Liquid pharmaceutical composition exhibiting excellent preservative effectiveness

Abstract

The present invention addresses the problem of improving the preservation efficacy of a liquid composition that contains N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide or a salt thereof. The liquid composition used has a pH of 8 or higher and comprises: N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide or a salt thereof; benzyl alcohol; and water.

Description

REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims priority to Japanese Patent Application No. 2020-164034, filed on September 29, 2020, the entire disclosure of which is incorporated herein by reference. [Technical Field]

[0002] The present invention relates to a liquid composition comprising N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide or a salt thereof, which exhibits excellent preservative effectiveness. [Background technology]

[0003] It is known that N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide or a salt thereof has a phospholipase A2 inhibitory activity and is useful as an active ingredient of an anti-inflammatory agent or an anti-pancreatitis agent (Patent Document 1).

[0004] There are also known therapeutic or preventive agents for digestive diseases, liver diseases, pulmonary failure or shock, which contain N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide or a salt thereof as an active ingredient (Patent Documents 2, 3, 4 and 5).

[0005] Furthermore, the above Patent Documents 1 to 5 describe formulation compositions such as injections containing the above active ingredients, and also state that in such cases, an antibacterial agent such as benzyl alcohol may be contained.

[0006] Benzyl alcohol is an antibacterial agent widely used in injections and the like, but its optimum condition for antibacterial activity is below pH 5, with almost no antibacterial activity at pH above 8 (Non-Patent Document 1). On the other hand, N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide or a salt thereof is almost insoluble in water at a pH of 5 or less. Therefore, contrary to the descriptions in the above Patent Documents 1 to 5, benzyl alcohol is considered to be unsuitable as an antibacterial agent for use in compositions containing N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide or a salt thereof.

[0007] From the viewpoint of user convenience, it is desirable to utilize N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide or a salt thereof for a long period of time as a composition such as an injection, particularly as a composition filled in a multi-dose vial. Therefore, there is still a need to develop a technical means for enhancing the preservative effectiveness of a liquid composition containing N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide or a salt thereof. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] Japanese Patent Application Publication No. 06-263735 [Patent Document 2] International Publication No. 2001 / 056568 [Patent Document 3] International Publication No. 2001 / 056569 [Patent Document 4] International Publication No. 2001 / 056570 [Patent Document 5] International Publication No. 2010 / 137484 [Non-patent literature]

[0009] [Non-Patent Document 1] Handbook of pharmaceutical Excipients, Eighth edition (2017), p.105 Summary of the Invention

[0010] The present inventors have now unexpectedly found that when N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide or a salt thereof coexists with benzyl alcohol, the antibacterial activity is exhibited even at a pH at which benzyl alcohol does not exhibit antibacterial activity, and the preservative effectiveness of a liquid composition containing N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide or a salt thereof is enhanced.

[0011] N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide (fuzapladib) is represented by the structural formula (1) below, and may be abbreviated as the compound of formula (1) hereinafter. [ka]

[0012] Accordingly, an object of the present invention is to provide a liquid composition comprising N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide or a salt thereof, which has enhanced preservative effectiveness.

[0013] The present invention includes the following inventions. [1] A compound of formula (1) or a salt thereof: [ka] and Benzyl alcohol and Water and A liquid composition comprising: pH 8 or higher composition. [2] The composition described in [1], further comprising a sugar and, optionally, a pH adjuster. [3] The composition described in [2], wherein the saccharide is at least one selected from the group consisting of monosaccharides, disaccharides, polysaccharides, and sugar alcohols. [4] The composition described in [2], wherein the pH adjuster is a buffering agent. [5] The composition according to any one of [1] to [4], wherein the content of benzyl alcohol in the liquid composition is 0.9 to 3 w / v %. [6] The composition according to any one of [1] to [5], wherein the content of the compound of formula (1) or a salt thereof in the liquid composition is 0.01 to 1 w / v %. [7] The composition according to any one of [1] to [6], for multiple administration. [8] A kit for producing the composition according to any one of [1] to [7], a first composition comprising a compound of formula (1) or a salt thereof; a second composition comprising benzyl alcohol and water; A kit comprising: [9] The kit according to [8], wherein the first composition comprises a sugar and, optionally, a pH adjuster.

[10] The kit according to [8] or [9], wherein the content of benzyl alcohol in the second composition is 0.9 to 3 w / v% relative to the second composition.

[11] The kit according to any one of [8] to

[10] , wherein the first composition is filled in a vial.

[12] The kit according to

[11] , wherein the vial is a single-use vial or a multi-use vial.

[13] The kit according to

[12] , wherein the vial is a multi-use vial.

[14] A method for producing the composition according to any one of [1] to [7], a first composition comprising a compound of formula (1) or a salt thereof; a second composition comprising benzyl alcohol and water; A manufacturing method comprising the step of mixing the above.

[15] A method for enhancing the preservative effectiveness of a liquid composition comprising a compound of formula (1) or a salt thereof, the method comprising causing the compound of formula (1) or a salt thereof and benzyl alcohol to coexist in the liquid composition, and adjusting the pH of the liquid composition to 8 or higher.

