Injectable preparations

Abstract

To provide an injectable preparation that has excellent storage stability, contains a poorly soluble drug as an active ingredient, and contains a composition that contains a dispersion medium; and to provide a prefilled syringe that is reduced in size and weight by filling a syringe with the injectable formulation.SOLUTION: The present invention provides an injectable preparation comprising a composition, which contains a poorly soluble drug, a dispersion medium, and a specific suspending agent and in which a value of 40 Pa s or more is measured at least one point in the range of shear rates from 0.01 to 0.02 s-1, and a value of 0.2 Pa s or less is measured at least one point in the range of shear rates from 900 to 1,000 s-1.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an injectable formulation comprising a composition containing a drug that is poorly soluble in a dispersion medium, such as aripiprazole or a salt thereof, a specific suspending agent, and a dispersion medium, and a pre-filled syringe containing the injectable formulation. [Background technology]

[0002] Aripiprazole, which is used as the active ingredient of the pharmaceutical composition, has the following structural formula:

[0003] [ka]

[0004] A pharmaceutical composition containing aripiprazole is known as an atypical antipsychotic drug useful for treating schizophrenia.

[0005] The pharmaceutical composition containing aripiprazole as an active ingredient can be used, for example, by suspending aripiprazole and a vehicle therefor in a dispersion medium, freeze-drying the suspension to prepare a cake-like composition, and then adding a desired dispersion medium (preferably The resuspension (injection formulation) is then administered intramuscularly to the patient. Methods of administering the drug by injection or subcutaneous injection are known (see, for example, Patent Documents 1 and 2).

[0006] The use form of the pharmaceutical composition as described in the above Patent Documents 1 and 2 requires a vial containing a cake-like composition, a container containing a dispersion medium, and a syringe for administration to a patient. Therefore, there is a demand for a formulation that uses a medical device with a simple structure, is smaller and lighter, and is more convenient to use. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] U.S. Pat. No. 5,006,528 [Patent Document 2] JP 2007-509148 A Summary of the Invention [Problem to be solved by the invention]

[0008] In order to obtain a formulation that is convenient to use and can make the medical equipment used as described above simpler, smaller, and lighter, it is conceivable to develop a prefilled syringe in which the suspension (injection formulation) is directly filled in the syringe. However, in a suspension containing an active ingredient such as aripiprazole or a salt thereof, which is a drug that is poorly soluble in water as a dispersion medium (hereinafter also referred to as a poorly soluble drug), the active ingredient particles settle over time, causing caking, making it difficult to redisperse the suspension. Even in a suspension that can be redispersed, vigorous shaking using, for example, an apparatus, is required for redispersion, which is inconvenient in clinical terms. Therefore, the caking caused by the settling of particles over time is difficult to achieve. There has been a demand for an injectable formulation containing a poorly soluble drug as an active ingredient, which exhibits reduced sagging and has excellent storage stability.

[0009] The present invention aims to provide an injectable preparation having excellent storage stability, which contains a composition containing a poorly soluble drug as an active ingredient and a dispersion medium. More specifically, the present invention aims to provide an injectable preparation which does not cause caking due to precipitation of the poorly soluble drug even after long-term storage, and which can easily provide a suspension in which the active ingredient is dispersed when used (when administered to a patient).

[0010] Another object of the present invention is to provide a small and lightweight prefilled syringe by filling the injection preparation into a syringe.Preferably, the object of the present invention is to provide a small and lightweight prefilled syringe that can administer a low-viscosity suspension by simply pushing the plunger rod of the syringe and pushing the injection preparation through the injection needle after shaking the syringe weakly or without shaking. [Means for solving the problem]

[0011] The present inventors conducted intensive research to solve the above problems, and as a result, discovered that in an injectable formulation containing a poorly soluble drug as an active ingredient, the inclusion of a dispersion medium and a specific suspending agent (hereinafter also referred to as "suspending agent A") suppresses caking due to settling of the active ingredient even when the formulation is stored for a long period of time after preparation (for example, until the time of administration to a patient). After further research, the inventors have completed the present invention.

[0012] The present invention encompasses, for example, the subject matter described in the following paragraphs. Item 1. A composition comprising a poorly soluble drug, a dispersion medium, and a suspending agent, The suspending agent is at least one suspending agent selected from the group consisting of: (i) and (ii) below; (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof When the viscosity is measured by a rheometer, Shear rate 0.01~0.02s -1 A value of 40 Pa s or more is measured at at least one point in the range. Shearing rate 900~1,000s -1 A value of 0.2 Pa s or less is measured at at least one point in the range. composition 13. An injectable formulation comprising:

[0013] Item 2. A composition comprising a poorly soluble drug, a dispersion medium, and a suspending agent, The suspending agent is at least one suspending agent selected from the group consisting of: (i) and (ii) below; (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof When the viscosity was measured at 25°C using a rheometer, Shear rate 0.01~0.02s -1 A value of 40 Pa s or more is measured at at least one point in the range. Shearing rate 900~1,000s -1 A value of 0.2 Pa s or less is measured at at least one point in the range. composition 13. An injectable formulation comprising:

[0014] Item 3. The injectable preparation according to Item 1 or 2, comprising a composition containing at least water as a dispersion medium.

[0015] Item 4. The injectable preparation according to any one of Items 1 to 3, wherein the poorly soluble drug is aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof.

[0016] Item 4a. The injectable preparation according to any one of Items 1 to 4, wherein the average primary particle size of the poorly soluble drug is 0.5 to 100 μm.

[0017] Item 4b. The injectable preparation according to any one of Items 1 to 4 and 4a, wherein the average secondary particle size of the poorly soluble drug is 3 times or less the average primary particle size.

[0018] Item 5. As a poorly soluble drug, aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof, Water, and At least one suspending agent selected from the group consisting of (i) and (ii) below: (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof Including, The average primary particle size of the poorly soluble drug is 0.5 to 30 μm; The concentration of the poorly soluble drug is 200 to 600 mg / mL. Gel composition.

[0019] Item 5a. Aripiprazole or a salt thereof, Water, and At least one suspending agent selected from the group consisting of (i) and (ii) below: (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof Including, The average primary particle size of aripiprazole or a salt thereof is 0.5 to 30 μm; The concentration of aripiprazole or a salt thereof is 200 to 600 mg / mL. Item 6. The gel composition according to item 5.

[0020] Item 5b. 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof; Water, and At least one suspending agent selected from the group consisting of (i) and (ii) below: (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof Including, The average primary particle size of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof is 0.5 to 30 μm, and the concentration of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof is 200 to 600 mg / mL. Item 6. The gel composition according to item 5.

[0021] Item 6. Contains (i) polyvinylpyrrolidone as a suspending agent, The concentration of polyvinylpyrrolidone is 0.1 to 100 mg / mL. The composition according to item 5, item 5a or item 5b.

[0022] Item 7. The above (ii) polyethylene glycol and carboxymethylcellulose are used as suspending agents. Contains rosacea or its salt, The concentration of polyethylene glycol is 0.05 to 2 mg / mL. The concentration of carboxymethylcellulose or a salt thereof is 0.5 to 50 mg / mL. The composition according to any one of items 5 to 6. (The term "item 5~" includes items 5, 5a, and 5b. The same applies below.)

[0023] Item 8. The composition according to any one of Items 5 to 7, comprising, as a suspending agent, (i) polyvinylpyrrolidone, and (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof.

[0024] Item 8a. The suspending agent includes (i) polyvinylpyrrolidone, and (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof; Item 7. The composition according to any one of Items 5 to 6, wherein the concentration of polyethylene glycol is 0.05 to 100 mg / mL.

[0025] Item 9. The composition according to any one of Items 5 to 8 and 8a, wherein the average secondary particle size of the poorly soluble drug is 3 times or less the average primary particle size.

[0026] Item 10. When viscosity is measured using a rheometer, Shear rate 0.01~0.02s -1 A value of 40 Pa s or more is measured at at least one point in the range. Shearing rate 900~1,000s -1 A value of 0.2 Pa s or less is measured at at least one point in the range. The composition according to any one of items 5 to 9.

[0027] Item 11. When the viscosity is measured at 25°C using a rheometer, Shear rate 0.01~0.02s -1 A value of 40 Pa s or more is measured at at least one point in the range. Shearing rate 900~1,000s -1 A value of 0.2 Pa s or less is measured at at least one point in the range. The composition according to any one of items 5 to 9.

[0028] Item 12. An injection preparation comprising the composition according to any one of items 5 to 11.

[0029] Item 13. Aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof, at a concentration of 200 to 600 mg / mL, Water, and At least one suspending agent selected from the group consisting of (i) and (ii) below: (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof Including, The average primary particle size of the aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof is 0.5 to 30 μm. Mix the liquid Leave it at 5 to 70℃ for at least 5 minutes. Including, Contains aripiprazole or its salt, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or its salt The method for producing a gel composition comprising the steps of:

[0030] Item 13a. Aripiprazole or a salt thereof is administered at 200 to 600 mg / mL, Water, and At least one suspending agent selected from the group consisting of (i) and (ii) below: (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof Including, The average primary particle size of the aripiprazole or salt thereof is 0.5 to 30 μm. Mix the liquid Leave it at 5 to 70℃ for at least 5 minutes. Including, Item 14. A method for producing a gel composition containing aripiprazole or a salt thereof according to item 13.

[0031] Item 13b. 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof, 200 to 600 mg / mL, water, and At least one suspending agent selected from the group consisting of (i) and (ii) below: (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof Including, The average primary particle size of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof is 0.5 to 30 μm. Mix the liquid Leave it at 5 to 70℃ for at least 5 minutes. Including, Item 14. A method for producing a gel composition comprising 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof according to item 13.

[0032] Item 14. Aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof, at a concentration of 200 to 600 mg / mL, Water, and At least one suspending agent selected from the group consisting of (i) and (ii) below: (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof In a mixture containing pulverizing aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof to an average primary particle size of 0.5 to 30 μm; and Allow the mixed liquid after grinding to stand at 5 to 70°C for 5 minutes or more. Including, Item 14. The method according to item 13.

[0033] Item 14a. Aripiprazole or a salt thereof is administered at 200 to 600 mg / mL, Water, and At least one suspending agent selected from the group consisting of (i) and (ii) below: (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof In a mixture containing pulverizing aripiprazole or a salt thereof to have an average primary particle size of 0.5 to 30 μm; and Allow the mixed liquid after grinding to stand at 5 to 70°C for 5 minutes or more. Including, Item 15. A method for producing a gel composition containing aripiprazole or a salt thereof according to item 14.

[0034] Item 14b. 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof, 200 to 600 mg / mL, water, and At least one suspending agent selected from the group consisting of (i) and (ii) below: (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof In a mixture containing pulverizing 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof to an average primary particle size of 0.5 to 30 μm; and Allow the mixed liquid after grinding to stand at 5 to 70°C for 5 minutes or more. Including, Item 15. A method for producing a gel composition containing 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof according to item 14.

