Water-based components

Abstract

To provide an aqueous composition containing delgocitinib or a salt thereof as an active ingredient that exhibits excellent stability even when trace amounts of iron are present. [Solution] The present invention relates to an aqueous composition containing (A) delgocitinib or a salt thereof, and (B) at least one selected from the group consisting of citric acid, phosphoric acid, and salts thereof.

Description

Technical Field

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

Background Art

[0002] Janus kinase (JAK) is a non-receptor tyrosine kinase that plays an important role in intracellular immune activation signal transduction. Drugs having Janus kinase inhibitory activity are expected to improve autoimmune diseases and allergic diseases by suppressing excessive activation of the immune response. Here, as one of the compounds having an inhibitory action on Janus kinase, 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 (for example, Patent Document 1).

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] When delgocitinib is used as a therapeutic agent for diseases in the ophthalmic field, the ophthalmic preparation containing delgocitinib is required to have a certain stability. Here, when even a trace amount of iron is mixed in the production stage of the ophthalmic preparation containing delgocitinib, a new problem has been found that the ophthalmic preparation is colored and its stability is reduced.

[0005] An object of the present invention is to provide an aqueous composition containing delgocitinib or a salt thereof as an active ingredient, which has excellent stability even when a trace amount of iron is mixed.

Means for Solving the Problems

[0006] The inventors of the present invention conducted diligent research to solve the above problems and found that by adding citric acid, phosphoric acid, or salts thereof to an aqueous composition containing delgocitinib and a trace amount of iron, the stability of the aqueous composition is significantly improved. The present invention is based on this finding and provides the following inventions.

[0007] [1] An aqueous composition comprising (A) delgocitinib or a salt thereof, and (B) at least one selected from the group consisting of citric acid, phosphoric acid, and salts thereof. [2] The aqueous composition according to [1], wherein the content of component (A) is 0.003% by mass to 3% by mass, based on the total amount of the aqueous composition. [3] The aqueous composition according to [1] or [2], wherein the content of component (B) is 0.0001% by mass to 1% by mass, based on the total amount of the aqueous composition. [4] An aqueous composition for ophthalmic use, as described in any of [1] to [3]. [Effects of the Invention]

[0008] According to the present invention, it is possible to provide an aqueous composition containing delgocitinib or a salt thereof as an active ingredient that exhibits excellent stability even when trace amounts of iron are present. [Modes for carrying out the invention]

[0009] The embodiments for carrying out the present invention will be described in detail below. However, the present invention is not limited to the following embodiments. In this specification, "mass%" is synonymous with "w / v%".

[0010] The aqueous composition according to this embodiment contains (A) delgocitinib or a salt thereof (also referred to as "component (A)") and (B) at least one selected from the group consisting of citric acid, phosphoric acid, and salts thereof (also referred to as "component (B)").

[0011] [Component (A)] Delgocitinib is also known as 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile, and is given the following formula: [ka] It is a known compound represented by [formula]. Delgocitinib 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.

[0012] The salts of delgocitinib are not particularly limited, as long as they are 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, and salts with basic amino acids.

[0013] Salts with inorganic acids include, for example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Salts with organic acids include, for example, 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, and p-toluenesulfonic acid. Salts with inorganic bases include, for example, alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, aluminum salts, and ammonium salts. Salts with organic bases include, for example, salts with diethylamine, diethanolamine, meglumine, and N,N-dibenzylethylenediamine. Salts with acidic amino acids include, for example, salts with aspartic acid and glutamic acid. Salts with basic amino acids include, for example, salts with arginine, lysine, and ornithine.

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

[0015] Furthermore, the aqueous composition according to this embodiment can also be used to improve dry eye because it contains delgocitinib or a salt thereof, thereby promoting tear secretion. Dry eye may be caused by an autoimmune disease such as Sjögren's syndrome, or by factors other than autoimmune diseases.

[0016] The content of component (A) in the aqueous composition according to this embodiment is not particularly limited and is set as appropriate depending on the type and content of other components, the formulation form, etc. As for the content of component (A), from the viewpoint of more significantly exhibiting the effects of the present invention, for example, the total content of component (A) may be 0.003% to 3% by mass, 0.005% to 1% by mass, 0.01% to 0.5% by mass, 0.015% to 0.4% by mass, or 0.03% to 0.3% by mass, based on the total amount of the aqueous composition according to this embodiment.