[0014] According to the present invention, the preservative effect of a liquid composition comprising the compound of formula (1) or a salt thereof can be effectively increased. Therefore, the composition of the present invention is advantageous in that it can be used as a composition for multiple administration, for example, as a composition filled in a multiple-use vial.

[0015] One of the characteristics of the liquid composition of the present invention is that it contains N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide or a salt thereof, water, and benzyl alcohol, and has a pH of 8 or higher.

[0016] N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide or its salt N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide in the present invention is represented by the structural formula (1) above. The salt of the compound of formula (1) may be any pharmaceutically acceptable salt, and examples thereof include alkali metal salts such as potassium salt and sodium salt, alkaline earth metal salts such as calcium salt, organic amine salts such as triethanolamine salt and tris(hydroxymethyl)aminomethane salt, etc. Furthermore, the salt of the compound of formula (1) may be a salt having water of crystallization, i.e., a hydrate, among these salts. The compound of formula (1) or a salt thereof can be produced, for example, by the method described in JP-A-06-263735.

[0017] According to a preferred embodiment of the present invention, the content of the compound of formula (1) or its salt in the composition of the present invention is not particularly limited as long as it does not interfere with the effects of the present invention, but may be, for example, 0.001 to 15 w / v (mass / volume)% of the total composition, preferably 0.005 to 10 w / v%, more preferably 0.01 to 5 w / v%, even more preferably 0.01 to 1 w / v%, and even more preferably 0.1 to 1 w / v%. The content of the compound of formula (1) or its salt in the composition of the present invention can be measured by HPLC, for example, according to the method described in Example 1 of WO 2019 / 167979.

[0018] benzyl alcohol In the present invention, benzyl alcohol can be used to provide preservative effect.

[0019] According to a preferred embodiment of the present invention, the content of benzyl alcohol in the composition of the present invention is not particularly limited as long as it does not impair the effects of the present invention. The lower limit of the benzyl alcohol content is, for example, 0.8 w / v% or more, preferably 0.9 w / v% or more, and more preferably 1.2 w / v% or more. The upper limit of the benzyl alcohol content is, for example, 5 w / v% or less, preferably 4 w / v% or less, more preferably 3 w / v% or less, and even more preferably 2 w / v% or less. Therefore, the content of benzyl alcohol in the composition of the present invention is, for example, 0.9 to 5 w / v%, preferably 0.9 to 4 w / v%, more preferably 0.9 to 3 w / v%, and even more preferably 1.2 to 2 w / v%, based on the total composition. The content of benzyl alcohol in the composition of the present invention can be measured, for example, by HPLC, but can also be measured by other methods commonly used in the art.

[0020] According to one embodiment of the present invention, in the composition of the present invention, the mass ratio of the compound of formula (1) or a salt thereof to benzyl alcohol [mass ratio of the compound of formula (1) or a salt thereof:benzyl alcohol] is, for example, 1:1.9 to 1:20, preferably 1:2.1 to 1:20, more preferably 1:2.2 to 1:10, and even more preferably 1:3 to 1:5.

[0021] water The water used in the present invention is not particularly limited and includes water that is currently or will be used as a pharmaceutical or food product, such as purified water, ion-exchanged water, distilled water, ultra-filtered water, ultra-pure water (e.g., Milli-Q water), water for injection, and physiological saline, with water for injection being preferred.

[0022] sugars According to one embodiment of the present invention, the composition may further comprise a sugar, including, but not limited to, sugars that are currently or will be used as pharmaceuticals or foods.

[0023] The saccharides of the present invention are not particularly limited as long as they do not interfere with the effects of the present invention, and examples thereof include monosaccharides, disaccharides, polysaccharides, sugar alcohols, and combinations thereof, with monosaccharides, disaccharides, and sugar alcohols being preferred, and sugar alcohols being more preferred.

[0024] Examples of the monosaccharide include glucose (grape sugar), galactose, mannose, fructose (fruit sugar), psicose, allose, sorbose, arabinose, galactosamine, glucosamine, xylose, thioglucose, deoxyribose, fucose, and combinations thereof, with glucose (grape sugar) being preferred.

[0025] Examples of the disaccharide include lactose (milk sugar), sucrose, maltose (malt sugar), isomaltose, nigerose, kojibiose, trehalose, gentiobiose, cellobiose, sophorose, nigerose, palatinose, melibiose, laminaribiose, and combinations thereof, with lactose (milk sugar) being preferred.

[0026] The polysaccharides include dextrin, glycogen, starch, modified starch, and combinations thereof, and are preferably dextrin and starch.

[0027] The sugar alcohols include mannitol, sorbitol, inositol, xylitol, magnesium gluconate, maltitol, meglumine, and combinations thereof, with mannitol being preferred, and D-mannitol being more preferred.

[0028] According to another embodiment of the present invention, the saccharide of the present invention is preferably a water-soluble saccharide. The "water solubility" of the saccharide that can be used in the present invention refers to the property of being "extremely soluble," "soluble," "slightly soluble," or "slightly soluble" according to the general rules of the Japanese Pharmacopoeia, 17th Edition. The solubility of the saccharide of the present invention in water, for example, at a normal handling temperature, for example, around room temperature (20°C), is about 10 mg / mL or more, preferably about 33 mg / mL or more, and more preferably 100 mg / mL or more.

