diatinib or a salt thereof as an active ingredient. DETAILED DESCRIPTION

[0020] Hereinafter, the embodiments for implementing the present invention will be described in detail. However, the present invention is not limited to the following embodiments.

[0021] The aqueous composition of the present embodiment contains diatinib or a salt thereof.

[0022] Digatinib is a known compound represented by the following formula and is also called 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropionitrile.

[0023] [Chemical formula 1]

[0024]

[0025] Digatinib or a salt thereof can be prepared by the method described in, for example, International Publication No. 2017 / 006968 and International Publication No. 2018 / 117151.

[0026] The salt of Digaotinib is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such salts include salts with inorganic acids, salts with organic acids, salts with inorganic bases, salts with organic bases, salts with acidic amino acids, salts with basic amino acids, and the like.

[0027] Examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Examples of salts with organic acids include salts with acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, mesylic acid, ethanesulfonic acid, p-toluenesulfonic acid, etc. Examples of salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, aluminum salts, ammonium salts, etc. Examples of salts with organic bases include salts with diethylamine, diethanolamine, meglumine, N,N-dibenzylethylenediamine, etc. Examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc. Examples of salts with basic amino acids include salts with arginine, lysine, ornithine, etc.

[0028] The aqueous composition of this embodiment contains digaotinib or its salt as an active ingredient, and can be used to treat corneal epithelial damage caused by endogenous diseases such as dry eye (Sjögren's syndrome), Sjögren's syndrome, Stevens-Johnson syndrome, or corneal epithelial damage caused by exogenous diseases such as postoperative, drug-induced, traumatic, contact lens wearing, etc.

[0029] In addition, the aqueous composition of this embodiment can promote tear secretion by containing digotinib or a salt thereof, and can therefore be used to improve dry eye syndrome. Dry eye syndrome may be caused by autoimmune diseases such as Sjögren's syndrome, or may be caused by factors other than autoimmune diseases.

[0030] The content of digaotinib or its salt in the aqueous composition of this embodiment is not particularly limited, and can be appropriately set according to the types and contents of other blending components, the formulation form, etc. With respect to the content of digaotinib or its salt, from the perspective of more significantly exerting the effects of the present invention, for example, based on the total amount of the aqueous composition of this embodiment, the total content of digaotinib or its salt is preferably 0.001% by mass to 5% by mass, more preferably 0.003% by mass to 3% by mass, further preferably 0.005% by mass to 1% by mass, further more preferably 0.01% by mass to 0.5% by mass, particularly preferably 0.015% by mass to 0.4% by mass, and particularly more preferably 0.02% by mass to 0.3% by mass.

[0031] [Buffer]

[0032] The aqueous composition of this embodiment may further contain a buffer. By making the aqueous composition further contain a buffer, the effect of the present invention can be more significantly exerted. The buffer is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.

[0033] As the buffer, for example, a boric acid buffer (e.g., boric acid, a combination of boric acid and borax, etc.) can be cited. The buffer can be a commercially available product. The buffer can be used alone or in combination of two or more. As the buffer, boric acid is preferred.

[0034] 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 components, the use of the aqueous composition, the formulation form, etc. With respect to the content of the buffer, from the perspective of more significantly exerting the effects of the present invention, for example, based on the total amount of the aqueous composition, the total content of the buffer is preferably 0.01% by mass to 10% by mass, more preferably 0.05% by mass to 5% by mass, and even more preferably 0.1% by mass to 3% by mass.

[0035] The content ratio of the buffer relative to digaotinib or its salt 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 components, the use of the aqueous composition, the formulation form, etc. With respect to the content ratio of the buffer relative to digaotinib or its salt, from the perspective of further improving the effect of the present invention, for example, the total content of the buffer relative to 1 part by mass of the total content of digaotinib or its salt contained in the aqueous composition of the present embodiment 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 even more preferably 0.3 parts by mass to 150 parts by mass.

[0036] [Inorganic salts]

[0037] The aqueous composition of the present embodiment may further contain inorganic salts. By making the aqueous composition further contain inorganic salts, the effect of the present invention can be more significantly exerted. The inorganic salts are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable inorganic salts.

