Aqueous composition

Abstract

To provide an aqueous composition exhibiting superior stability and comprising delgocitinib or a salt thereof as an active ingredient.SOLUTION: The present invention relates to an aqueous composition comprising delgocitinib or a salt thereof and having a pH of 4.0 to 6.5.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an aqueous composition. [Background technology]

[0002] Janus kinase (JAK) is a non-receptor tyrosine kinase that plays an important role in intracellular immune activation signal transduction, and drugs with Janus kinase inhibitory activity are expected to improve autoimmune diseases and allergic diseases by suppressing excessive activation of immune responses. Here, 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile (generic name: delgocitinib) is known as one of the compounds that have an inhibitory effect on Janus kinase (for example, Patent Document 1). [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2017 / 006968 Summary of the Invention [Problem to be solved by the invention]

[0004] When delgocitinib is used as a therapeutic agent for diseases in the field of ophthalmology, ophthalmic formulations containing delgocitinib are required to have a certain level of stability.

[0005] The present invention aims to provide an aqueous composition having excellent stability and containing delgocitinib or a salt thereof as an active ingredient. [Means for solving the problem]

[0006] The present inventors have conducted intensive research to solve the above problems, and have found that the stability of an aqueous composition containing delgocitinib is significantly improved by adjusting the pH of the aqueous composition to a specific range. The present invention is based on this finding, and provides the following inventions.

[0007] [1] An aqueous composition containing delgocitinib or a salt thereof, the aqueous composition having a pH of 4.0 to 6.5. [2] The aqueous composition according to [1], which is contained in a container, a part or all of which comes into contact with the aqueous composition being formed from a polyolefin-based resin. [3] The aqueous composition according to [1] or [2], wherein the content of delgocitinib or a salt thereof is 0.001% by mass to 5% by mass based on the total amount of the aqueous composition. [4] The aqueous composition according to [2] or [3], wherein the polyolefin resin is polyethylene. [5] The aqueous composition according to any one of [1] to [4], further comprising a buffering agent. [6] The aqueous composition according to any one of [1] to [5], which is for ophthalmic use. Effect of the Invention

[0008] According to the present invention, it is possible to provide an aqueous composition having excellent stability and containing delgocitinib or a salt thereof as an active ingredient. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] Hereinafter, an embodiment of the present invention will be described in detail. However, the present invention is not limited to the following embodiment.

[0010] The aqueous composition according to this embodiment contains delgocitinib or a salt thereof.

[0011] Delgocitinib is 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-oxopropanenitrile and has the following formula: [ka] It is a known compound represented by the formula: Delgocitinib or a salt thereof can be produced by, for example, the methods described in WO 2017 / 006968 and WO 2018 / 117151.

[0012] The salt of delgocitinib is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical) 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, etc.

[0013] 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, methanesulfonic 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.

[0014] The aqueous composition of this embodiment contains delgocitinib or a salt thereof as an active ingredient, and can be used for treating corneal and conjunctival epithelial disorders caused by endogenous diseases such as dry eye (xerophthalmia), Sjogren's syndrome, Stevens-Johnson syndrome, etc., or corneal and conjunctival epithelial disorders caused by exogenous diseases such as postoperative, drug-induced, traumatic, contact lens wearing, etc.

[0015] In addition, the aqueous composition according to the present embodiment contains delgocitinib or a salt thereof, and therefore can be used to improve dry eye, which may be caused by an autoimmune disease such as Sjogren's syndrome, or may be caused by a factor other than an autoimmune disease.

[0016] The content of delgocitinib or its salt in the aqueous composition according to this embodiment is not particularly limited, and is appropriately set according to the type and content of other blended components, the formulation form, etc. As for the content of delgocitinib or its salt, from the viewpoint of more significantly exhibiting the effects of the present invention, for example, based on the total amount of the aqueous composition according to this embodiment, the total content of delgocitinib or its salt is preferably 0.001% by mass to 5% by mass, more preferably 0.003% by mass to 3% by mass, even more preferably 0.005% by mass to 1% by mass, even more preferably 0.01% by mass to 0.5% by mass, particularly preferably 0.015% by mass to 0.4% by mass, and particularly preferably 0.02% by mass to 0.3% by mass.