[0035] Item 15. The mixture contains (i) polyvinylpyrrolidone, The concentration of polyvinylpyrrolidone is 0.1 to 100 mg / mL. The method according to item 13, 13a, 13b, 14, 14a or 14b.

[0036] Item 16. The mixture contains (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof; The concentration of polyethylene glycol is 0.05 to 2 mg / mL. The concentration of carboxymethylcellulose or a salt thereof is 0.5 to 50 mg / mL. The method according to item 13, 13a, 13b, 14, 14a, 14b or 15.

[0037] Item 17. The method according to any one of Items 13 to 16, wherein the mixture contains (i) polyvinylpyrrolidone, and (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof.

[0038] Item 17a. The mixture contains (i) polyvinylpyrrolidone, and (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof; The concentration of polyethylene glycol is 0.05 to 100 mg / mL. The method according to any one of items 13 to 15. (The above "Items 13 to 15" and "Items 13 to 16" include items 13a, 13b, 14a, and 14 b is also included.)

[0039] Item 18. A gel composition comprising aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof, obtained by the method according to any one of items 13 to 17. (The above "items 13 to 17" also include items 13a, 13b, 14a, 14b, and 17a.)

[0040] Item 19. Aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof at 200 to 600 mg / mL, Water, and At least one suspending agent selected from the group consisting of (i) and (ii) below: (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof Including, The average primary particle size of the aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof is 0.5 to 30 μm. Mix the liquid Filling into a syringe; and Allow the mixture to stand at 5 to 70°C for 5 minutes or more. Including, A method for producing a prefilled syringe prefilled with a gel composition containing aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof.

[0041] Item 19a. Aripiprazole or a salt thereof is 200 to 600 mg / mL, Water, and At least one suspending agent selected from the group consisting of (i) and (ii) below: (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof Including, The average primary particle size of the aripiprazole or salt thereof is 0.5 to 30 μm. Mix the liquid Filling into a syringe; and Allow the mixture to stand at 5 to 70°C for 5 minutes or more. Including, Item 20. A method for producing a prefilled syringe prefilled with a gel composition containing aripiprazole or a salt thereof according to item 19.

[0042] Item 19b. 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof at 200 to 600 mg / mL, Water, and At least one suspending agent selected from the group consisting of (i) and (ii) below: (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof Including, The average primary particle size of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof is 0.5 to 30 μm. Mix the liquid Filling into a syringe; and Allow the mixture to stand at 5 to 70°C for 5 minutes or more. Including, Item 19. A method for producing a prefilled syringe prefilled with a gel composition containing 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof according to item 19.

[0043] Item 20. Aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof at 200 to 600 mg / mL, Water, and At least one suspending agent selected from the group consisting of (i) and (ii) below: (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof In a mixture containing pulverizing aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof to an average primary particle size of 0.5 to 30 μm; and Filling the mixed liquid after grinding into a syringe and leaving it at rest at 5 to 70°C for 5 minutes or more; Including, Item 19. The manufacturing method according to item 19.

[0044] Item 20a. Aripiprazole or a salt thereof is 200 to 600 mg / mL, Water, and At least one suspending agent selected from the group consisting of (i) and (ii) below: (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof In a mixture containing pulverizing aripiprazole or a salt thereof to have an average primary particle size of 0.5 to 30 μm; and Filling the mixed liquid after the grinding into a syringe and leaving it at rest at 5 to 70°C for 5 minutes or more; Including, Item 21. A method for producing a prefilled syringe prefilled with a gel composition containing aripiprazole or a salt thereof according to item 20.

[0045] Item 20b. 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof, 200 to 600 mg / mL; Water, and At least one suspending agent selected from the group consisting of (i) and (ii) below: (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof In a mixture containing pulverizing 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof to an average primary particle size of 0.5 to 30 μm; and Filling the mixed liquid after the grinding into a syringe and leaving it at rest at 5 to 70°C for 5 minutes or more; Including, Item 20. A method for producing a prefilled syringe prefilled with a gel composition containing 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof according to item 20.

[0046] Item 21. The mixture contains (i) polyvinylpyrrolidone, The concentration of polyvinylpyrrolidone is 0.1 to 100 mg / mL. The method according to item 19, 19a, 19b, 20, 20a or 20b.

[0047] Item 22. The mixture is (ii) polyethylene glycol and carboxymethyl cellulose. or its salt, The concentration of polyethylene glycol is 0.05 to 2 g / mL. The concentration of carboxymethylcellulose or a salt thereof is 0.5 to 50 mg / mL. 22. The method according to any one of items 19 to 21.

[0048] Item 23. The method according to any one of Items 19 to 22, wherein the mixture contains (i) polyvinylpyrrolidone, and (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof.

[0049] Item 23a. The mixture contains (i) polyvinylpyrrolidone, and (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof; The concentration of polyethylene glycol is 0.05 to 100 mg / mL. 22. The method according to any one of items 19 to 21. (The above "items 19 to 21" and "items 19 to 22" also include items 19a, 19b, 20a, and 20b.)

[0050] Item 24. A prefilled syringe prefilled with a gel composition containing aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof, obtained by the method according to any one of items 19 to 23 and 23a.

[0051] Item 25. A kit comprising the prefilled syringe according to item 24.

[0052] Item 26. As a poorly soluble drug, aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof, Water, and At least one suspending agent selected from the group consisting of (i) and (ii) below: (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof The poorly soluble drug has an average primary particle size of 1 to 10 μm; The concentration of the poorly soluble drug is 200 to 400 mg / mL; When left standing, it is in a gel state, but when impacted, it turns into a sol. The composition comprises: A long-acting injectable formulation administered once per month.

[0053] Item 27. The injectable preparation according to Item 26, wherein the average primary particle size of the poorly soluble drug is 2 to 7 μm.

[0054] Item 28. As a poorly soluble drug, aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof, Water, and At least one suspending agent selected from the group consisting of (i) and (ii) below: (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof The average primary particle size of the poorly soluble drug is 4 to 30 μm; The concentration of the poorly soluble drug is 300 to 600 mg / mL; When left standing, it is in a gel state, but when impacted, it turns into a sol. The composition comprises: A long-acting injectable formulation administered once every 2 or 3 months.

[0055] Item 29. The injectable preparation according to Item 28, wherein the average primary particle size of the poorly soluble drug is 5 to 20 μm.

[0056] Item 30. The composition contains the above-mentioned (i) polyvinylpyrrolidone as a suspending agent, The concentration of polyvinylpyrrolidone is 0.1 to 100 mg / mL. 30. The injectable preparation according to any one of items 26 to 29.

[0057] Item 31. The composition contains the above-mentioned (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof as a suspending agent, The concentration of polyethylene glycol is 0.05 to 2 mg / mL. The concentration of carboxymethylcellulose or a salt thereof is 0.5 to 50 mg / mL. Item 31. The injectable preparation according to any one of Items 26 to 30.

[0058] Item 32. The injectable preparation according to any one of Items 26 to 31, comprising as a suspending agent (i) polyvinylpyrrolidone, and (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof.

[0059] Item 33. The injectable preparation according to any one of Items 26 to 32, wherein the average secondary particle size of the poorly soluble drug is 3 times or less the average primary particle size.

[0060] Item 34. The composition, When the viscosity is measured by a rheometer, Shear rate 0.01~0.02s -1 A value of 40 Pa s or more is measured at at least one point in the range. Shearing rate 900~1,000s -1 A value of 0.2 Pa s or less is measured at at least one point in the range. Item 34. The injectable preparation according to any one of Items 26 to 33, which is a composition.

[0061] Item 35. The composition, When the viscosity was measured at 25°C using a rheometer, Shear rate 0.01~0.02s -1 A value of 40 Pa s or more is measured at at least one point in the range. Shearing rate 900~1,000s -1 A value of 0.2 Pa s or less is measured at at least one point in the range. Item 34. The injectable preparation according to any one of Items 26 to 33, which is a composition.

[0062] Item 36. A method for treating or preventing recurrence of schizophrenia, bipolar disorder, or depression, comprising administering the injectable preparation according to any one of items 1 to 4, 12, and 26 to 35.

[0063] Item 37. The method according to Item 36, wherein the injectable formulation is administered intramuscularly or subcutaneously.

[0064] Section A-1. An aqueous suspension injection preparation that contains a poorly soluble drug, a specific suspending agent (suspending agent A), and a dispersion medium, and that has high viscosity when left to stand and low viscosity when shaken or discharged from a syringe needle and has storage stability.

[0065] Item A-2. The injectable preparation according to Item A-1, which has a viscosity of 1,000 mPa·s or more when left standing and a viscosity of 300 mPa·s or less when shaken or discharged from a syringe needle.

[0066] Item A-3. The injectable preparation according to Item A-1 or A-2, which has a viscosity of 5,000 mPa s or more when left standing and a viscosity of 300 mPa s or less when shaken or discharged from a syringe needle.

[0067] Item A-4. The injectable preparation according to any one of Items A-1 to A-3, which has a viscosity of 10,000 mPa·s or more when left standing and a viscosity of 300 mPa·s or less when shaken or discharged from a syringe needle.

[0068] Item A-5. The injectable preparation according to Item A-1 or A-2, which has a viscosity of 1,000 mPa s or more when left standing and a viscosity of 200 mPa s or less when shaken or discharged from a syringe needle.

[0069] Item A-6. The injectable preparation according to Item A-1, A-2, A-3 or A-5, which has a viscosity of 5,000 mPa s or more when left standing and a viscosity of 200 mPa s or less when shaken or discharged from a syringe needle.

[0070] Item A-7. The injectable preparation according to any one of Items A-1 to A-6, which has a viscosity of 10,000 mPa·s or more when left standing and a viscosity of 200 mPa·s or less when shaken or discharged from a syringe needle.

[0071] Item A-8. The injectable preparation according to any one of Items A-1 to A-7, wherein the concentration of the poorly soluble drug is 100 to 500 mg / mL.

[0072] Item A-9. The injectable preparation according to any one of Items A-1 to A-8, wherein the concentration of the poorly soluble drug is 200 to 480 mg / mL.

[0073] Item A-10. The injectable preparation according to any one of Items A-1 to A-9, wherein the concentration of the poorly soluble drug is 250 to 450 mg / mL.

[0074] Item A-11. The injectable preparation according to any one of Items A-1 to A-10, wherein when the concentration of the poorly soluble drug is about 300 mg / mL or more, the injectable preparation becomes gel-like when left standing, but the gel-like composition becomes a sol exhibiting fluidity when stirred, shaken, or subjected to an external impact, etc.

[0075] Item A-12. The injectable preparation according to any one of Items A-1 to A-11, wherein the average primary particle size of the poorly soluble drug is about 0.5 to about 30 μm.

[0076] Item A-13. The injectable preparation according to any one of Items A-1 to A-12, wherein the average primary particle size of the poorly soluble drug is about 1.0 to about 10 μm.