[0038] Examples of inorganic salts include chloride salts such as sodium chloride, potassium chloride, calcium chloride, and magnesium chloride. Commercially available inorganic salts may be used. One inorganic salt may be used alone, or two or more inorganic salts may be used in combination. Preferred inorganic salts are sodium chloride and potassium chloride.

[0039] The content of inorganic salts in the aqueous composition of the present embodiment is not particularly limited and can be appropriately set according to the type of inorganic salts, the type and content of other blending components, the purpose of the aqueous composition, the formulation form, etc. With respect to the content of inorganic salts, from the perspective of more significantly exerting the effects of 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, more preferably 0.0001% by mass to 2% by mass, and further preferably 0.001% by mass to 1.5% by mass.

[0040] The pH of the aqueous composition of this embodiment is 4.0 to 6.5. By setting the pH of the aqueous composition within this range, the stability of the aqueous composition containing diatinib or a salt thereof as an active ingredient is significantly improved. From the perspective of further significantly improving the stability of the aqueous composition, the pH of the aqueous composition is preferably 4.5 to 6.5, 4.5 to 6.0 or 5.0 to 6.5, and more preferably 5.0 to 6.0.

[0041] The osmotic pressure ratio of the aqueous composition of the present embodiment can be adjusted within the range allowed by the organism as needed. The appropriate osmotic pressure ratio can be appropriately set according to the purpose, formulation form, and method of use of the aqueous composition, for example, the osmotic pressure ratio can be set to 0.4 to 5.0, preferably 0.6 to 3.0, more preferably 0.8 to 2.2, and further preferably 0.8 to 2.0. According to the seventeenth revised edition of the Japanese Pharmacopoeia, the osmotic pressure ratio is set to the ratio of the osmotic pressure of the sample to 286mOsm (the osmotic pressure of 0.9w / v% sodium chloride aqueous solution), and the osmotic pressure is measured with reference to the osmotic pressure determination method (freezing point depression method) recorded in the Japanese Pharmacopoeia. In addition, for the standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution), sodium chloride (Japanese Pharmacopoeia standard reagent) can be dried at 500~650°C for 40~50 minutes, naturally cooled in a desiccator (silica gel), and 0.900g of the sodium chloride can be accurately weighed and dissolved in pure water to accurately prepare 100mL for use, or a commercially available standard solution for osmotic pressure ratio measurement (0.9w / v% sodium chloride aqueous solution) can be used.

[0042] The viscosity of the aqueous composition of the present embodiment is not particularly limited as long as it is within the pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable range. The viscosity of the aqueous composition of the present embodiment is preferably 0.5 to 10 mPa·s at 20°C, more preferably 1 to 5 mPa·s, and further preferably 1 to 3 mPa·s, as measured, for example, using a rotational viscometer (RE550 viscometer, manufactured by TOKI SANGYO CO., LTD., rotor; 1°34'×R24).

[0043] The aqueous composition of the present embodiment can be prepared, for example, by adding and mixing diatinib or its salt and other components as required at a desired content. Specifically, for example, the above components can be dissolved or suspended in pure water and sterilized by filtration sterilization or the like.

[0044] The aqueous composition of the present embodiment can be made into various dosage forms according to the purpose, and examples thereof include solutions, gels, and semisolid preparations (ointments, etc.).

[0045] The aqueous composition of this embodiment can be used in ophthalmology. In addition, the aqueous composition of this embodiment can be used as, for example, eye drops (also called eye drops or eye drops; in addition, eye drops include artificial tears and eye drops that can be instilled into the eyes while wearing contact lenses).

[0046] When the aqueous composition of the present embodiment is an eye drop, its usage and dosage are not particularly limited as long as they can exert the effect and have few side effects. For example, for adults (over 15 years old) and children over 7 years old, examples include a method of dripping 4 times a day with 1 drop or 1 to 2 drops each time, and a method of dripping 5 to 6 times a day with 1 drop or 1 to 2 drops each time.