[0017] [(B) component] (B) The citric acid, phosphoric acid, and their salts that constitute the component are not particularly limited, as long as they are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.

[0018] Examples of citrates and phosphates include salts with inorganic bases (e.g., ammonium salts; salts with alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), aluminum, etc.), and salts with organic bases (e.g., salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, and picoline).

[0019] As the citric acid or its salt, citric acid and alkali metal salts of citric acid are preferable, citric acid and sodium citrate are more preferable, and citric acid is even more preferable. The citric acid and its salts may be hydrates or anhydrides. The citric acid or its salt may be used alone or in combination of two or more kinds.

[0020] As the phosphoric acid or its salt, phosphoric acid and alkali metal salts of phosphoric acid are preferable, phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate and dipotassium hydrogen phosphate are more preferable, and phosphoric acid is even more preferable. The phosphoric acid and its salts may be hydrates or anhydrides. The phosphoric acid or its salt may be used alone or in combination of two or more kinds.

[0021] The content of component (B) in the aqueous composition according to this embodiment is not particularly limited and is appropriately set according to the types and contents of other compounding components, the dosage form, etc. From the viewpoint of more significantly exhibiting the effects according to the present invention, for example, based on the total amount of the aqueous composition according to this embodiment, the total content of component (B) may be 0.00001% by mass or more, 0.00005% by mass or more, 0.0001% by mass or more, 0.0005% by mass or more, and may be 0.05% by mass or less, 0.04% by mass or less, 0.03% by mass or less, 0.02% by mass or less. Further, it may be 0.000001% by mass to 10% by mass, 0.00001% by mass to 1% by mass, 0.0001% by mass to 0.1% by mass, 0.0005% by mass to 0.05% by mass, 0.0001% by mass to 0.05% by mass, 0.00001% by mass to 0.1% by mass or 0.00001% by mass to 0.05% by mass.

[0022] In the aqueous composition according to this embodiment, the content ratio of component (B) to component (A) is not particularly limited and is set as appropriate depending on the type of component (B), the types and content of other components, the formulation form, etc. As for the content ratio of component (B) to component (A), from the viewpoint of further enhancing the effects of the present invention, for example, the total content of component (B) in the aqueous composition according to this embodiment may be 0.0000003 to 4000 parts by mass, 0.00001 to 200 parts by mass, 0.0002 to 10 parts by mass, or 0.001 to 4 parts by mass per 1 part by mass of the total content of component (A) contained in the aqueous composition according to this embodiment.

[0023] [Cushioning material] The aqueous composition according to this embodiment may further contain buffering agents other than component (B). The effects of the present invention are more pronounced when the aqueous composition further contains buffering agents. The buffering agent is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.

[0024] While not limited to these, examples of buffering agents include boric acid buffers (e.g., boric acid, a combination of boric acid and borax), carbonate buffers, acetate buffers, Tris buffers, aspartic acid, aspartate salts, etc. Commercially available buffering agents may be used. Buffering agents may be used individually or in combination of two or more. Boric acid is preferred as the buffering agent.

[0025] The buffering agent content in the aqueous composition according to this embodiment is not particularly limited and is set appropriately depending on the type of buffering agent, the types and amounts of other components, the use of the aqueous composition, and the formulation form. From the viewpoint of more significantly demonstrating the effects of the present invention, for example, the total buffering agent content may be 0.01% to 10% by mass, 0.05% to 5% by mass, or 0.1% to 3% by mass, based on the total amount of the aqueous composition.

[0026] In the aqueous composition according to this embodiment, the content ratio of the buffering agent to component (A) is not particularly limited and is set appropriately depending on the type of component (B) and the buffering agent, the type and content of other compounding components, the use of the aqueous composition and the formulation form, etc. As for the content ratio of the buffering agent to component (A), from the viewpoint of further enhancing the effects of the present invention, for example, the total content of the buffering agent may be 0.03 to 500 parts by mass, 0.1 to 250 parts by mass, or 0.3 to 150 parts by mass per 1 part by mass of the total content of component (A) contained in the aqueous composition according to this embodiment.