[0017] [Buffer] The aqueous composition according to the present embodiment may further contain a buffering agent. When the aqueous composition further contains a buffering agent, the effect of the present invention is more pronounced. The buffering agent is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical) or physiologically acceptable.

[0018] Examples of the buffer include boric acid buffers (e.g., boric acid, a combination of boric acid and borax, etc.). Commercially available buffers may be used. One type of buffer may be used alone, or two or more types may be used in combination. Boric acid is preferred as the buffer.

[0019] The content of the buffering agent in the aqueous composition according to the present embodiment is not particularly limited, and is appropriately set depending on the type of buffering agent, the type and content of other blended components, the application and formulation form of the aqueous composition, etc. From the viewpoint of more significantly exhibiting the effects of the present invention, the content of the buffering agent is, for example, 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, based on the total amount of the aqueous composition.

[0020] In the aqueous composition according to the present embodiment, the content ratio of the buffering agent relative to delgocitinib or its salt is not particularly limited, and is appropriately set according to the type of buffering agent, the type and content of other blended components, the use of the aqueous composition, the formulation form, etc. As the content ratio of the buffering agent relative to delgocitinib or its salt, from the viewpoint of further enhancing the effect according to the present invention, for example, the total content of the buffering agent relative to delgocitinib or its salt contained in the aqueous composition according to 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.

[0021] [Inorganic salts] The aqueous composition according to the present embodiment may further contain an inorganic salt. When the aqueous composition further contains an inorganic salt, the effect of the present invention is more remarkable. The inorganic salt is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical) or physiologically acceptable.

[0022] 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 type of inorganic salt may be used alone, or two or more types may be used in combination. Sodium chloride and potassium chloride are preferred inorganic salts.

[0023] The content of inorganic salts in the aqueous composition according to the present embodiment is not particularly limited, and is appropriately set depending on the type of inorganic salts, the type and content of other blended components, the application and formulation form of the aqueous composition, etc. From the viewpoint of more significantly exhibiting the effects of the present invention, the content of inorganic salts is, for example, preferably 0.00001% by mass to 3% by mass, more preferably 0.0001% by mass to 2% by mass, and even more preferably 0.001% by mass to 1.5% by mass, based on the total amount of the aqueous composition.

[0024] The pH of the aqueous composition according to this embodiment is 4.0 to 6.5. By setting the pH of the aqueous composition in this range, the stability of the aqueous composition containing delgocitinib or a salt thereof as an active ingredient is significantly improved. From the viewpoint 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.

[0025] The aqueous composition according to the present embodiment can be adjusted to an osmotic pressure ratio within a range acceptable to the living body, if necessary. The appropriate osmotic pressure ratio can be appropriately set according to the application, formulation, and method of use of the aqueous composition, and can be, for example, 0.4 to 5.0, preferably 0.6 to 3.0, more preferably 0.8 to 2.2, and even more preferably 0.8 to 2.0. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (the osmotic pressure of a 0.9 w / v% sodium chloride aqueous solution) based on the 17th revised Japanese Pharmacopoeia, and the osmotic pressure is measured with reference to the osmometric method (freezing point depression method) described in the Japanese Pharmacopoeia. The standard solution for measuring osmolality ratios (0.9 w / v% sodium chloride aqueous solution) can be prepared by drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500-650°C for 40-50 minutes, allowing it to cool in a desiccator (silica gel), accurately measuring 0.900 g of it, and dissolving it in purified water to make exactly 100 mL; alternatively, a commercially available standard solution for measuring osmolality ratios (0.9 w / v% sodium chloride aqueous solution) can be used.

[0026] The viscosity of the aqueous composition according to this embodiment is not particularly limited as long as it is within a medicamentously, pharmacologically (pharmaceutical) or physiologically acceptable range. The viscosity of the aqueous composition according to this embodiment is preferably 0.5 to 10 mPa·s, more preferably 1 to 5 mPa·s, and even more preferably 1 to 3 mPa·s, as measured at 20°C using a rotational viscometer (RE550 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1°34'×R24).