[0029] According to a preferred embodiment of the present invention, the content of sugars in the composition of the present invention is not particularly limited as long as it does not interfere with the effects of the present invention, but may be, for example, 0.01 to 20 w / v%, preferably 0.1 to 10 w / v%, and more preferably 1 to 3 w / v% of the total composition.

[0030] pH adjuster According to one embodiment of the present invention, the composition may further comprise a pH adjuster, including, but not limited to, those currently used or to be used in pharmaceuticals or foods.

[0031] The pH adjuster used herein includes compounds suitable for adjusting the pH of the liquid composition to 8 or higher, for example, to a pH described below (e.g., pH 8 to 11). Such a pH adjuster may contain a buffering agent. Here, the buffering agent may be a buffer substance or buffer solution for adjusting the pH changed by an acid or base to a desired pH. Therefore, the pH adjuster contained in the composition of the present invention is not particularly limited as long as it does not interfere with the effects of the present invention, and examples thereof include acids, bases, and buffering agents.

[0032] The acid may be an organic acid or an inorganic acid, and specific examples of the acid include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, maleic acid, acetic acid, citric acid, tartaric acid, propionic acid, succinic acid, oxalic acid, lactic acid, malic acid, glutamic acid, pamoic acid, and combinations thereof, with hydrochloric acid, phosphoric acid, acetic acid, and citric acid being preferred.

[0033] The base may be an organic base or an inorganic base. Specific examples of the base include sodium hydroxide, potassium hydroxide, ammonia, tromethamine (Tris), and combinations thereof, and preferably sodium hydroxide and tromethamine (Tris).

[0034] The buffering agent is not particularly limited as long as it does not interfere with the effects of the present invention, and examples thereof include organic acid salts such as acetate, lactate, tartrate, citrate, succinate, histidine hydrochloride, and phosphate (e.g., potassium phosphate, sodium phosphate), as well as aqueous buffers known in the field of solution formulations, such as citrate buffers (e.g., sodium citrate buffer), Tris buffers (e.g., Tris-hydrochloride buffer), histidine buffer, imidazole buffer, carbonate buffer, and triethanolamine buffer, and combinations thereof.

[0035] According to a preferred embodiment of the present invention, the concentration of the acid or base in the composition of the present invention is not particularly limited as long as it does not impair the effects of the present invention, and is, for example, 0.001 to 2 w / v%, preferably 0.01 to 1.5 w / v%, and more preferably 0.1 to 1 w / v%.

[0036] According to a preferred embodiment of the present invention, the concentration of the buffer solution in the composition of the present invention is not particularly limited as long as it does not impair the effects of the present invention, and is, for example, 1 to 500 mM, preferably 5 to 200 mM, and more preferably 10 to 100 mM.

[0037] According to one embodiment of the present invention, the composition of the present invention contains, if necessary, a pharmaceutically acceptable additive. The pharmaceutically acceptable additive is not particularly limited, but includes an aqueous medium, a solvent, a base, a solubilizing agent, an isotonic agent, a stabilizer, a regulator, a chelating agent, an excipient, a thickener, a colorant, an antioxidant, a dispersant, an emulsifier, a solubilizer, etc., and can be added within a range that does not impair the effects of the present invention.

[0038] According to one embodiment of the present invention, the composition of the present invention is in a liquid form. The composition of the present invention comprises a combination of a compound of formula (1) or a salt thereof, benzyl alcohol, and water. As long as the characteristics of the combination are maintained, the dosage form is not particularly limited, and the composition can be provided as an injection, drip infusion, syrup, enema, or the like. The dosage form is preferably an injection or drip infusion. Here, injections include products in which the composition of the present invention is filled in a vial or syringe. Examples of vials include single-use vials and multiple-use vials, preferably multiple-use vials. Here, multiple times refers to, for example, 2 to 20 times, preferably 3 to 18 times. When a multiple-use vial is used, it is preferable that the preservative effectiveness of the composition of the present invention is maintained even after puncture.

[0039] According to one embodiment of the present invention, the composition of the present invention may be a composition for single administration or multiple administrations, preferably a composition for multiple administrations. Such a composition may be, for example, a composition filled in a vial, preferably a composition filled in a multiple-use vial. Here, multiple administrations refer to the number of times as described above.

[0040] The pH of the composition of the present invention is 8 or higher, and from the viewpoint of improving the solubility of the compound of formula (1) or its salt, it is preferably 8 to 11, more preferably 8 to 10. Furthermore, the time point at which the pH of the composition of the present invention is measured is not particularly limited, and it may be measured at any time during preparation, storage, or use of the composition. The pH of the composition can be measured using a commercially available pH meter (e.g., LAQUA F-74, manufactured by Horiba, Ltd.).