[0027] In the aqueous composition according to this embodiment, the content ratio of the buffering agent to component (B) is not particularly limited and is set appropriately depending on the type of buffering agent, the type and content of other components, the use of the aqueous composition and the formulation form, etc. As for the content ratio of the buffering agent to component (B), from the viewpoint of further enhancing the effects of the present invention, for example, the total content of the buffering agent may be 0.01 parts by mass to 1,000,000 parts by mass, 0.5 parts by mass to 50,000 parts by mass, or 2 parts by mass to 6,000 parts by mass per 1 part by mass of the total content of component (B) contained in the aqueous composition according to this embodiment.

[0028] [Inorganic salts] The aqueous composition according to this embodiment may further contain inorganic salts. The effects of the present invention are more pronounced when the aqueous composition further contains inorganic salts. The inorganic salts are not particularly limited, as long as they are pharmaceutically, pharmacologically (pharmaceutically), or physiologically acceptable.

[0029] 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 as inorganic salts.

[0030] The inorganic salt content in the aqueous composition according to this embodiment is not particularly limited and is set appropriately depending on the type of inorganic salt, the type and content of other components, the use of the aqueous composition, and the formulation form. From the viewpoint of more significantly exhibiting the effects of the present invention, for example, the total inorganic salt content may be 0.00001% to 3% by mass, 0.0001% to 2% by mass, or 0.001% to 1.5% by mass, based on the total amount of the aqueous composition.

[0031] The pH of the aqueous composition according to this embodiment is 5.0 to 6.5. By setting the pH of the aqueous composition within 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 5.0 to 6.0. Alternatively, the pH of the aqueous composition may be 4.0 to 6.0, 4.2 to 5.8, 4.3 to 5.7, or 4.5 to 5.5.

[0032] The aqueous composition according to this embodiment can be adjusted to an osmotic pressure ratio within a range acceptable to living organisms, if necessary. The appropriate osmotic pressure ratio can be set appropriately depending on the use, formulation, and method of use of the aqueous composition, but for example, it can be 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 (osmotic pressure of 0.9 w / v% sodium chloride aqueous solution) based on the 17th edition of the Japanese Pharmacopoeia, and the osmotic pressure is measured by referring to the osmotic pressure measurement method (freezing point depression method) described in the Japanese Pharmacopoeia. The standard solution for osmotic pressure ratio measurement (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, then cooling it in a desiccator (silica gel), accurately weighing 0.900 g of it, dissolving it in purified water to make exactly 100 mL, or by using a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution).

[0033] The viscosity of the aqueous composition according to this embodiment is not particularly limited, as long as it is within a range that is pharmaceutically, pharmacologically (pharmaceutically), or physiologically acceptable. For example, 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 viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1°34' × R24).

[0034] The aqueous composition according to this embodiment can be prepared, for example, by adding and mixing component (A), component (B), and other components as needed, in desired amounts. Specifically, it can be prepared, for example, by dissolving or suspending the above components in purified water and sterilizing them by filtration sterilization or the like.

[0035] The aqueous composition according to this embodiment can take various dosage forms depending on the purpose, such as liquids, gels, and semi-solids (ointments, etc.).

[0036] The aqueous composition according to this embodiment can be used for ophthalmic purposes. Furthermore, the aqueous composition according to this embodiment can be used, for example, as an eye drop (also called an eye solution or eye drop; eye drops include artificial tears and eye drops that can be administered while wearing contact lenses).

[0037] When the aqueous composition according to this embodiment is an eye drop, the method of use and dosage 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 7 years of age or older, examples include using one drop or one to two drops four times a day, or using one drop or one to two drops five to six times a day. [Examples]

[0038] The present invention will be described in detail below based on test examples, but the present invention is not limited to these. Unless otherwise specified, the units for each component in the table are in mass percent.