[0027] The aqueous composition according to the present embodiment can be prepared, for example, by adding and mixing delgocitinib or a salt thereof, and other components as necessary, to a desired content. Specifically, for example, the above components are dissolved or suspended in purified water, and sterilized by filtration sterilization or the like.

[0028] The aqueous composition according to this embodiment can take various dosage forms depending on the purpose, and examples thereof include liquids, gels, semi-solids (ointments, etc.), and the like.

[0029] The aqueous composition according to the present embodiment can be used for ophthalmic purposes. The aqueous composition according to the present embodiment can be used, for example, as an eye drop (also called eye drops or eye drops. Eye drops include artificial tears and eye drops that can be applied while wearing contact lenses).

[0030] When the aqueous composition according to the present embodiment is an eye drop, the dosage and administration method are not particularly limited as long as they are effective and have few side effects. For example, for adults (15 years of age or older) and children aged 7 years or older, one drop or one to two drops can be instilled into the eyes four times a day, or one drop or one to two drops can be instilled into the eyes five to six times a day.

[0031] (Polyolefin resin container) The aqueous composition according to this embodiment is preferably provided in a container (also simply referred to as a "polyolefin resin container") in which a part or all of the part in contact with the aqueous composition is formed of a polyolefin resin. The polyolefin resin container may be any packaging body having a part in contact with the aqueous composition, and may be composed of, for example, a container body part that contains the aqueous composition, a part including a discharge part of the container (e.g., a nozzle, an inner plug), a suction tube, a cap, etc.

[0032] The polyolefin resin may be either a polymer obtained by polymerizing one kind of olefin alone or a polymer obtained by copolymerizing two or more kinds of olefins. These polymers may contain other monomers that can be polymerized as constituents. Specific examples of polyolefin resins include 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. Among these, polyethylene and polypropylene are preferred, and polyethylene is more preferred.

[0033] The polyolefin resin container for storing the aqueous composition may be a container generally used in the field of ophthalmology, specifically, for example, an eye drop container or an eyewash container. The type of the container is preferably an eye drop container.

[0034] In the polyolefin resin container according to the present embodiment, a part or the whole of the part that comes into contact with the aqueous composition is formed of a polyolefin resin. Here, the part of the polyolefin resin container that contains the aqueous composition that comes into contact with the aqueous composition can be, for example, the containing part (innermost layer when the container has a structure consisting of multiple layers), the inner plug, or the perforated inner plug. For example, when the polyolefin resin container has a perforated inner plug (nozzle), the containing part of the aqueous composition other than the perforated inner plug may be formed of a polyolefin resin, or the entire container may be formed of a polyolefin resin. In the polyolefin resin container according to the present embodiment, it is sufficient that a part of the part that comes into contact with the aqueous composition is formed of a polyolefin resin, but from the viewpoint of more significantly exerting the effect of the present invention, it is preferable that the containing part is formed of a polyolefin resin.

[0035] The shape and capacity of the polyolefin-based resin container according to the present embodiment are not particularly limited and may be appropriately set according to the application. For example, when the polyolefin-based resin container is a container for storing an eye drop, the capacity may be, for example, 0.3 mL or more and 25 mL or less, preferably 1 mL or more and 10 mL or less, and more preferably 2 mL or more and 7 mL or less.

[0036] The polyolefin-based resin container according to the present embodiment may be a multi-dose type that contains an amount for multiple uses, or a unit dose type that contains an amount for a single use. When the polyethylene-based resin container is a unit dose type, the capacity may be, for example, 0.1 mL or more and 1 mL or less, and preferably 0.2 mL or more and 0.5 mL or less. EXAMPLES

[0037] The present invention will be specifically described below based on test examples, but the present invention is not limited to these. Furthermore, unless otherwise specified, the unit of each component in the table is w / v %.