[0041] According to one embodiment of the present invention, the composition of the present invention can be produced by a known method, such as by mixing a compound of formula (1) or a salt thereof, water, and benzyl alcohol, optionally together with other solvents. Furthermore, the composition of the present invention may further contain a sugar and, optionally, a pH adjuster, and therefore can be produced by a known method, such as by mixing a compound of formula (1) or a salt thereof, water, benzyl alcohol, a sugar, optionally a pH adjuster and / or other solvents. For example, the composition of the present invention can be produced by a known method, such as by mixing and dissolving a compound of formula (1) or a salt thereof, water, benzyl alcohol, optionally with other solvents. More specifically, examples of methods for producing the composition of the present invention include (A) mixing a compound of formula (1) or a salt thereof, benzyl alcohol, a sugar, and a pH adjuster, followed by adding water, (B) mixing water, benzyl alcohol, a sugar, and a pH adjuster, followed by adding the compound of formula (1) or a salt thereof, and (C) mixing water, benzyl alcohol, and a compound of formula (1) or a salt thereof, followed by adding the sugar and a pH adjuster. In addition, in producing the composition of the present invention, the mixture may be subjected to homogenization or sterilization, provided that the effects of the present invention are not impaired.

[0042] The other solvents used in the preparation of the composition of the present invention are not particularly limited and include those that are currently or will be used as pharmaceuticals or foods. Specific examples of the other solvents include alcohols (e.g., methanol, ethanol, propanol, propylene glycol, etc.), organic acids (e.g., acetic acid, propionic acid, etc.), polyethylene glycol, and mixtures thereof.

[0043] composition According to one embodiment of the present invention, the composition of the present invention can effectively enhance the preservative effectiveness of a liquid composition comprising the compound of formula (1) of the present invention or a salt thereof. Preferably, the preservative effectiveness complies with at least one standard specified in USP (e.g., USP43-NF38-S2), European Pharmacopoeia (e.g., Ph.Eur.10.4), and Japanese Pharmacopoeia (e.g., Japanese Pharmacopoeia 17th Edition, Japanese Pharmacopoeia 18th Edition). Specific preservative effectiveness, when the target is bacteria, is 10 per ml or 1 g of the liquid composition of the present invention. 5 ~10 6 After 24 hours, the viable count of bacteria is, for example, 10 2 ~10 3 or less, preferably 10 1 ~10 2 or less, more preferably 10 1 The preservative effect when the target is a fungus is expressed as a reduction of 10 or less per ml or 1 g of the liquid composition of the present invention. 5 ~10 6 After 7 days, the number of viable fungi is, for example, 10 3 ~10 4 or less, preferably 10 2 ~10 3 or less, more preferably 10 1The preservative effectiveness test is based on the USP43-NF38-S2 General Chapter <51> Alternatively, the test can be carried out in accordance with the preservative effectiveness test of Ph.Eur.10.4 General Chapter 5.1.3, for example, under the same conditions as in Test Examples 1, 3 and 4.

[0044] According to one embodiment of the present invention, the preservative effect is not particularly limited to, but may be applied to, for example, bacteria and / or fungi, such as Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus, and fungi such as Candida albicans and Aspergillus brasiliensis.

[0045] According to one embodiment of the present invention, the composition of the present invention containing the compound of formula (1) or its salt and benzyl alcohol has enhanced preservative effect and can be used continuously or discontinuously for a long period of time. Specifically, the composition of the present invention can be used for, for example, 1 day or more, preferably 7 days or more, more preferably 14 days or more, even more preferably 21 days or more, and even more preferably 28 days or more. There is no particular upper limit, but 40 days or less is preferred.

[0046] kit According to another aspect of the present invention, there is provided a kit for producing the composition of the present invention described above, the kit comprising a first composition comprising a compound of formula (1) or a salt thereof, and a second composition comprising benzyl alcohol and water.

[0047] According to a preferred embodiment of the present invention, the first composition contains a sugar and, optionally, a pH adjuster. The first composition may also contain a pharmaceutically acceptable additive, if necessary. The sugar, pH adjuster, and pharmaceutically acceptable additive are as described above. Furthermore, the first composition is preferably freeze-dried.

[0048] According to a further preferred embodiment of the present invention, the first composition is filled in a vial. Such a vial may be, for example, a single-use vial or a multiple-use vial, preferably a multiple-use vial. Here, "multiple times" refers to, for example, 2 to 20 times, preferably 3 to 18 times. When a multiple-use vial is used, it is preferable that the preservative effectiveness of the composition of the present invention is maintained even after puncturing.

[0049] According to another preferred embodiment of the present invention, the content of benzyl alcohol in the second composition is, for example, 0.9 to 5 w / v%, preferably 0.9 to 4 w / v%, more preferably 0.9 to 3 w / v%, and even more preferably 1.2 to 2 w / v%, based on the entire second composition or the entire composition of the present invention.

[0050] According to another aspect of the present invention, there is provided a method for producing the composition of the present invention, comprising the step of mixing a first composition containing a compound of formula (1) or a salt thereof with a second composition containing benzyl alcohol and water. More specifically, when the first composition is filled in a vial, such a method includes adding the second composition to the vial and mixing the first and second compositions. Here, the first composition is preferably lyophilized. Therefore, the above-mentioned production method may also be a method in which the first composition containing the compound of formula (1) or a salt thereof is reconstituted with the second composition, which is benzyl alcohol and water.