[0077] Item A-14. The average primary particle size of the poorly soluble drug is about 1.0 to about 5 μm. The injectable preparation according to any one of claims 1 to 13.

[0078] Item A-15. The poorly soluble drug is aripiprazole or a salt thereof; At least one suspending agent selected from the group consisting of polyvinylpyrrolidone and polyethylene glycol, and Including a dispersion medium, The injectable preparation according to any one of items A-1 to A-14, comprising a composition.

[0079] Item A-16. The injectable preparation according to Item A-15, wherein the poorly soluble drug is aripiprazole monohydrate.

[0080] Item A-17. The poorly soluble drug is aripiprazole or a salt thereof; At least one suspending agent selected from the group consisting of polyvinylpyrrolidone and polyethylene glycol, and sodium carboxymethylcellulose, and Including a dispersion medium, The injectable preparation according to item A-15 or A-16, which contains the composition and has storage stability.

[0081] Item A-18. A prefilled syringe comprising the injectable preparation according to any one of items A-1 to A-17.

[0082] As used herein, "comprise" means "essentially consist" It also includes the meaning of "of" and the meaning of "consist of." Effect of the Invention

[0083] The injectable preparation of the present invention has excellent storage stability since particles of a poorly soluble drug (i.e., an active ingredient) do not cause caking due to sedimentation.

[0084] Therefore, there is no need to prepare a suspension at the time of use, and clogging is less likely to occur in the injection needle.

[0085] More specifically, (α) the injectable preparation of the present invention gels upon standing, suppressing the settling and caking of poorly soluble drug particles, and thus exhibits the effect of excellent storage stability. Furthermore, (β) the injectable preparation of the present invention, even after gelling, easily becomes fluid upon weak impact, so that it can be easily injected at the time of use (injection). In particular, the gelled injectable preparation (gel composition) becomes fluid (becomes sol-like) simply by pushing the plunger of the syringe to eject it from the injection needle, so that it can be smoothly ejected from the injection needle as it is. Therefore, there is relatively little pain or local damage during injection, and it can be dispersed well into the muscle or subcutaneously.

[0086] Furthermore, as described above, the injectable preparation of the present invention has excellent storage stability, and therefore can be filled directly into a syringe as an injectable preparation to form a prefilled syringe, which enables a reduction in size and weight of the medical device. [Brief description of the drawings]

[0087] [Figure 1] 1 is a photograph of the injectable preparation obtained in Example 1 immediately after preparation. [Diagram 2]1 is a photograph of the injectable preparation obtained in Example 1 after it was left to stand for a certain period of time and then slowly tilted. [Diagram 3] 1 is a photograph of the injectable preparation obtained in Example 1 after it was left to stand for a certain period of time, and then the container was tapped and tilted. [Figure 4a] The injectable preparations of Preparation Examples A1 to A6 were placed in a transparent container, left to stand at 5° C. for 5 days, and then slowly tilted and turned to a horizontal position, as shown in the photograph. [Figure 4b] The injectable preparations of Preparation Examples A1 to A6 were placed in a transparent container, left to stand at 25° C. for 5 days, and then slowly tilted and turned to a horizontal position, as shown in the photograph. [Figure 4c] The injectable preparations of Preparation Examples A1 to A6 were placed in a transparent container, left to stand at 40° C. for 5 days, and then slowly tilted and turned to a horizontal position, as shown in the photograph. [Figure 5a] The viscosity of the injectable preparations of Production Examples A1 to A6 was measured using a rheometer (measurement temperature: 5° C.) and the results are shown below. [Figure 5b] The viscosity of the injectable preparations of Production Examples A1 to A6 was measured using a rheometer (measurement temperature: 25° C.) and the results are shown below. [Figure 5c] The viscosity of the injectable preparations of Production Examples A1 to A6 was measured using a rheometer (measurement temperature: 40° C.) and the results are shown below. [Figure 6] The viscosity of the injection preparation of Preparation Example B was measured using a rheometer at 5°C, 25°C, and 40°C, and the results are shown below. [Figure 7] The viscosity of the injection preparation of Preparation Example C was measured using a rheometer at 5°C, 25°C, and 40°C, and the results are shown below. [Figure 8] The viscosity of the injection preparation of Preparation Example D was measured using a rheometer at 5°C, 25°C, and 40°C, and the results are shown below. [Figure 9a] The viscosity of the injection preparation of Preparation E was measured by a rheometer at 5° C., 25° C., and 40° C., and the results are shown in the figure. In the figure, 5d indicates the measurement at 5° C., 25d indicates the measurement at 25° C., and 40d indicates the measurement at 40° C. [Figure 9b] The injectable formulation of Preparation E after storage at 5°C, 25°C or 40°C for 5 days is shown. [Figure 9c] The injectable formulation of Preparation E (i.e., each Preparation shown in FIG. 9b) was stored stationary for 5 days at 5° C., 25° C. or 40° C., and then slowly tilted and turned to a horizontal position. [Figure 10a] The viscosity of the injection preparations of Preparation Examples F1 (povidone K17, 0.1 mg / mL) and F2 (povidone K17, 4 mg / mL) was measured by a rheometer at 5° C. or 25° C. In the figure, 5d indicates the measurement at 5° C., and 25d indicates the measurement at 25° C., respectively. [Figure 10b] The injectable preparations of Preparation Examples F1 (povidone K17, 0.1 mg / mL) and F2 (povidone K17, 4 mg / mL) when stored at 5°C, 25°C, or 40°C for 5 days are shown. [Figure 10c] The injectable formulations of Preparations F1 (povidone K17, 0.1 mg / mL) and F2 (povidone K17, 4 mg / mL) were stored at 5°C, 25°C, or 40°C for 5 days (i.e., each Preparation shown in Figure 10b), and then slowly tilted down. [Figure 11] The injectable preparations of Preparation Examples G (containing 400 mg / mL ethyl 4-aminobenzoate), H (containing 300 mg / mL probucol) and I (containing 300 mg / mL cilostazol) were placed in transparent containers and stored at 5°C, 25°C or 40°C for 5 days, after which they were slowly tilted over and then turned horizontally. [Figure 12] The viscosity of the injectable preparation of Preparation Example G was measured using a rheometer at 5°C, 25°C, and 40°C. The results are shown below. [Figure 13] The viscosity of the injectable preparation of Preparation Example H was measured using a rheometer at 5°C, 25°C, and 40°C. The results are shown below. [Figure 14] The viscosity of the injectable preparation of Preparation Example I was measured using a rheometer at 5°C, 25°C, and 40°C. The results are shown below. [Figure 15] The viscosity of the injectable preparation of Preparation Example J was measured by a rheometer at 5° C., 25° C., and 40° C. In the figure, 5d indicates the measurement at 5° C., 25d indicates the measurement at 25° C., and 40d indicates the measurement at 40° C. [Figure 16]1 is a graph showing the average blood concentration versus time profile after administration of the injection preparations of Production Example K, Production Example L, Comparative Example 200, and Comparative Example 400 into the lower leg muscle of rats (n=4, mean ± standard deviation). [Figure 17] The injectable preparations of Production Examples A3 to A6 were subjected to a rheometer, allowed to stand at 40° C. for 5 minutes, and then returned to 25° C., whereupon the viscosity was measured. The results are shown below. [Figure 18] The injection preparations of Production Examples B and C were subjected to a rheometer, allowed to stand at 40° C. for 5 minutes, and then returned to 25° C., and the viscosity was measured. The results of viscosity measurement at a measurement temperature of 5° C. or 25° C. in Test Example 2 are also shown in FIG. [Figure 19a] The injectable formulations of Production Examples E and E' were subjected to a rheometer, left to stand at 40° C. for 5 minutes, and then returned to 25° C., and the viscosity was measured. FIG. 19a also shows the viscosity measurement results of the injectable formulation of Production Example E' at 5° C. or 25° C. in the same manner as in Test Example 3. FIG. 19a also shows the viscosity measurement results of the injectable formulation of Production Example E at 5° C. or 25° C. in Test Example 3. [Figure 19b] The injection preparation of Preparation E' (Povidone K17, 4 mg / mL) was stored at 5°C, 25°C or 40°C for 5 days, then slowly tilted and turned to a horizontal position. Only the one stored at 40°C had gelled. [Figure 20a] The viscosity of the injection preparations of Preparation Examples M1 and M2 was measured at 5° C., 25° C., and 40° C. using a rheometer. The results are shown below. [Figure 20b] The injectable preparations of Preparation Examples M1 and M2 were stored at 5°C, 25°C or 40°C for 5 days, and then slowly tilted and turned to a horizontal position. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0088] The injectable formulation of the present invention includes a composition containing a poorly soluble drug, a specific suspending agent (suspending agent (A)), and a dispersion medium. Therefore, when the injectable formulation of the present invention is described below, it is the same as describing the composition. For example, when it is described that the injectable formulation of the present invention contains a certain component, this means that the injectable formulation of the present invention contains a specific composition, and the composition contains the component. In the present invention, a poorly soluble drug refers to a drug that is poorly soluble in water, and is a drug that falls under the category of "extremely poorly soluble" or "practically insoluble" as described in the 16th Edition of the Japanese Pharmacopoeia. Specifically, a drug is placed in water (when the drug solidifies), and then the drug is dissolved in water. If the product is in powder form, powder it and then place it in water. Shake vigorously for 30 seconds every 5 minutes at 20±5℃. When mixing, the degree to which the drug dissolves within 30 minutes is examined; if the amount of water required to dissolve 1 g or 1 mL of drug is 1,000 mL or more but less than 10,000 mL, the drug is "extremely soluble," and if the amount of water required is 10,000 mL or more, the drug is "practically insoluble."

[0089] The poorly soluble drug contained in the injectable formulation of the present invention may be, for example, aripiprazole or a salt thereof. In addition, other poorly soluble drugs may be, for example, 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one (also called "brexpiprazole") or a salt thereof. Further examples include rebamipide, cilostazol, probucol, ethyl 4-aminobenzoate, etc. These may also be in the form of a salt. Among these, aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof is preferred.

[0090] In addition, when the poorly soluble drug is in the form of a salt, the salt is not particularly limited as long as it is a pharmacologically acceptable salt, and examples of the salt include metal salts such as alkali metal salts (e.g., sodium salt, potassium salt, etc.); alkaline earth metal salts (e.g., calcium salt, magnesium salt, etc.); ammonium salts; alkali metal carbonates (e.g., lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, etc.); alkali metal hydrogen carbonates (e.g., lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, salts of inorganic bases such as alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.); tri(lower) alkylamines (e.g., trimethylamine, triethylamine, N-ethyldiisopropylamine, etc.), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-(lower) alkyl-morpholines (e.g., N-methylmorpholine, etc.), 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0] Examples of the salt include salts of organic bases such as undecene-7 (DBU) and 1,4-diazabicyclo[2.2.2]octane (DABCO); salts of inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate; salts of organic acids such as formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, picrate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, glutamate, and pamoate. Here, the term "(lower) alkyl" refers to "alkyl having 1 to 6 carbon atoms."