[0047] (Polyolefin resin container)

[0048] The aqueous composition of the present embodiment is preferably provided in a container (also referred to as a "polyolefin resin container") wherein part or all of the portion of the container in contact with the aqueous composition is formed of a polyolefin resin. The polyolefin resin container may be any packaging body having a portion in contact with the aqueous composition, and may be composed of, for example, a container body portion for containing the aqueous composition, a portion including a container discharge portion (e.g., a nozzle, an inner stopper), a straw, a cap, and the like.

[0049] The polyolefin resin may be any one of a polymer obtained by polymerizing a single olefin or a polymer obtained by copolymerizing two or more olefins. These polymers may also contain other polymerizable monomers as constituent components. As specific examples of the polyolefin resin, polyethylene (including low-density polyethylene, medium-density polyethylene, high-density polyethylene, etc.), polypropylene (including isotactic polypropylene, syndiotactic polypropylene, atactic polypropylene), ethylene-propylene copolymer, polymethylpentene, etc. may be cited. Among them, polyethylene and polypropylene are preferred, and polyethylene is more preferred.

[0050] The polyolefin resin container for containing the aqueous composition may be a container commonly used in the field of ophthalmology, and specifically, may be, for example, an eye drop container or an eye wash container. The type of the container is preferably an eye drop container.

[0051] The part of the polyolefin resin container of the present embodiment that contacts the aqueous composition is partially or entirely formed of a polyolefin resin. Among them, the part in contact with the aqueous composition in the polyolefin resin container for containing the aqueous composition can be, for example, a containing part (when the container is a structure consisting of multiple layers, it refers to the innermost layer), an inner plug, and a perforated inner plug. For example, when the polyolefin resin container is a container with a perforated inner plug (nozzle), the containing part of the aqueous composition other than the perforated inner plug can be formed of a polyolefin resin, or the entire container can be formed of a polyolefin resin. The polyolefin resin container of the present embodiment only needs to be partially formed of a polyolefin resin in contact with the aqueous composition. From the perspective of further significantly exerting the effect produced by the present invention, it is preferred that the containing part is formed of a polyolefin resin.

[0052] The shape and capacity of the polyolefin resin container of the present embodiment are not particularly limited, and can be appropriately set according to the purpose. For example, when the polyolefin resin container is a container for eye drops, the capacity can be 0.3 mL to 25 mL, preferably 1 mL to 10 mL, and more preferably 2 mL to 7 mL.

[0053] The polyolefin resin container of this embodiment can be a multi-dose type that can accommodate multiple doses, or a single-dose type that can accommodate a single dose. When the polyethylene resin container is a single-dose type, for example, the capacity can be 0.1 mL to 1 mL, preferably 0.2 mL to 0.5 mL.

[0054] Example

[0055] The present invention will be specifically described below based on the test examples, but the present invention is not limited thereto. In addition, the unit of each component in the table is w / v% unless otherwise specified.

[0056] [Test Example 1: Stability Test (1)]

[0057] An aqueous composition was prepared according to the conventional method with the composition shown in Table 1. Each prepared aqueous composition was filtered and sterilized using a 0.2 μm membrane filter. Then, the aqueous composition was filled into an eye drop bottle (material: polyethylene, capacity: 5 mL) and stored at 50°C for 2 months under light-proof conditions. The content of digotinib contained in the preparation just prepared and the preparation after storage was quantitatively determined by HPLC (the measurement conditions are as follows, using any of the measurement conditions 1 or 2), and the residual rate of digotinib was calculated according to the following (Formula 1). The results are shown in Table 1.

[0058] (Formula 1) Residual rate of Digotinib (%) = (Content of Digotinib after storage at 50°C for 2 months / Content of Digotinib immediately after preparation × 100) - Moisture permeability

[0059] In addition, the "water vapor transmission rate" in the above-mentioned (Formula 1) is calculated according to the following (Formula 2).