[0051] According to one embodiment of the present invention, the first composition can be prepared by a known method, such as by mixing and dissolving a compound of formula (1) or a salt thereof in a solvent. As described above, the first composition is preferably freeze-dried. Furthermore, since the first composition may contain a sugar and, optionally, a pH adjuster, it can be prepared by a known method, such as by mixing and dissolving a compound of formula (1) or a salt thereof, a sugar and, optionally, a pH adjuster in a solvent (e.g., water and / or other solvent). For example, the first composition can be prepared by a known method, such as by mixing and dissolving a compound of formula (1) or a salt thereof, a sugar and a pH adjuster in water and / or other solvent. More specifically, examples of methods for producing the first composition include: (A) mixing a compound of formula (1) or its salt with a sugar and a pH adjuster, followed by adding water; (B) mixing water, a sugar, and a pH adjuster, followed by adding the compound of formula (1) or its salt; and (C) mixing water and a compound of formula (1) or its salt with a sugar and a pH adjuster. The solution obtained by the above method can then be freeze-dried, if necessary. Furthermore, in producing the first composition, the first composition may be subjected to a homogenization treatment or a sterilization treatment, provided that the effects of the present invention are not impaired.

[0052] The other solvents used in the production of the first composition are the same as the other solvents used in the production of the composition of the present invention described above.

[0053] According to another embodiment of the present invention, the second composition can be produced by a known method such as mixing benzyl alcohol with water. In addition, in producing the second composition, the second composition may be subjected to a homogenization treatment or a sterilization treatment, as long as the effects of the present invention are not impaired.

[0054] According to one embodiment of the present invention, the composition of the present invention or the first composition can be widely applied to diseases, pathological conditions, or symptoms associated with inflammatory cells (e.g., granulocytes (neutrophils, eosinophils, basophils), lymphocytes (e.g., T lymphocytes, NK cells), monocytes, macrophages, plasma cells, mast cells, platelets) (e.g., pancreatitis, surgical stress, disseminated intravascular coagulation (DIC), neoplastic disease, pyometra, heatstroke, immune-mediated hemolytic anemia (IMHA), sepsis, angiosarcoma, gastric volvulus, ischemia-reperfusion injury, purpura, liver failure, hepatitis, pneumonia, systemic inflammatory response syndrome (SIRS), trauma, osteoarthritis, cystitis, intervertebral disc disease, atopy / allergy, dermatitis, immune-mediated disease, otitis, inflammatory bowel disease, chronic pain, colitis, chronic obstructive pulmonary disease (COPD), cholecystitis, cholangitis, etc.). Advantageously, the composition of the present invention or the first composition can provide therapeutic and preventive effects against pancreatitis, surgical stress, disseminated intravascular coagulation (DIC), and the like. Therefore, according to another embodiment of the present invention, the composition of the present invention or the first composition is provided as a composition for treating or preventing a disease, pathology, or symptom associated with inflammatory cells, preferably pancreatitis, surgical stress, or disseminated intravascular coagulation (DIC). The composition of the present invention or the first composition can also be used as a pharmaceutical or quasi-drug for humans or animals. Furthermore, the composition of the present invention or the first composition may be used in combination with other pharmaceuticals or quasi-drugs commonly used in this technical field, as needed. When applying the first composition, it is preferable to use it together with water and benzyl alcohol.

[0055] According to one embodiment of the present invention, the subject to which the composition of the present invention is applied may be, for example, an animal, preferably a non-human animal such as a mammal, bird, reptile, amphibian, or fish, more preferably a mouse, rat, rabbit, dog, cat, pig, cow, or horse. The animal may be livestock, pet, farm animal, wild animal, or racing animal. The subject may be a healthy individual (healthy animal) or a patient (patient animal). Furthermore, when the composition of the present invention is a composition for multiple administration, for example, when the composition of the present invention is filled in a multi-use vial, the subject to which the composition is applied multiple times may be the same individual or different individuals (i.e., multiple individuals).

[0056] Furthermore, according to another embodiment of the present invention, there is provided a method for treating or preventing a disease, pathology, or symptom associated with inflammatory cells in a subject, preferably pancreatitis, surgical stress, or disseminated intravascular coagulation (DIC), comprising administering a composition of the present invention to the subject. According to yet another embodiment of the present invention, the above-mentioned method for treating or preventing a disease, pathology, or symptom associated with inflammatory cells in a subject is considered a non-therapeutic method excluding medical treatment if the subject is healthy. The method for treating or preventing a disease, pathology, or symptom associated with inflammatory cells in a subject of the present invention can be carried out in accordance with the contents described herein for the composition of the present invention.

[0057] The effective amount of the compound of formula (1) or its salt of the present invention and the frequency of administration of the composition of the present invention are not particularly limited and can be appropriately determined by those skilled in the art depending on the type and purity of the compound of formula (1) or its salt, the dosage form of the composition, and the type, nature, sex, age, symptoms, etc. of the subject. For example, the effective amount of the compound of formula (1) or its salt is 0.01 to 1000 mg / kg body weight, preferably 0.05 to 500 mg / kg body weight. The frequency of administration is, for example, 1 to 5 times per day, preferably 1 to 3 times per day, and more preferably 1 to 2 times per day in the same individual. The administration period is, for example, 1 to 7 days, preferably 1 to 5 days, and more preferably 1 to 3 days in the same individual.