[0091] When the poorly soluble drug contained in the injectable formulation of the present invention is aripiprazole or a salt thereof, the crystal form of aripiprazole or a salt thereof is not particularly limited. Aripiprazole or a salt thereof may be in the form of a monohydrate (aripiprazole hydrate A) or in a number of anhydrous forms, i.e. It is known to exist in the forms of anhydrous crystalline B, anhydrous crystalline C, anhydrous crystalline D, anhydrous crystalline E, anhydrous crystalline F, and anhydrous crystalline G, all of which can be used as aripiprazole or a salt thereof in the injectable formulation of the present invention. Among them, the monohydrate form is preferred.

[0092] The above-mentioned poorly soluble drugs are known compounds, and commercially available ones may be used, or they can be easily obtained by known production methods.

[0093] In the injectable preparation of the present invention, it is preferable that at least water is contained as a dispersion medium. As a dispersion medium containing at least water, water or a water-containing solvent of water and an organic solvent is preferably used. The organic solvent here is miscible with water, for example, alcohols such as methanol, ethanol, propanol, isopropanol, etc.; ketones such as acetone; ethers such as tetrahydrofuran; dimethylformamide; and mixtures thereof, among which alcohols are preferable, and ethanol is particularly preferable. The content of water in the above-mentioned water-containing solvent is not particularly limited, but is preferably set to about 50% by weight or more, for example.

[0094] The dispersion medium is preferably water, and it is particularly preferable to use sterilized water for injection.

[0095] The specific suspending agent (suspending agent A) contained in the injectable formulation of the present invention comprises at least one suspending agent selected from the group consisting of (i) and (ii) below. (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof

[0096] The polyvinylpyrrolidone used has a K value (Fikenscher's K value) of preferably about 10 to about 90, more preferably about 12 to about 30, and even more preferably about 12 to about 20. The average molecular weight of the polyvinylpyrrolidone used is preferably about 2,000 to about 700,000, more preferably about 2,000 to about 40,000, and even more preferably about 2,000 to about 10,000. By using polyvinylpyrrolidone having the above K value and average molecular weight range, it is possible to form a gel when the suspension of a poorly soluble drug is left standing, to suppress caking due to the settling of particles, and to prepare an injection preparation with excellent storage stability. Examples of polyvinylpyrrolidone include povidone K12, povidone K17, povidone K25, and povidone K30, and povidone K17 is the most preferable. These various polyvinylpyrrolidones may be used alone, or Two or more types may be mixed and used.

[0097] The polyethylene glycol (macrogol) used as the suspending agent A preferably has an average molecular weight of about 100 to about 10,000, more preferably about 150 to about 8,000, and even more preferably about 200 to about 5,000. By using a polyethylene glycol having the above average molecular weight range, caking due to particle precipitation can be suppressed, and an injectable preparation with excellent storage stability can be prepared. Examples of polyethylene glycol include polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 4000, polyethylene glycol 6000, and polyethylene glycol 8000, with polyethylene glycol 400 being the most preferred. These various polyethylene glycols may be used alone. Alternatively, two or more of them may be mixed and used.

[0098] As the carboxymethylcellulose or its salt, in addition to carboxymethylcellulose, preferred examples of the salt of carboxymethylcellulose include alkali metal salts of carboxymethylcellulose and ammonium salts of carboxymethylcellulose. Examples of the carboxymethylcellulose include salts such as lithium carboxymethylcellulose and ammonium carboxymethylcellulose, and among these, carboxymethylcellulose and sodium carboxymethylcellulose are preferred, and sodium carboxymethylcellulose is particularly preferred. These various carboxymethylcelluloses or salts thereof can be used alone or in combination of two or more.

[0099] The injectable preparation of the present invention becomes highly viscous and loses fluidity when left to stand for a period of time after preparation. However, once the injectable preparation has been gelled, it regains fluidity when subjected to a weak shock (for example, stirring, shaking, tapping, external shock, or pressure when extruding from an injection needle). The formulation is considered to exhibit structural viscosity. Structural viscosity is a type of non-Newtonian flow, in which, when shear stress increases, the weaker internal structures of the liquid are destroyed, decreasing the viscosity and approaching Newtonian flow.

[0100] When the injection preparation exhibiting this fluidity is allowed to stand for a while, it gels again, and the gel-like injection preparation also exhibits fluidity when subjected to a weak impact (e.g., stirring, shaking, etc.), and when allowed to stand again, it gels. That is, the injection preparation of the present invention has a thixotropic property (thixotropic property). It is also thought to exhibit a tropism.

[0101] Such properties can be confirmed by measuring the viscosity of the injectable formulation using a rheometer. The rheometer is an advanced version of a viscometer, and is a device that can freely change various parameters and precisely measure the viscosity for each parameter condition. When the viscosity of the injectable formulation of the present invention is measured using a rheometer while gradually increasing the shear rate, the viscosity of the injectable formulation of the present invention generally decreases gradually. As the rheometer, it is preferable to use a rotational rheometer. As the rheometer, for example, Discovery Hybrid Rheometer-2 (DHR-2) or Discovery Hybrid Rheometer-3 (DHR-3) (manufacturer: TA Instruments) can be exemplified.

[0102] In particular, (α) the injectable preparation of the present invention gels upon standing, suppressing the settling and caking of poorly soluble drug particles, and thus exhibits the effect of excellent storage stability. Furthermore, (β) the injectable preparation of the present invention, even after gelling, easily becomes fluid upon weak impact, so that it can be easily injected at the time of use (injection). In particular, the gelled injectable preparation (gel composition) becomes fluid (becomes sol-like) simply by pushing the plunger of the syringe to eject it from the injection needle, so that it can be smoothly ejected from the injection needle as it is. Therefore, the pain and local damage during injection are relatively small, and it can be dispersed well into the muscle or subcutaneously.

[0103] Whether the injection preparation is gelled (and therefore whether the above-mentioned effect (α) is exerted) can be determined by measuring the viscosity with a rheometer at a shear rate of 0.01 to 0.02 s. -1 A small range of This can be confirmed by checking whether a value of 40 Pa·s or more is measured at at least one point. -1 At this shear rate, values ​​of approximately 40 Pa s or more were measured. The fact that the injection preparation to be measured has lost its fluidity and become gel-like indicates that the injection preparation to be measured has lost its fluidity and become gel-like. -1 At a shear rate of about 100 Pa·s or more If a value of 0.01 to 0.02 s is measured, it indicates that the injection preparation being measured has definitely lost fluidity and become gel-like. -1 At least one point in the range Preferably, a value of about 40 to about 20,000 Pa·s is measured, more preferably a value of about 50 to about 10,000 Pa·s is measured, even more preferably a value of about 75 to about 5,000 Pa·s is measured, and even more preferably a value of about 100 to about 3,000 Pa·s is measured. Furthermore, at a shear rate of 0.01 to 0.02 s -1 In the range of The viscosity is preferably about 40 Pa·s or more (particularly, about 100 Pa·s or more). It is more preferably from 40 to about 20,000 Pa·s, even more preferably from about 50 to about 10,000 Pa·s, even more preferably from about 75 to about 5,000 Pa·s, and particularly preferably from about 100 to about 3,000 Pa·s.

[0104] In addition, whether the injection preparation exhibits the above-mentioned effect (β) can be determined by measuring the viscosity with a rheometer at a shear rate of 900 to 1,000 s -1 At least one point in the range is about 0 This can be confirmed by checking whether a value of .2 Pa·s or less is measured. In other words, the shear rate is 900 to 1,000 s -1 A value of approximately 0.2 Pa s or less was measured at at least one point in the range. This indicates that the injection preparation being measured has acquired fluidity and is in a sol state. -1 At least one point in the range of about It is preferable that a value of 0.1 Pa·s or less is measured, and it is more preferable that a value of about 0.05 Pa·s or less is measured. Furthermore, at shear rates of 900 to 1,000 s -1 In the range of In this case, the viscosity is preferably about 0.2 Pa·s or less, more preferably about 0.1 Pa·s or less, and even more preferably about 0.05 Pa·s or less.

[0105] Whether the injection preparation is gelled (and therefore whether the above-mentioned effect (α) is exerted) can be determined by the viscosity measurement at 25°C using a rheometer at a shear rate of 0.01 to 0.02 s -1 Check that a value of approximately 40 Pa·s or more is measured at at least one point in the range. That is, the shear rate is 0.01 to 0.02 s -1 At least one point in the range A value of 40 Pa·s or more indicates that the injection preparation being measured has lost its fluidity and has become gel-like. -1 The shear force If a value of about 100 Pa·s or more is measured at a shear rate of 0.01 to 0.02 s, it indicates that the injection preparation being measured has definitely lost its fluidity and become gel-like. -1 At least one point in the range of about 40 to about 20,000 Pa s is measured. It is preferable that the shear rate is about 50 to about 10,000 Pa·s, more preferable that the shear rate is about 75 to about 5,000 Pa·s, and even more preferable that the shear rate is about 100 to about 3,000 Pa·s. -1 Within this range, the viscosity is preferably about 40 Pa·s or more (particularly, about 100 Pa·s or more), more preferably about 40 to about 20,000 Pa·s, even more preferably about 50 to about 10,000 Pa·s, even more preferably about 75 to about 5,000 Pa·s, and particularly preferably about 100 to about 3,000 Pa·s.

[0106] In addition, whether the injection preparation exhibits the above-mentioned effect (β) can be determined by measuring the viscosity at 25°C using a rheometer at a shear rate of 900 to 1,000 s -1 At least in the range This can be confirmed by checking whether a value of approximately 0.2 Pa s or less is measured at one point. In other words, at a shear rate of 900 to 1,000 s -1Approximately 0.2 Pa· at least one point in the range The measurement of a value of 0.05 to 0.25 μm indicates that the injection preparation has acquired fluidity and is in a sol state. -1 At least in the range At one point, it is preferable that a value of about 0.1 Pa·s or less is measured, and it is more preferable that a value of about 0.05 Pa·s or less is measured. -1 In this range, the viscosity is preferably about 0.2 Pa·s or less, and more preferably about 0.1 Pa·s or less. It is more preferably a·s or less, and even more preferably about 0.05 Pa·s or less.

[0107] In addition, these shear rates (0.01 to 0.02 s -1 and 900-1,000s -1 It is preferable to start with a viscosity measurement at a low shear rate and then measure the viscosity while gradually increasing the shear rate. For example, a rheometer is used to measure the viscosity at a shear rate of 0.001 to 1,000 s -1 It is preferable to measure the viscosity in the range of 100 to 200 mm.