[0038] [Test Example 1: Stability Test (1)] Aqueous compositions were prepared according to the usual method with the compositions shown in Table 1. Each prepared aqueous composition was filtered and sterilized with a 0.2 μm membrane filter. The aqueous composition was then filled into an eye dropper bottle (material: polyethylene, capacity: 5 mL) and stored at 50 ° C. for 2 months under light-shielded conditions. The content of delgocitinib in the formulation immediately after preparation and in the formulation after storage was quantified by HPLC (measurement conditions are described below, either measurement condition 1 or 2 was used), and the delgocitinib residual rate was calculated according to the following (formula 1). The results are shown in Table 1. (Formula 1) Delgocitinib residual rate (%) = (delgocitinib content after storage at 50 ° C for 2 months / delgocitinib content immediately after preparation × 100) - moisture permeability The "moisture permeability" in the above formula (1) was calculated according to the following formula (2). (Formula 2) Moisture permeability (%) = (weight of filled product immediately after preparation - weight of filled product after 2 months of storage at 50°C) / (weight of filled product immediately after preparation - empty weight of eye drop bottle) x 100 (HPLC measurement condition 1) Detector: Ultraviolet spectrophotometer (measurement wavelength: 254 nm) Column: Inertsil ODS-2 (inner diameter 4.6 mm, length 150 mm, particle size 5 μm) Column temperature: constant temperature around 40℃ Mobile phase: 1.50 g of sodium lauryl sulfate dissolved in 1000 mL of acetonitrile / dilute acetic acid (100) (1 → 60) mixture (7:3) Flow rate: 0.9mL / min (HPLC measurement condition 2) Detector: Ultraviolet spectrophotometer (measurement wavelength: 283 nm) Column: Inertsil Ph-3 (inner diameter 4.6 mm, length 150 mm, particle size 5 μm) Column temperature: constant temperature around 40℃ Mobile phase: 3.9 g of ammonium acetate and 12.5 mL of acetic acid (100) were added, and the resulting solution was made up to 1000 mL with water / acetonitrile (4:1). Flow rate: approx. 0.8mL / min

[0039] [Table 1]

[0040] [Test Example 2: Stability Test (2)] Aqueous compositions were prepared according to the usual method with the compositions shown in Table 2. Each prepared aqueous composition was filtered and sterilized with a 0.2 μm membrane filter. The aqueous composition was then filled into an eye dropper bottle (material: polyethylene, capacity: 5 mL) and stored at 40 ° C. for 5 months under light-shielded conditions. The content of delgocitinib in the formulation immediately after preparation and in the formulation after storage was quantified by HPLC (measurement conditions were the same as in Test Example 1), and calculated as the delgocitinib residual rate according to the following (Equation 3). The results are shown in Table 2. (Formula 3) Delgocitinib residual rate (%) = (delgocitinib content after 5 months storage at 40 ° C. / delgocitinib content immediately after preparation × 100) - moisture permeability The "moisture permeability" in the above formula (3) was calculated according to the following formula (4). (Formula 4) Moisture permeability (%) = (weight of filled product immediately after preparation - weight of filled product after 5 months of storage at 40°C) / (weight of filled product immediately after preparation - empty weight of eye drop bottle) x 100

[0041] [Table 2]

[0042] [Test Example 3: Stability Test (3)] Aqueous compositions were prepared according to the usual method with the compositions shown in Table 3. Each prepared aqueous composition was filtered and sterilized with a 0.2 μm membrane filter. Then, 5 mL of the aqueous composition was poured into a centrifuge tube (material: polypropylene, capacity: 15 mL) and stored at 50 ° C. for one month under light-shielded conditions. The content of delgocitinib in the formulation immediately after preparation and in the formulation after storage was quantified by HPLC (measurement conditions were the same as in Test Example 1), and calculated as the delgocitinib residual rate according to the following (Equation 5). The results are shown in Table 3. (Formula 5) Delgocitinib residual rate (%) = (delgocitinib content after storage at 50 ° C for 1 month / delgocitinib content immediately after preparation × 100) - moisture permeability The "moisture permeability" in the above formula (5) was calculated according to the following formula (6). (Formula 6) Moisture permeability (%) = (weight of filled product immediately after preparation - weight of filled product after one month storage at 50°C) / (weight of filled product immediately after preparation - empty weight of eye drop bottle) x 100

[0043] [Table 3]

Claims

[Claim 1] The invention described in the specification.

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