[0058] Furthermore, according to another aspect of the present invention, there is provided use of a combination of the compound of formula (1) or a salt thereof, benzyl alcohol, and water in the production of a liquid composition, wherein the pH of the liquid composition is not less than 8. Furthermore, according to another preferred embodiment of the present invention, the composition is used for the treatment or prevention of a disease, pathological condition, or symptom associated with inflammatory cells, preferably pancreatitis, surgical stress, or disseminated intravascular coagulation (DIC).

[0059] According to another aspect of the present invention, there is provided use of a combination of the compound of formula (1) or a salt thereof with benzyl alcohol to enhance preservative efficacy in a liquid composition having a pH of 8 or higher. According to another preferred embodiment of the present invention, there is provided use of the above combination for the treatment or prevention of a disease, pathological condition, or symptom associated with inflammatory cells, preferably pancreatitis, surgical stress, or disseminated intravascular coagulation (DIC).

[0060] According to another aspect of the present invention, there is provided a combination of the compound of formula (1) or a salt thereof with benzyl alcohol for enhancing preservative efficacy in a liquid composition having a pH of 8 or higher. According to another preferred embodiment of the present invention, there is provided the above combination for the treatment or prevention of a disease, pathological condition, or symptom associated with inflammatory cells, preferably pancreatitis, surgical stress, or disseminated intravascular coagulation (DIC).

[0061] According to another aspect of the present invention, there is provided a method for enhancing the preservative effectiveness of a liquid composition comprising a compound of formula (1) or a salt thereof, the method comprising causing the compound of formula (1) or a salt thereof to coexist with benzyl alcohol in the liquid composition and adjusting the pH of the liquid composition to at least 8. Here, the preservative effectiveness is preferably preservative effectiveness against bacteria and / or fungi.

[0062] All of the above uses, combinations and combinations can be carried out in accordance with the description of the compositions and methods of the present invention. [Example]

[0063] The present invention will be described in more detail below with reference to test examples, but the technical scope of the present invention is not limited to these examples. Furthermore, unless otherwise specified, the units and measurement methods described in this specification are in accordance with JIS standards.

[0064] The substances used in the test examples are as follows: Compound 1: N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide monosodium salt monohydrate (fuzapladib sodium hydrate) D-mannitol: manufactured by Nacalai Tesque, Inc. (Test Examples 1 and 2), manufactured by Rockete Freres (Test Examples 3 and 4) Tromethamine: manufactured by Nacalai Tesque, Inc. (Test Examples 1 and 2), manufactured by Biospectra, Inc. (Test Examples 3 and 4) Benzyl alcohol: Spectrum Chemical Manufacturing Co. (Test Examples 1 and 2), Lanxess Deutschland GmbH (Test Examples 3 and 4)

[0065] The equipment used in the test examples is as follows: Magnetic stirrer: Pasolina Mini Stirrer CT-1AT, AS ONE Corporation (Test Examples 1 and 2) High Shear Mixer: BX-60, manufactured by Silverson (Test Examples 3 and 4) pH meter: LAQUA F-74, manufactured by Horiba Ltd. Sterile filter: DISMIC-25AS, manufactured by ADVANTEC (Test Examples 1 and 2), KA2EKVP1G, manufactured by Pall Manufacturing Ltd. (Test Examples 3 and 4)

[0066] Test Example 1: Examination of antibacterial properties of liquid composition containing Compound 1 (1) (a) Preparation of liquid compositions (test areas 1 to 4) One or more of Compound 1, D-mannitol, tromethamine, and benzyl alcohol were weighed and placed in a 20 mL screw-cap bottle. 15 mL of water for injection was added and mixed and dissolved using a magnetic stirrer. Then, 0.1 M HCl or 0.1 M NaOH was added to adjust the pH to the values ​​shown in Table 1. The resulting solution was transferred to a 20 mL volumetric flask, adjusted to a total volume of 20 mL with water for injection, and mixed to homogeneity. The liquid compositions for the test groups listed in Table 1 were obtained by passing through a sterilizing filter. (b) Antibacterial evaluation of liquid compositions containing Compound 1 The antibacterial activity was evaluated based on the Efficacy of Antimicrobial Preservation Test of European Pharmacoeia 9.0. Specifically, the test was carried out as follows: Escherichia coli (hereinafter also referred to as E. coli) stock solution was prepared using Luria Bertani medium (the number of viable bacteria per 1 mL of E. coli stock solution was 4.08 x 10 7 500 μL of the liquid composition prepared in (a) was then inoculated with 5 μL of the E. coli stock solution and mixed. The mixture was stored at 20-25°C in the dark, and the viable cell count was measured after 24 hours. The viable cell count 0 hours after inoculation was the viable cell count immediately after inoculating the E. coli stock solution into physiological saline and mixing.

[0067] [Table 1]

[0068] At pH 8.7 to 8.8, benzyl alcohol alone (Test Group 3) showed viable bacteria remaining 24 hours after inoculation, indicating insufficient antibacterial efficacy (i.e., preservative efficacy). However, by mixing benzyl alcohol with Compound 1 (Test Groups 1 and 4), the number of viable bacteria dropped to zero 24 hours after inoculation, significantly enhancing antibacterial efficacy.