[0108] The results of the viscosity measurements of the gel composition in this manner were plotted against the shear rate (s -1 ) and the y-axis is viscosity (Pa s), the graph generally slopes downwards. The above content can be explained again using the graph. For example, when the shear rate is 0.01 to 0.02 s -1 A value of 40 Pa s or more was measured at at least one point in the range. This means that in the range of shear rates of 0.01≦x≦0.02, at least a part of the graph satisfies y≧40. -1 In the range of shear rate 0.01≦x≦0, the viscosity is 40 Pa s or more. In the range of .02, the entire graph satisfies y≧40. For example, in the range of shear rates of 900 to 1,000 s -1 At least one point in the range is about 0 The measurement of a value of .2 Pa·s or less means that at least a part of the graph satisfies y≦0.2 in the range of shear rates of 900≦x≦1,000. -1 In the range, the viscosity is approximately 0.2 Pa s or less. Being below this can be said to mean that in the range of shear rates 900≦x≦1,000, the entire graph satisfies y≦0.2.

[0109] As the rheometer, for example, a Discovery Hybrid Rheometer-2 (DHR-2) or a Discovery Hybrid Rheometer-3 (DHR-3) (manufacturer: TA Instruments) can be used.

[0110] One of the main reasons why the injectable formulation of the present invention can achieve the above effects (α) and (β) is that the above specific suspending agent (suspending agent A) is used in combination with a poorly soluble drug. That is, a wide variety of suspending agents for poorly soluble drugs are known, and many suspending agents cannot be used to prepare a composition that achieves the above effects (α) and (β), but the above suspending agent A is extremely suitable for obtaining an injectable formulation that achieves the above effects (α) and (β). Therefore, the injectable formulation of the present invention can be prepared by combining a poorly soluble drug and a dispersion medium with suspending agent A to prepare a suspension, measuring the viscosity of the suspension, and selecting one that satisfies the above conditions.

[0111] Other important factors for achieving the above effects (α) and (β) include, for example, the particle size and concentration of the poorly soluble drug.

[0112] The average primary particle size of the poorly soluble drug contained in the injectable formulation of the present invention is usually about 0.5 to about 100 μm, preferably about 0.5 to 50 μm, more preferably about 0.5 to about 30 μm, even more preferably about 1 to about 20 μm, even more preferably about 1 to about 10 μm, especially preferably about 1 to about 5 μm, and particularly preferably about 2 to about 5 μm. The average secondary particle size of the poorly soluble drug is preferably 3 times or less, more preferably 2 times or less, of the average primary particle size.

[0113] The "primary particle size" refers to the particle size when each particle is not aggregated and is in a separate state, and the "average primary particle size" is calculated from the volume average diameter calculated from the particle size distribution of the average primary particles measured by a laser diffraction scattering method. In the present invention, the average primary particle size is measured under conditions in which the injection preparation is circulated in an aqueous solvent and subjected to ultrasonic irradiation. In addition, the "secondary particle size" refers to the particle size when the particles are aggregated, and the "average secondary particle size" is calculated from the volume average diameter calculated from the particle size distribution of the average secondary particles measured by a laser diffraction scattering method. In the present invention, the average secondary particle size is measured by circulating the injection preparation in an aqueous solvent without ultrasonic irradiation.

[0114] For measuring the average particle size by the laser diffraction scattering method, for example, SALD-3000J (manufacturer: Shimadzu Corporation) can be used.

[0115] Although the average secondary particle size will never be smaller than the average primary particle size (except within the measurement error range), the injectable formulation of the present invention also includes an injectable formulation containing a poorly soluble drug whose average primary particle size and average secondary particle size are almost the same (i.e., little particle aggregation has occurred). Unless a specific operation such as ultrasonic irradiation (operation to convert secondary particles into primary particles) is performed, a poorly soluble drug whose average secondary particle size is larger than the average primary particle size is preferred.

[0116] By setting the average primary particle size of the poorly soluble drug to 1 μm or more, the effect of exhibiting long-term sustained release when used as an injection can be preferably obtained. In addition, it is preferable to set the average primary particle size of the poorly soluble drug to 100 μm or less, preferably 50 μm or less, more preferably 30 μm or less, even more preferably 10 μm or less, and particularly preferably 2 to 5 μm, in order to suppress precipitation of the poorly soluble drug during preparation of the composition of the present invention or during the period from preparation to administration to a patient, and to prevent clogging of the injection needle during injection.

[0117] The method for preparing poorly soluble drugs having the above average primary particle size is preferably a wet milling method. As the wet milling method, wet ball milling, high pressure homogenization, high shear homogenization, etc. are preferred. In addition to the above milling methods, other low and high energy mills (e.g., roller mills) can also be used.

[0118] Other methods that can be used include controlled crystallization.

[0119] In addition, methods for producing poorly soluble drugs having the above-mentioned average primary particle size include, for example, the impinging jet crystallization method applied for by Bristol-Myers Squibb (see JP Patent Publication No. 2007-509153) and the wet grinding method using a high-pressure homogenizer applied for by Otsuka Pharmaceutical Co., Ltd. (see JP Patent Application No. 2007-200088). The high-pressure homogenizer applied for by Otsuka Pharmaceutical Co., Ltd. The wet milling method used (especially the two-stage wet milling method) is more preferred.

[0120] The concentration of the poorly soluble drug contained in the injectable preparation of the present invention is preferably about 200 to about 600 mg / mL, more preferably about 200 to about 500 mg / mL, even more preferably about 200 to about 480 mg / mL, and even more preferably about 250 to about 450 mg / mL.

[0121] An injectable preparation containing the above suspending agent A and containing a poorly soluble drug that satisfies the above average particle size and concentration conditions more preferably exhibits the above effects (α) and (β).

[0122] The concentration of suspending agent A (the above (i) or (ii)) contained in the injectable preparation of the present invention is preferably about 0.05 to about 150 mg / mL, more preferably about 0.1 to about 100 mg / mL, and even more preferably about 0.2 to about 50 mg / mL.

[0123] When the injectable formulation of the present invention contains the above (i) and (ii) as suspending agent A, the total concentration thereof is preferably about 0.05 to about 150 mg / mL, more preferably about 0.1 to about 100 mg / mL, and even more preferably about 0.2 to about 50 mg / mL.

[0124] In addition to the poorly soluble drug, suspending agent A, and dispersion medium, the injectable preparation of the present invention may contain additives such as a suspending agent other than suspending agent A (hereinafter also referred to as "suspending agent B"), a buffer, a pH adjuster, an excipient, a lubricant, a flow agent, a disintegrant, a binder, a surfactant, a preservative, a flavoring agent, an odorant, an isotonicity agent, etc.

[0125] As these additives, for example, those listed in JP-T-2007-509148 are can be used.

[0126] Other suspending agents suitable for use as suspending agent B include various polymers, low molecular weight oligomers, natural products, and surfactants (nonionic and ionic). surfactants), such as cetylpyridinium chloride, gelatin, casein, resin (phosphatides), dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g. macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives; dodecyltrimethylammonium bromide, polyoxyethylene stearate, colloidal silicon dioxide, phosphates, sodium dodecyl sulfate, methylcellulose, hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), 4-(1,1,3,3-tetramethylcellulose) with ethylene oxide and formaldehyde. (tetramethylbutyl)-phenol polymers (also known as tyloxapol, superione, and triton), poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908®, which are propylene glycol derivatives of ethylenediamine). tetrafunctional block copolymers derived from the sequential addition of ethylene oxide and ethylene oxide (BASF Wyandotte Corporation, Parsippany, NJ); charged phospholipids, e.g., dimyristoyl phosphatidylglycerol, dioctyl stearate, dialkyl esters of sodium sulfosuccinate (DOSS); Tetronic 1508® (T-1508) (BASF Wyandotte Corporation); Aerosol OT®, which is the dioctyl ester of sodium sulfosuccinate (American Cyanamid); Duponol P®, which is sodium lauryl sulfate (DuPont); Tritons X-200 (Registered Trademark) (Rohm and Haas), which is an alkylaryl polyether sulfonate; Crodestas F-110®, which is a sucrose stearate and sucrose distearate; (Croda Inc.); p-isononylphenoxypoly-(glycidol), also known as Olin-10G® or Surfactant 10-G® (Olin Chemicals, Stamford, Conn.); Crodestas SL-40 (Croda, Inc.); and SA9OHCO, which is a mixture of C 18 H 37 CH2(CON(CH3))-CH2(CHOH)4(CH2OH)2 (Eastman Kodak Co.); decanoyl-N-methylglucamide; n-decyl-β-D-glucopyranoside; n-decyl-β-D-maltopyranoside; n-dodecyl-β-D-glucopyranoside; n-dodecyl-β-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-β-D-glucopyranoside; n-heptyl-β-D-thioglucoside; n-hexyl-β-D-glucopyranoside; nonanoyl-N-methylglucamide; n-nonyl-β-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-β-D-glucopyranoside; octyl-β-D-thioglucopyranoside, and the like.

[0127] These suspending agents B are known pharmaceutical excipients and are described in detail in the Handbook of Pharmaceutical Excipients, jointly published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain (The Pharmaceutical Press, 1986), specifically incorporated by reference. and can be prepared by techniques known in the art.

[0128] The concentration of suspending agent B is, for example, preferably about 0.1 to about 50 mg / mL, more preferably about 0.1 to about 20 mg / mL, and even more preferably about 0.3 to about 15 mg / mL.

[0129] In addition, (i) polyethylene glycol is mixed in addition to polyvinylpyrrolidone. It is also preferable that the concentration of polyvinylpyrrolidone is about 0.1 mg / mL or more, and more preferably about 0.1 to about 100 mg / mL. In this case, the concentration of polyethylene glycol is preferably about 0.05 to about 100 mg / mL, and more preferably about 0.1 to about 50 mg / mL. Furthermore, when polyethylene glycol 400 is used as the polyethylene glycol, the concentration of polyethylene glycol 400 is preferably about 0.1 to about 100 mg / mL, more preferably about 0.1 to about 10 mg / mL, and even more preferably about 0.5 to about 5 mg / mL. Furthermore, when polyethylene glycol 4000 is used, the concentration of polyethylene glycol 4000 is preferably about 0.1 to about 40 mg / mL.

[0130] When (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof is used as suspending agent A, the concentration of polyethylene glycol is preferably about 0.05 to about 2 mg / mL, more preferably about 0.1 to about 1 mg / mL.

[0131] Furthermore, in the case where (i) carboxymethylcellulose or a salt thereof is mixed and used in addition to polyvinylpyrrolidone, or in the case where (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof are used as suspending agent A, the concentration of carboxymethylcellulose or a salt thereof is preferably about 0.5 to 50 mg / mL, more preferably 1 to 30 mg / mL, and even more preferably 2 to 20 mg / mL.

[0132] Carboxymethylcellulose or a salt thereof can suppress the increase in viscosity during production. Therefore, it is preferable that the poorly soluble drug such as aripiprazole or a salt thereof can be efficiently pulverized to a desired particle size. In addition, polyethylene glycol can be preferably contained, since it can prevent syneresis when the obtained injection preparation is stored for a long period of time.