[0039] [Example 1: Visual Stability Evaluation] Aqueous compositions were prepared according to conventional methods with the compositions shown in Table 1. Each aqueous composition was adjusted to a pH of 5.5 using hydrochloric acid and sodium hydroxide. 5 mL of each prepared aqueous composition was dispensed into three glass containers. Iron sulfate heptahydrate was added to each dispensed aqueous composition to a concentration of 4 ppm, and the mixture was then allowed to stand at 60°C for 3 weeks. Each aqueous composition, left to stand under the above conditions, was poured into a colorless test tube (15mm inner diameter: Fisherbrand Disposable Cultur Tubes Borosilicate Glass 16×150mm (Cat.No.14-961-31)) to a liquid layer of 30mm, in accordance with the properties test of the 17th edition of the Japanese Pharmacopoeia. Four trained evaluators visually evaluated the degree of coloration of each aqueous composition (n=3) under a white light source (illuminance 3000-5000 lux (measured value 4680 lux), using a Hiroki Lux Meter FT3424 as the light source). The evaluation was performed by assigning a score of 0-3 points to each evaluator according to the following criteria, and calculating the average of the scores from the four evaluators. The results are shown in Table 1. Rating 0: No color is visible on the white background (colorless). 1: A slight discoloration is visible against a white background (the discoloration is only noticeable when compared side-by-side with purified water). 2: Coloration is visible against a white background (the coloration is noticeable even without comparing it side-by-side with purified water). 3: Even without a white background, coloration is clearly visible.

[0040] [Table 1]

[0041] [Example 2: Stability evaluation by absorbance measurement] Aqueous compositions were prepared according to conventional methods by pouring them into glass containers (Test Examples 14-21) and polyethylene containers (Test Examples 22-32) with the compositions shown in Tables 2 and 3. In Tables 2 and 3, "phosphoric acid" refers to sodium dihydrogen phosphate, and "EDTA" refers to sodium EDTA. The pH of each aqueous composition was adjusted to 5.5 using hydrochloric acid and sodium hydroxide. Iron sulfate heptahydrate was added to each prepared aqueous composition to a concentration of 4 ppm, and then the mixture was allowed to stand at 60°C for 10 days. The absorbance of each aqueous composition, which was left standing under the above conditions, at 420 nm was measured using a microplate reader. Next, the stability improvement rate of delgocitinib was calculated from the measured absorbance according to (Equation 1), (Equation 2), or (Equation 3) below. The results are shown in Tables 2 and 3. For example, (Equation 1) was used for example 15 to 21, (Equation 2) for example 23 to 25, and (Equation 3) for example 27 to 32. (Equation 1) Stability improvement rate (%) = 100 × {(Absorbance of Test Example 14) - (Absorbance of each test example)} / (Absorbance of Test Example 14) (Equation 2) Stability improvement rate (%) = 100 × {(Absorbance of Test Example 22) - (Absorbance of each test example)} / (Absorbance of Test Example 22) (Equation 3) Stability improvement rate (%) = 100 × {(Absorbance of Test Example 26) - (Absorbance of each test example)} / (Absorbance of Test Example 26)

[0042] [Table 2]

[0043] [Table 3]

[0044] It was confirmed that adding a small amount of iron to an aqueous composition containing delgocitinib resulted in discoloration, i.e., a decrease in stability. In contrast, in the aqueous compositions of the test examples in which citric acid or phosphoric acid was added to the delgocitinib aqueous composition, discoloration was suppressed even when a small amount of iron was added, i.e., stability was improved. On the other hand, in the aqueous compositions of the test examples in which edetic acid or acetic acid was added to the delgocitinib aqueous composition, discoloration was observed when a small amount of iron was added compared to the aqueous compositions of the test examples in which citric acid or phosphoric acid was added, and stability hardly improved or even worsened.

[0045] [Examples of formulations] Tables 4 and 5 below show examples of formulations. Unless otherwise specified in the table, all units for each component in Tables 4 and 5 are in mass percent. Note that all formulation examples are 5 mL filled into polyethylene eye drop containers.

[0046] [Table 4]

[0047] [Table 5]

Claims

[Claim 1] An aqueous ophthalmic composition comprising (A) delgocitinib or a salt thereof, and (B) at least one selected from the group consisting of citric acid, phosphoric acid, and salts thereof.

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