[0069] Test Example 2: Examination of antibacterial properties of liquid composition containing Compound 1 (2) (a) Preparation of liquid compositions (test plots 5 to 10) One or more of Compound 1, D-mannitol, tromethamine, and benzyl alcohol were weighed into a 20 mL screw-cap bottle, 15 mL of water for injection was added, and the mixture was mixed and dissolved using a magnetic stirrer. Then, 0.1 M HCl or 0.1 M NaOH was added to adjust the pH to the values ​​shown in Table 2. The resulting solution was transferred to a 20 mL volumetric flask, adjusted to a total volume of 20 mL with water for injection, and mixed to homogeneity. The liquid compositions for the test groups listed in Table 2 were obtained by passing through a sterilizing filter. (b) Antibacterial evaluation of liquid compositions containing Compound 1 The antibacterial properties were evaluated based on the preservative effectiveness test of EUROPEAN PHARMACOEIA 9.0. Specifically, the test was carried out as follows. In the same manner as in Test Example 1, an E. coli stock solution was prepared (the number of viable bacteria per 1 mL of E. coli stock solution was 9.90 × 10 7 500 μL of the liquid composition prepared in (a) was then inoculated with 5 μL of the E. coli stock solution and mixed. The mixture was stored at 20-25°C in the dark, and the viable cell count was measured after 24 hours. The viable cell count 0 hours after inoculation was the viable cell count immediately after inoculating the E. coli stock solution into physiological saline and mixing.

[0070] [Table 2]

[0071] Benzyl alcohol alone showed antibacterial activity at pH 4.9 (Test Area 5), ​​but showed almost no activity at pH 8.7 (Test Area 6), and Compound 1 alone (Test Area 7) also showed almost no antibacterial activity at pH 8.7. However, when benzyl alcohol and Compound 1 were mixed (Test Area 8), the viable cell count at pH 8.7 24 hours after inoculation was 0, and the antibacterial activity was significantly enhanced.

[0072] Test Example 3: Examination of antibacterial properties of liquid composition containing Compound 1 (3) (a) Preparation of freeze-dried formulation Compound 1 (160 g), D-mannitol (600 g), tromethamine (240 g), and water (17 kg) were mixed. The pH was adjusted to 8.7 with 1 M hydrochloric acid, and water was added to make a total volume of 20 L. The resulting mixture was sterilized by filtration using a 0.2 μm filter, and 1.75 mL was placed in a vial, partially stoppered with a rubber stopper, and then freeze-dried. After freeze-drying, the vial was fully stoppered with a rubber stopper and sealed with an aluminum seal to obtain a freeze-dried formulation. (b) Preparation of liquid composition The lyophilized formulation was reconstituted by adding 1.8 w / v % benzyl alcohol-containing water for injection (3.5 mL) to the vial obtained in (a) using a syringe equipped with a 20-gauge needle to obtain a liquid composition. (c) Storage of liquid compositions Each vial was punctured with a syringe equipped with a 20-gauge needle, and approximately 0.05 mL of the drug solution was extracted. This process was repeated twice, with a new syringe used for each puncture, and the vials were then stored at room temperature. On the second and third days, the vials were removed and punctured once with a syringe equipped with a 20-gauge needle, and approximately 0.05 mL of the drug solution was extracted. The vials were then stored at room temperature for a predetermined period of time. (d) pH measurement and antibacterial evaluation of liquid compositions containing Compound 1 The pH was measured immediately after reconstitution, and on day 8 the pH was measured and the antibacterial activity was evaluated. The pH was measured by the glass electrode method. Antibacterial properties are evaluated according to USP43-NF38-S2 General Chapter <51> The test was conducted in accordance with the preservative effectiveness test of Ph.Eur.10.4 General Chapter 5.1.3. The test organisms used in this test were Staphylococcus aureus (S. aureus), Pseudomonas aeruginosa (P. aeruginosa), and Escherichia coli (E. coli) as bacteria, and Candida albicans (C. albicans) and Aspergillus brasiliensis (A. brasiliensis) as fungi. The test organisms were inoculated into the liquid composition prepared and stored in (b), mixed, and incubated at 20-25°C. The number of colonies formed (CFU / mL) was measured at 0 hours, 6 hours, 24 hours, 7 days, 14 days, and 28 days after inoculation. The number of bacteria in the suspension after inoculation was 1 x 10 5 ~1×10 6 The colony formation count (CFU / mL) was determined to be between the range of 0.01 and 0.01. The evaluation criteria were based on the USP acceptance criteria for injections and other parenteral preparations and the Ph.Eur. acceptance criteria for parenteral preparations, as shown in the table below.

[0073] [Table 3]

[0074] [Table 4]

[0075] Test results 1. pH of the liquid composition The pH of the liquid composition was 8.7 immediately after reconstitution and 8.7 after 8 days of storage.

[0076] 2. Antibacterial properties of the liquid composition after 8 days of storage The results are shown in the table below. As shown in the table below, this liquid composition met the USP acceptance criteria for injections and other parenteral preparations and the Ph.Eur. acceptance criteria for parenteral preparations.