[0133] The dispersion medium is added in an appropriate amount so that the content of the poorly soluble drug falls within the range described above. For example, the dispersion medium is added in such an amount that the total volume of the injection preparation is finally adjusted to about 0.2 to about 5.0 mL, more specifically, about 0.4 to about 3.0 mL, and further preferably about 0.5 to about 2.0 mL.

[0134] Furthermore, even if the composition (injection preparation) prepared using the poorly soluble drug, the dispersion medium, and the suspending agent A does not gel when left to stand, it can be gelled by carrying out a heat treatment (aging treatment). Even in this case, the composition that can preferably achieve the effects of the present invention can be preferably used as the injection preparation of the present invention. That is, even if the injection preparation is gelled in this manner, when the viscosity is measured by a rheometer under the above conditions, particularly at 25°C, it is preferable that the viscosity is at least 0.01 to 0.02 s. -1 Less than the range At each point, a value of 40 Pa s or more was measured, and the shear rate was 900 to 1,000 s -1 An injectable formulation that satisfies the condition that a value of 0.2 Pa s or less is measured at at least one point in the range can be suitably used as the injectable formulation of the present invention. For example, gelation of the injectable formulation can be preferably promoted by setting the temperature condition during standing at a higher temperature, or by temporarily standing at a higher temperature and then storing the same at room temperature (about 25°C), thereby producing the injectable formulation of the present invention.

[0135] The aging treatment is carried out at a temperature of, for example, about 30° C. or higher (preferably about 30 to 70° C., more preferably The reaction can be carried out by heating at a temperature of about 40°C to 60°C, more preferably about 45°C to 55°C) for several minutes to several days (for example, preferably about 5 minutes to 5 days, more preferably about 1 hour to 3 days, and even more preferably about 12 hours to 24 hours). However, when the reaction is heated at a temperature of 90°C or higher, This is not preferred because the water will evaporate. Although the secondary particle size of the poorly soluble drug tends to increase by the aging treatment, as described above, it is preferred that the average secondary particle size of the poorly soluble drug is about 3 times or less the average primary particle size even if the aging treatment is performed. It is more preferable that the temperature is about 2 times or less. In addition, it is also not preferable to leave the injection preparation at such a low temperature that the injection preparation freezes.

[0136] As can be understood from the above, when the injectable preparation of the present invention is allowed to stand to gel, the standing temperature is preferably about 5 to 70°C, more preferably about 20 to 70°C, and even more preferably about 25 to 65°C.

[0137] The time of standing still may be longer than the time required for gelation, depending on the amount of the injection preparation to be gelled and the temperature at which it is left standing, and is preferably 5 minutes or more, more preferably 10 minutes or more, even more preferably 30 minutes or more, and even more preferably 1 hour or more. In the case of 1 hour or more, it is preferably 4 hours or more, more preferably 12 hours or more, and even more preferably 24 hours or more. The upper limit is not particularly limited, but may be, for example, several days (2, 3, 4, or 5 days).

[0138] As mentioned above, an aging treatment can also be incorporated during the resting period (preferably at the beginning).

[0139] An isotonicity agent can be added to the injection preparation of the present invention. The isotonicity agent is not particularly limited, but includes sodium chloride, potassium chloride, mannitol, glycerin, sorbitol, glucose, xylitol, trehalose, maltose, maltitol, etc., and one or more of these can be used. Sodium chloride is more preferable. The amount of the agent added is such that the preparation is isotonic.

[0140] The buffer is used to adjust the pH of the suspension to about 6 to about 8, preferably about 7. To achieve such a pH, the concentration of the buffer is appropriately set depending on the type of the buffer, and is preferably about 0.02 to about 2 mg / mL, more preferably about 0.03 to about 1 mg / mL.

[0141] Specific examples of the buffer include, but are not limited to, one or a mixture of two or more selected from sodium phosphate, monosodium hydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, hydrates thereof, TRIS buffer, etc. Sodium phosphate, monosodium hydrogen phosphate, disodium hydrogen phosphate, and hydrates thereof are preferred.

[0142] The pH adjuster is used in an amount that adjusts the pH of the aqueous suspension of the poorly soluble drug to a range of about 6 to about 7.5, preferably about 7, and an acid or base is used depending on the pH of the injectable formulation of the present invention. When the pH of the injectable formulation is to be lowered, an acidic pH adjuster such as hydrochloric acid or acetic acid is used, and preferably hydrochloric acid is used. When the pH needs to be increased, a basic pH adjuster such as sodium hydroxide, potassium hydroxide, calcium carbonate, magnesium oxide, magnesium hydroxide, and the like is used, and preferably sodium hydroxide is used. The pH adjuster may be used alone or in combination of two or more.

[0143] The method for preparing the injectable formulation of the present invention is not particularly limited, but it is prepared by mixing a poorly soluble drug, suspending agent A, a dispersion medium, and, if necessary, an additive. More specifically, the suspending agent A, a dispersion medium, and, if necessary, an additive are mixed, the resulting vehicle solution is mixed with a poorly soluble drug, and the injectable formulation of the present invention can be obtained by wet pulverization according to the above-mentioned method. In order to prevent the injectable formulation from starting to gel, it is preferable to keep the temperature during preparation low (for example, about 2 to 10°C, particularly about 5°C).

[0144] By the above-mentioned method, a storage-stable injectable formulation containing a poorly soluble drug having a desired average particle size can be obtained.

[0145] The injectable formulations of the present invention are suitably prepared as formulations for administration preferably once a month, once every two months, or once every three months. The injectable formulations are preferably administered intramuscularly, although subcutaneous injections are acceptable as well.

[0146] In particular, when the poorly soluble drug contained in the injectable formulation of the present invention is aripiprazole or a salt thereof, the injectable formulation can be used to treat, for example, schizophrenia and related disorders (e.g. It is preferred for treating or preventing recurrence of symptoms of certain conditions (e.g., bipolar disorder, depression, dementia, etc.) It is widely used.

[0147] As described above, the injectable formulation of the present invention contains a specific suspending agent A, which inhibits caking due to precipitation of the poorly soluble drug from the time of preparation until the time of administration to a patient, thereby providing excellent storage stability and allowing the formulation to be smoothly discharged from a syringe and a thin injection needle during injection.

[0148] In particular, when the injectable formulation of the present invention exhibits structural viscosity, it takes the form of a sol exhibiting fluidity immediately after preparation (see FIG. 1). When the sol-form injectable formulation is left to stand, it changes into a gel-form, and does not exhibit fluidity even when tilted slowly (see FIG. 2). The injectable formulation that has changed into a gel-form is stable even when left for a long time, without caking due to sedimentation of the poorly soluble drug particles. Furthermore, the gel-form injectable formulation quickly changes into a sol-form by stirring, shaking, tapping, external impact, or extrusion pressure from the injection needle (see FIG. 3). In the sol-form injectable formulation, the poorly soluble drug does not caking due to sedimentation, and is uniformly dispersed, reproducing the injectable formulation immediately after preparation.

[0149] Although not wishing to be limited in any way, it is speculated that the structural viscosity and thixotropy of such an injectable preparation arises from the following mechanism.

[0150] The injectable preparation is considered to have a structure in which particles of the poorly soluble drug adhere to a part of suspending agent A in the dispersion medium. Therefore, the adhered suspending agent A causes interactions between the particles of the poorly soluble drug.

[0151] It is believed that a network structure is formed by intermolecular and interparticle interactions between the molecules of suspending agent A attached to the surface of the particles of the poorly soluble drug, or between the molecules of suspending agent A attached to the surface of the particles of the poorly soluble drug and the molecules of suspending agent A not attached and present in the dispersion medium, or between the particles of the poorly soluble drug. It is believed that the injectable formulation changes into a gel state due to the network structure.

[0152] The intermolecular interaction by the suspending agent A in which the network structure is constructed is a weak binding force. Therefore, the network structure collapses when subjected to stirring, shaking, tapping, external impact, or extrusion pressure from an injection needle, and as a result, the gel-like injection preparation changes into a sol state. When the injection preparation is in a sol state, the network structure is reconstructed when the preparation is allowed to stand, and the injection preparation changes into a gel state again.

[0153] Another great advantage of the injectable preparation of the present invention is that it can be filled directly into vials or syringes.

[0154] For example, the conventional administration form of aripiprazole or a salt thereof is to prepare a suspension containing aripiprazole or a salt thereof as an active ingredient, and then freeze-dry the suspension in a vial. At the time of use, an injection liquid is injected into the vial, sucked up with a syringe, and administered to a patient.

[0155] In the present invention, the composition is used as an injection preparation by filling it directly into a vial or syringe. Therefore, freeze-drying is not required during the manufacturing process of the injection formulation, and it can be easily prepared.

[0156] In particular, the injectable preparation of the present invention can be used as a prefilled syringe by filling it directly into a syringe. In this case, the structure of the syringe becomes simple and it is possible to reduce the size and weight. In addition, when the injectable preparation of the present invention is filled into a syringe, in a preferred case, it is not necessary to shake the syringe, and the suspension in a sol state can be administered by simply pushing the plunger rod of the syringe and pushing out the injectable preparation of the present invention through the injection needle. It is possible to provide a prefilled syringe that is clinically very convenient and easy to operate, and is extremely useful in medical and industrial terms. In producing such a prefilled syringe, for example, after preparing the injectable preparation as described above, the injectable preparation is prefilled into a syringe, and the injection preparation is allowed to stand and stored as described above to gel. The present invention also includes a kit equipped with the prefilled syringe.

[0157] In addition, as the poorly soluble drug used in the injectable preparation of the present invention, aripiprazole or its salt, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or its salt is particularly suitable. Therefore, more preferred embodiments of the injectable preparation containing aripiprazole or its salt as the poorly soluble drug, or the injectable preparation containing 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or its salt will be described in detail below. However, unless otherwise limited by the following description, the above explanation also applies to the injectable preparation containing aripiprazole or its salt as the poorly soluble drug, or the injectable preparation containing 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or its salt.

[0158] The injectable formulation of the present invention containing aripiprazole or a salt thereof comprises aripiprazole or a salt thereof, water, and at least one suspending agent selected from the group consisting of the following (i) and (ii): (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof Including, It is preferable that the average primary particle size of aripiprazole or a salt thereof is about 0.5 to about 30 μm, and the concentration of aripiprazole or a salt thereof is 200 to 600 mg / mL.