[0060] (Formula 2) Moisture permeability (%) = (weight of the filling immediately after preparation - weight of the filling after storage at 50°C for 2 months) / (weight of the filling immediately after preparation - weight of the empty eye drop bottle) × 100

[0061] (HPLC measurement conditions 1)

[0062] Detector: UV spectrophotometer (measurement wavelength: 254nm)

[0063] Chromatographic column: Inertsil ODS-2 (inner diameter 4.6 mm, length 150 mm, particle size 5 μm)

[0064] Column temperature: Constant temperature around 40°C

[0065] Mobile phase: 1.50 g of sodium lauryl sulfate dissolved in 1000 mL of a mixture of acetonitrile / dilute acetic acid (100) (1→60) (7:3)

[0066] Flow rate: 0.9 mL / min

[0067] (HPLC measurement conditions 2)

[0068] Detector: UV spectrophotometer (measurement wavelength: 283nm)

[0069] Chromatographic column: Inertsil Ph-3 (inner diameter 4.6 mm, length 150 mm, particle size 5 μm)

[0070] Column temperature: Constant temperature around 40°C

[0071] Mobile phase: A liquid / acetonitrile mixture (4:1) prepared by adding 3.9 g of ammonium acetate and 12.5 mL of acetic acid (100) to 1000 mL of water.

[0072] Flow rate: about 0.8mL / min

[0073] [Table 1]

[0074]

[0075] [Test Example 2: Stability Test (2)]

[0076] An aqueous composition was prepared according to the conventional method with the composition shown in Table 2. Each prepared aqueous composition was filtered and sterilized using a 0.2 μm membrane filter. Then, the aqueous composition was filled into an eye drop bottle (material: polyethylene, capacity: 5 mL) and stored at 40°C for 5 months under light-proof conditions. The content of digotinib contained in the preparation just prepared and the preparation after storage was quantitatively determined by HPLC (the measurement conditions were the same as those in Test Example 1), and the residual rate of digotinib was calculated according to the following (Formula 3). The results are shown in Table 2.

[0077] (Formula 3) Residual rate of Digotinib (%) = (Content of Digotinib after storage at 40°C for 5 months / Content of Digotinib immediately after preparation × 100) - Moisture permeability

[0078] In addition, the "water vapor transmission rate" in the above-mentioned (Formula 3) is calculated according to the following (Formula 4).

[0079] (Formula 4) Moisture permeability (%) = (weight of the filling immediately after preparation - weight of the filling after storage at 40°C for 5 months) / (weight of the filling immediately after preparation - weight of the empty eye drop bottle) × 100

[0080] [Table 2]

[0081]

[0082] [Test Example 3: Stability Test (3)]

[0083] An aqueous composition was prepared according to the conventional method with the composition shown in Table 3. Each prepared aqueous composition was filtered and sterilized using a 0.2 μm membrane filter. Then, 5 mL of the aqueous composition was injected into a centrifuge tube (material: polypropylene, capacity: 15 mL) and stored at 50°C for 1 month under light-proof conditions. The content of digotinib contained in the preparation just prepared and the preparation after storage was quantitatively determined by HPLC (the measurement conditions were the same as those in Test Example 1), and the residual rate of digotinib was calculated according to the following (Formula 5). The results are shown in Table 3.

[0084] (Formula 5) Residual rate of Digotinib (%) = (Content of Digotinib after storage at 50°C for 1 month / Content of Digotinib immediately after preparation × 100) - Moisture permeability

[0085] In addition, the "water vapor transmission rate" in the above-mentioned (Formula 5) is calculated according to the following (Formula 6).

[0086] (Formula 6) Moisture permeability (%) = (weight of the filling immediately after preparation - weight of the filling after storage at 50°C for 1 month) / (weight of the filling immediately after preparation - weight of the empty eye drop bottle) × 100

[0087] [Table 3]

[0088]

Claims

1. An ophthalmic aqueous composition, comprising digotinib or a salt thereof, wherein the pH of the ophthalmic aqueous composition is 4.0 to 6.

5. 2 . The ophthalmic aqueous composition according to claim 1 , which is contained in a container wherein part or all of a portion of the container that contacts the ophthalmic aqueous composition is formed of a polyolefin-based resin.

3. The ophthalmic aqueous composition according to claim 1 or 2, wherein The content of diatinib or a salt thereof is 0.001% by mass to 5% by mass based on the total amount of the ophthalmic aqueous composition.

4. The ophthalmic aqueous composition according to claim 2 or 3, wherein The polyolefin resin is polyethylene. 5 . The ophthalmic aqueous composition according to claim 1 , further comprising a buffer.

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