[0077] [Table 5]

[0078] Test Example 4: Examination of antibacterial properties of liquid composition containing Compound 1 (4) (a) Preparation of freeze-dried formulation Compound 1 (160 g), D-mannitol (600 g), tromethamine (240 g), and water (17 kg) were mixed. The pH was adjusted to 8.7 with 1 M hydrochloric acid, and water was added to make a total volume of 20 L. The resulting mixture was sterilized by filtration using a 0.2 μm filter, and 1.75 mL was placed in a vial, partially stoppered with a rubber stopper, and then freeze-dried. After freeze-drying, the vial was fully stoppered with a rubber stopper and sealed with an aluminum seal to obtain a freeze-dried formulation. (b) Preparation of liquid composition The lyophilized formulation was reconstituted by adding 1.8 w / v % benzyl alcohol-containing water for injection (3.5 mL) to the vial obtained in (a) using a syringe equipped with a 20-gauge needle to obtain a liquid composition. (c) Storage of liquid compositions Each vial was punctured with a syringe equipped with a 20-gauge needle, and approximately 0.05 mL of the drug solution was extracted. This process was repeated twice, with a new syringe used for each puncture. The vials were then stored in a refrigerator (2-8°C). From day 2 to day 13, the vials were removed from the refrigerator once a day, punctured with a syringe equipped with a 20-gauge needle, and approximately 0.05 mL of the drug solution was extracted. The vials were then stored in the refrigerator for the specified period. (d) pH measurement and antibacterial evaluation of liquid compositions containing Compound 1 The pH was measured immediately after reconstitution, and on the 29th day, the vials were removed from the refrigerator and the pH was measured and the antibacterial activity was evaluated. The pH was measured using the glass electrode method. The antibacterial activity was evaluated according to USP43-NF38-S2 General Chapter <51> The test was conducted in accordance with the preservative effectiveness test of Ph.Eur.10.4 General Chapter 5.1.3. The test organisms used in this test example were Staphylococcus aureus (S. aureus), Pseudomonas aeruginosa (P. aeruginosa), and Escherichia coli (E. coli) as bacteria, and Candida albicans (C. albicans) and Aspergillus brasiliensis (A. brasiliensis) as fungi. The test organisms were inoculated into the liquid composition prepared and stored in (b), mixed, and incubated at 20-25°C. The number of colonies formed (CFU / mL) was measured at 0 hours, 6 hours, 24 hours, 7 days, 14 days, and 28 days after inoculation. The number of bacteria in the suspension after inoculation was 1 x 10 5 ~1×10 6 The colony formation count (CFU / mL) was used. The evaluation criteria were the same as those in Test Example 3.

[0079] Test results 1. pH of the liquid composition The pH of the liquid composition was 8.7 immediately after reconstitution and 8.7 after 29 days of storage.

[0080] 2. Antibacterial properties of the liquid composition after storage for 29 days The results are shown in the table below. As shown in the table below, this liquid composition met the USP acceptance criteria for injections and other parenteral preparations and the Ph.Eur. acceptance criteria for parenteral preparations.

[0081] [Table 6]

Claims

1. A compound of formula (1) or a salt thereof: 【Chemistry 1】 and Benzyl alcohol and Water and A liquid composition comprising: pH is 8 to 11 composition.

2. The composition of claim 1, further comprising a sugar or a sugar and a pH adjuster.

3. The composition according to claim 2, wherein the saccharide is at least one selected from the group consisting of monosaccharides, disaccharides, polysaccharides, and sugar alcohols.

4. The composition of claim 2 , wherein the pH adjusting agent is a buffering agent.

5. The composition according to any one of claims 1 to 4, wherein the content of benzyl alcohol in the liquid composition is 0.9 to 3 w / v %.

6. The composition according to any one of claims 1 to 5, wherein the content of the compound of formula (1) or a salt thereof in the liquid composition is 0.01 to 1 w / v %.

7. The composition according to any one of claims 1 to 6, for multiple administration.

8. A kit for producing the composition according to any one of claims 1 to 7, comprising: a first composition comprising a compound of formula (1) or a salt thereof; a second composition comprising benzyl alcohol and water; A kit comprising:

9. The kit according to claim 8 , wherein the first composition comprises a sugar or a sugar and a pH adjuster.

10. The kit according to claim 8 or 9, wherein the content of benzyl alcohol in the second composition is 0.9 to 3 w / v % relative to the second composition.

11. The kit according to any one of claims 8 to 10, wherein the first composition is filled in a vial.

12. 12. The kit of claim 11, wherein the vial is a single-use vial or a multi-use vial.

13. A method for producing the composition according to any one of claims 1 to 7, comprising the steps of: a first composition comprising a compound of formula (1) or a salt thereof; a second composition comprising benzyl alcohol and water; A manufacturing method comprising the step of mixing the above.

14. A method for enhancing the preservative effectiveness of a liquid composition comprising the compound of formula (1) or its salt according to claim 1, the method comprising causing the compound of formula (1) or its salt to coexist with benzyl alcohol in the liquid composition, and adjusting the pH of the liquid composition to 8 to 11.

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