[0159] In particular, when the injectable preparation of the present invention contains aripiprazole or a salt thereof (hereinafter, The concentration of aripiprazole or its salt is important for the injection formulation (also called "aripiprazole injection formulation"). At a concentration outside the range of 200 to 600 mg / mL, it is difficult to produce an injectable preparation exhibiting the above-mentioned effects (α) and (β). In particular, at a concentration of 100 mg / mL or less, it is difficult to produce an injectable preparation that gels even if suspending agent A is used (and even if aging treatment is performed). Therefore, when the injectable preparation of the present invention contains aripiprazole or a salt thereof, it is preferable to use a specific suspending agent (suspending agent A) and a specific concentration of aripiprazole or a salt thereof (200 to 600 mg / mL, more preferably 250 to 450 mg / mL). The combination of aripiprazole salts (mL) is particularly important. When the active ingredient is a stearate, the concentration is preferably expressed as an aripiprazole equivalent concentration.

[0160] The injectable preparation of the present invention containing 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof comprises 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof, water, and at least one suspending agent selected from the group consisting of the following (i) and (ii): (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof Including, The average primary particle size of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof is about 0.5 to about 30 μm, and the concentration of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof is 200 to 600 mg / mL.

[0161] In particular, when the injectable preparation of the present invention contains 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof (hereinafter In the present invention, the concentration of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof is important, and it is difficult to produce an injectable formulation exhibiting the above-mentioned effects (α) and (β) at a concentration outside the range of 200 to 600 mg / mL. In particular, at a concentration of 100 mg / mL or less, even if suspending agent A is used (and even after aging treatment), It is difficult to produce an injectable formulation that gels (even if the gelling agent is treated with a gelling agent). When the injectable preparation of the invention contains 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof, the concentration of a specific suspending agent (suspending agent A) and a specific 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof (200 to 600mg / mL, more preferably 250-450mg / mL) is particularly important. When the injectable preparation of the present invention contains a salt of brexpiprazole, the concentration is preferably expressed as a brexpiprazole equivalent concentration.

[0162] In the aripiprazole injection formulation or brexpiprazole injection formulation of the present invention, when the suspending agent A contains the (i) polyvinylpyrrolidone, the concentration of polyvinylpyrrolidone is preferably 0.1 to 100 mg / mL, more preferably 1 to 50 mg / mL, and even more preferably 2 to 20 mg / mL.

[0163] In addition, when the aripiprazole injection formulation or brexpiprazole injection formulation of the present invention contains (i) polyvinylpyrrolidone as suspending agent A and further contains one or more other suspending agents, the one or more other suspending agents preferably contain at least one selected from the group consisting of polyethylene glycol and carboxymethylcellulose or a salt thereof. That is, when these injection formulations of the present invention contain (i) polyvinylpyrrolidone as suspending agent A and further contain one or more other suspending agents, the suspending agents preferably contain any of the following (i-1) to (i-3). (i-1) Polyvinylpyrrolidone and polyethylene glycol (i-2) Polyvinylpyrrolidone, and carboxymethylcellulose or its salt (i-3) Polyvinylpyrrolidone, polyethylene glycol, and carboxymethylcellulose or a salt thereof

[0164] In addition, in these injectable preparations of the present invention, regardless of whether they contain any of (i-1) to (i-3), the concentration of polyvinylpyrrolidone is, as described above, preferably 0.1 to 100 mg / mL, more preferably 1 to 50 mg / mL, and even more preferably 2 to 20 mg / mL. In (i-1) or (i-3), the concentration of polyethylene glycol is preferably about 0.05 to about 100 mg / mL, and more preferably about 0.1 to about 50 mg / mL. In (i-2) or (i-3), the concentration of carboxymethylcellulose or a salt thereof is preferably about 0.5 to about 50 mg / mL, more preferably 1 to 30 mg / mL, and even more preferably 2 to 20 mg / mL.

[0165] Carboxymethylcellulose or a salt thereof can suppress the increase in viscosity during production. Therefore, it is preferable that aripiprazole or a salt thereof, or brexpiprazole or a salt thereof can be efficiently pulverized to a desired particle size. In addition, polyethylene glycol can be preferably contained, since it can prevent syneresis when the resulting injection preparation is stored for a long period of time. Among (i-1) to (i-3), (i-3) is particularly preferable, since it can obtain both of these effects.

[0166] When the aripiprazole injection formulation or brexpiprazole injection formulation of the present invention contains (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof as suspending agent A, the concentration of polyethylene glycol is preferably about 0.05 to about 2 mg / mL, more preferably about 0.1 to about 1 mg / mL. The concentration of carboxymethylcellulose or a salt thereof is preferably about 0.5 to 50 mg / mL, more preferably 1 to 30 mg / mL, and even more preferably 2 to 20 mg / mL.

[0167] In addition, when the aripiprazole injection formulation or brexpiprazole injection formulation of the present invention contains (ii) polyethylene glycol and carboxymethylcellulose or its salt as suspending agent A and further contains one or more other suspending agents, it is preferable that the one or more other suspending agents contain polyvinylpyrrolidone. That is, when the injection formulation of the present invention contains (ii) polyethylene glycol and carboxymethylcellulose or its salt as suspending agent A and further contains other suspending agents, it is more preferable that the injection formulation of the present invention contains the above-mentioned (i-3) as a suspending agent. In this case, the concentrations of polyethylene glycol, carboxymethylcellulose or its salt, and polyvinylpyrrolidone are as described for the above-mentioned (i-3).

[0168] When the suspending agent (i-3) is used in the aripiprazole injection formulation or brexpiprazole injection formulation of the present invention, a particularly preferred composition is one in which polyvinylpyrrolidone is 0.5 to 20 mg / mL, polyethylene glycol is 0.1 to 100 mg / mL, carboxymethylcellulose or a salt thereof is 0.5 to 50 mg / mL, and aripiprazole or a salt thereof is 250 to 450 mg / mL (more preferably 300 to 400 mg / mL). Or, more preferably, polyethylene glycol 4000. Furthermore, it is more preferable that the polyvinylpyrrolidone has a K value of about 12 to about 20. Furthermore, it is even more preferable that the average primary particle size of aripiprazole or a salt thereof is 1 to 10 μm.

[0169] In addition, the average primary particle size of aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof is preferably about 0.5 to about 30 μm, more preferably about 1 to about 20 μm, since too large particles may cause precipitation. In order to maintain sustained efficacy, the average primary particle size of aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof in the injection formulation of the present invention administered once a month is preferably about 1 to about 10 μm, more preferably 2 to 7 μm, and even more preferably 2 to 4 μm. The average primary particle size of aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof in the injectable formulation of the present invention when administered once a month or once every three months is preferably about 1 to about 50 μm, more preferably 4 to 30 μm, and even more preferably 5 to 20 μm. Moreover, the average secondary particle size is preferably 3 times or less, and more preferably 2 times or less, the average primary particle size.

[0170] The aripiprazole injection formulation of the present invention is more specifically described as being administered once a month. The content of aripiprazole or a salt thereof in the injectable preparation of the present invention in terms of aripiprazole is preferably about 200 to about 600 mg / mL, more preferably about 200 to about 400 mg / mL, and even more preferably about 300 mg / mL. In the injectable preparation of the present invention administered once a month, the average primary particle size of aripiprazole or a salt thereof is preferably about 1 about 10 μm, more preferably 1 to 5 μm, and even more preferably 2 to 4 μm. The amount of the solution is preferably 0.3 to 3 mL, more preferably 0.6 to 2 mL, and even more preferably 1 to 1.5 mL.

[0171] The content of aripiprazole or a salt thereof in the injectable preparation of the present invention when administered once every two months or once every three months is, in terms of aripiprazole, preferably about 300 to about 600 mg / mL, more preferably about 350 to about 500 mg / mL, and even more preferably about 400 mg / mL. In the injectable preparation of the present invention when administered once every two months or once every three months, the average primary particle size of aripiprazole or a salt thereof is preferably about 1 to about 30 μm, more preferably about 1 to about 30 μm. When administered once every two months, the administration volume is preferably 0.5 to 5 mL, more preferably 1 to 3 mL, and even more preferably 1.5 to 2. When administered once every three months, the administration volume is preferably 0.7 to 8 mL, more preferably 1.5 to 4.5 mL, and even more preferably 2 to 4 mL.

[0172] Further, to explain the brexpiprazole injection formulation of the present invention in more detail, the content of brexpiprazole or a salt thereof in the injection formulation of the present invention administered once a month is preferably about 200 to about 600 mg / mL, more preferably about 200 to about 400 mg / mL, and even more preferably about 300 mg / mL in terms of brexpiprazole. In the injection formulation of the present invention administered once a month, the average primary particle size of brexpiprazole or a salt thereof is preferably about 1 to about 10 μm, more preferably 1 to 5 μm, and even more preferably 2 to 4 μm. The administration volume is preferably 0.3 to 3 mL, more preferably 0.6 to 2 mL, and even more preferably 1 to 1.5 mL.

[0173] The content of brexpiprazole or a salt thereof in the injectable preparation of the present invention when administered once every two months or once every three months is, in terms of brexpiprazole, preferably about 300 to about 600 mg / mL, more preferably about 350 to about 500 mg / mL, and even more preferably about 400 mg / mL. In the injectable preparation of the present invention when administered once every two months or once every three months, the average primary particle size of brexpiprazole or a salt thereof is preferably about 1 to about 30 μm, more preferably about 1 to about 20 μm. In the case of administration once every two months, the administration volume is preferably 0.5 to 5 mL, more preferably 1 to 3 mL, and even more preferably 1.5 to 2.5 mL. In the case of administration once every three months, the administration volume is preferably 0.7 to 8 mL, more preferably 1.5 to 2.5 mL. mL, more preferably 1.5 to 4.5 mL, and even more preferably 2 to 4 mL.

[0174] The aripiprazole injection formulation or brexpiprazole injection formulation of the present invention exhibits the above-mentioned effects (α) and (β), and is in the form of a gel or exhibits fluidity (i.e. In addition, the effects of (α) and (β) can be confirmed by a rotary rheometer. As mentioned above, the meter can be used to objectively verify the above.

[0175] In producing the aripiprazole injectable formulation or brexpiprazole injectable formulation of the present invention, a method is preferred in which raw materials are mixed to prepare a mixed solution, and the aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof contained therein is pulverized to a desired average primary particle size, and further aging treatment is performed as necessary.

[0176] In particular, the gel-like aripiprazole injection formulation of the present invention is prepared by mixing 200 to 600 mg / mL of aripiprazole or a salt thereof, water, and At least one suspending agent selected from the group consisting of (i) and (ii) below: (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof and allowing the mixture having an average primary particle size of aripiprazole or a salt thereof to stand at 5 to 70° C. for 5 minutes or more. Also, for example, a method for producing the aripiprazole or a salt thereof, which comprises dissolving 200 to 600 mg / mL of aripiprazole or a salt thereof in water and at least one suspending agent selected from the group consisting of (i) and (ii) below, can be suitably used. (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof and allowing the mixed solution after the grinding to stand at 5 to 70° C. for 5 minutes or more.

[0177] In particular, the gel-form brexpiprazole injection formulation of the present invention is produced by mixing 200 to 600 mg / mL of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof, water, and At least one suspending agent selected from the group consisting of (i) and (ii) below: (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof and allowing the mixture, in which the average primary particle size of the 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof is 0.5 to 30 μm, to stand at 5 to 70° C. for 5 minutes or more. Also, for example, a method for producing a 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof at 200 to 600 mg / mL, water, and at least one suspending agent selected from the group consisting of (i) and (ii) below can be suitably used. (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof and allowing the mixed solution after the grinding to stand at 5 to 70° C. for 5 minutes or more.

[0178] In producing these injection preparations, it is preferable to leave them at 5 to 70°C for 5 minutes or more as described above, and it is more preferable to carry out aging treatment. By carrying out aging treatment (for example, when the preparations are left at low temperatures or in a situation where they are subjected to intermittent impacts), In addition, the gel composition can be produced more reliably than in the above-mentioned aging method. Under the specified processing conditions, problems such as water evaporating or gelling so that the material does not easily become a sol even when subjected to impact hardly occur.

[0179] In addition, the concentration of the suspending agent contained in the above-mentioned mixture is preferably the same as the concentration of the suspending agent contained in the above-mentioned injectable preparation, because the concentration of the suspending agent in the mixture is the same as the concentration in the injectable preparation.

[0180] In addition, when producing the aripiprazole injection formulation of the present invention, the aripiprazole or a salt thereof to be mixed in the mixed solution may be, for example, in the monohydrate form (aripiprazole) as described above. hydrate A), as well as a number of anhydrous forms, namely anhydrous B, anhydrous C, anhydrous D, anhydrous E, anhydrous F, anhydrous G, anhydrous H, anhydrous I ... It may be crystalline E, anhydrous crystalline F, or anhydrous crystalline G. Aripiprazole or a salt thereof is preferably in the form of a monohydrate, and particularly preferably aripiprazole hydrate A. These may be used alone or in combination of two or more.

[0181] In addition, when producing the brexpiprazole injection formulation of the present invention, 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof to be mixed in the mixed solution is not particularly limited, and may be, for example, an anhydrous form or a dihydrate form. The dihydrate form is preferable. These may be used alone or in combination of two or more.

[0182] The method for grinding aripiprazole or a salt thereof or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof in the mixture is not particularly limited, and a known method can be used. For example, the above-mentioned method can be used. Specifically, a wet grinding method is preferable. As the wet grinding method, wet ball milling, high pressure homogenization, high shear homogenization, etc. are preferable. In addition to the above grinding techniques, other low and high energy mills (e.g. roller mills) can also be used. Crystallization) is also available from Bristol-Myers Squibb. The impinging jet crystallization method applied for by 007-509153) and the high pressure homogenizer filed by Otsuka Pharmaceutical Co., Ltd. Examples of such a method include a wet grinding method using a homogenizer (see Japanese Patent Application No. 2007-200088), but the wet grinding method using a high-pressure homogenizer (particularly the two-stage wet grinding method) applied for by Otsuka Pharmaceutical Co., Ltd. is more preferred.

[0183] Furthermore, in the above-mentioned method for producing a gel-like aripiprazole injection formulation or a method for producing a gel-like brexpiprazole injection formulation, the mixed solution is filled into a syringe and allowed to stand, thereby producing a prefilled syringe prefilled with a gel-like aripiprazole injection formulation or a gel-like brexpiprazole injection formulation.

[0184] The prefilled syringe thus obtained contains the injection preparation (gel-like composition Simply push the plunger rod of the syringe and eject the liquid from the needle. Since the injectable formulation of the present invention exhibits the above (sol-like) effect, it can be smoothly discharged from the injection needle as it is (i.e., the above-mentioned (β) effect is achieved), and furthermore, precipitation and caking of aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof is inhibited, and therefore the injectable formulation of the present invention has excellent storage stability (i.e., the above-mentioned (α) effect is achieved), and therefore the injectable formulation of the present invention is extremely useful, particularly in clinical settings.

[0185] The present invention also includes a kit including the prefilled syringe. EXAMPLES

[0186] The present invention will be described in more detail below. Note that the present invention is not limited to the following embodiments. Note that "qs" is an abbreviation for quantum sufficiency, which means sufficient quantity.

[0187] Examples 1 to 7 The suspending agent, sodium chloride, and sodium dihydrogen phosphate monohydrate shown in Table 1 were added to water (for injection). Water) and adjusted to pH 7.0 with sodium hydroxide to prepare a vehicle solution. The ingredient (aripiprazole monohydrate) was suspended in the prepared vehicle solution and mixed with Clearmix S1.5 (manufacturer: M Technique Co., Ltd.), and then crushed using a high-pressure homogenizer Panda model NS1001L2K (manufacturer: Niro Soavi) to prepare each injection formulation. Note that the preparation of the injection formulations was carried out at a temperature of 10°C or below for all operations after suspending the active ingredient in the vehicle solution. went.

[0188] Immediately after preparation, each of the resulting injection preparations was in the form of a sol-like suspension that exhibited fluidity. Figure 1 shows a photograph of the injection preparation of Example 1 immediately after preparation. When each of the resulting injection preparations was placed in a transparent container and allowed to stand at 25°C for 1 hour, all of the injection preparations lost fluidity and became gel-like. The injection preparations of Example 1 were obtained. Figure 2 shows a photograph of the container containing the injection preparation of Example 1, which was left to stand and then slowly tilted over. Furthermore, when each gelled injection preparation was gently shaken, all of the gelled injection preparations became a sol and showed flowability again. After the injection preparation of Example 1 was placed in a container and left to stand, the container was further struck (i.e., a weak impact was applied to the gelled injection preparation) to obtain a satisfactory result. Figure 3 shows a photograph of the container after it was tilted and then turned horizontal.

[0189] After gelation, each of the injection preparations of Examples 1 to 7 was stored at 40°C for one week, and then shaken. The average particle size (average secondary particle size) measured in this manner is shown in Table 1. The average particle size (average primary particle size) when ultrasonic treatment was performed during the shaking is also shown in Table 1. The average particle size was measured using a SALD-3000J (manufacturer: Shimadzu Corporation) as a measuring device, using a laser diffraction scattering method. The average particle size of the drug in the following injectable preparations (production examples) was also measured using this measuring device by the laser diffraction scattering method.

[0190] Furthermore, for each of the injection preparations of Examples 1 to 7, 1.0 to 1.2 mL of the shaken sample was The sample was collected and measured at 25°C, 50 rpm, and 120 seconds using a B-type rotational viscometer (Tokimet Co., Ltd.). The viscosity was measured using a TVE-30H cone-plate type rotational viscometer manufactured by Epson Corporation. The measurement results are shown in Table 1. The viscosity was measured according to the Viscosity Measurement Method 2 of the Japanese Pharmacopoeia.

[0191] [Table 1]

[0192] Test Example 1 The above-mentioned Examples 1 to 7 were prepared in the same manner (i.e., ingredients other than the active ingredient were mixed). First, a vehicle solution adjusted to pH 7.0 was prepared, and the active ingredient was suspended in the vehicle solution and pulverized to prepare injection preparations (Production Examples A1 to A6) having the compositions shown in Table 2 below. For the obtained manufacturing examples, the average primary particle size and average secondary particle size of aripiprazole monohydrate were measured immediately after preparation, and the average primary particle size was about 2.0 to 4.0 μm, and the average secondary particle size was about 2.0 to 7.5 μm (Table 2).

[0193] [Table 2]

[0194] After preparation, each manufacturing example was placed in a transparent container and stored at 5°C, 25°C, or 40°C for 5 days. Photographs of the injectable preparations in the containers, which were then slowly tilted and turned horizontal after storage, are shown in Figure 4a (storage at 5°C), Figure 4b (storage at 25°C), and Figure 4c (storage at 40°C). Note that in the explanation of Test Example 1 (especially in the figures and tables), Manufacturing Example A1 is referred to as "Povidone K17 0.1 mg / mL" and Manufacturing Example B1 is referred to as "Povidone K17 0.1 mg / mL". Example A2 may be referred to as "Povidone K17 1.0 mg / mL", Manufacturing Example A3 as "Povidone K17 4.0 mg / mL", Manufacturing Example A4 as "Povidone K17 10.0 mg / mL", Manufacturing Example A5 as "Povidone K17 50.0 mg / mL", and Manufacturing Example A6 as "Povidone K17 100 mg / mL".

[0195] From the results in Figures 4a to 4c, the gelation was more pronounced with lower concentrations of polyvinylpyrrolidone (povidone K17). It was found that the higher the temperature at which the solution was left to stand, the more likely it was to gel. However, when the solution was left to stand at 90°C, the water evaporated, making the solution unsuitable for use as an injection.

[0196] Furthermore, the preparations of each manufacturing example stored at 5°C were shaken well by hand to form a sol (preparations that remained in a sol state even after standing were shaken just to be sure) and then subjected to a rheometer to measure the viscosity of each. The conditions for the viscosity measurement were as follows:

[0197] Measurement device: Rheometer (Discovery Hybrid Rheometer-2 (DHR-2) or Discovery Hybrid Rheometer-3 (DHR-3) (Manufacturer: TA Instruments) ·Shear rate: 10 -5 →1,000 (1 / s) ·Measurement temperature: 5, 25, 40℃ Uses a concentric cylinder The formulations of each manufacturing example stored at 5°C were shaken by hand to form a sol, and then 10 mL was placed in the measuring device. After adding the formulations of each manufacturing example, the device was left to stand at the measuring temperature for 5 to 10 minutes, and the measurement was started. For injectable preparations that gel, the intention is to gel them within the measuring device by leaving them stationary within the measuring device.

[0198] In addition, in the following, when measuring the viscosity of the injection preparation (manufacturing example), the same measuring device was used and the change range of the shear rate was the same. Also, a coaxial double cylinder was used in the same manner. Also, after putting the sample into the measuring device, the measurement was started after leaving it at the measuring temperature for 5 to 10 minutes.

[0199] The results of the viscosity measurement are shown in FIG. 5a (measurement temperature: 5° C.), FIG. 5b (measurement temperature: 25° C.), and FIG. 5c (measurement temperature: 40° C.). -2 ~1,000( The results are shown for a shear rate range of 0.01 to 0.1 / s. Tables 3 to 5 show specific values ​​of the viscosity measured at a shear rate range of 0.02 (1 / s) and at a shear rate range of 900 to 1,000 (1 / s). Table 3 corresponds to the data in Figure 5a, Table 4 corresponds to the data in Figure 5b, and Table 5 corresponds to the data in Figure 5c.

[0200] [Table 3]

[0201] [Table 4]

[0202] [Table 5]

[0203] In particular, Fig. 5b and Table 4 (measurement results at 25°C) show that when the polyvinylpyrrolidone concentration is about 2 to 50 mg / mL, the viscosity is the lowest at any shear rate and gelation is also achieved. Therefore, when the polyvinylpyrrolidone concentration is low, It was found that the viscosity was higher in the 100 mg / mL solution, and that as the polyvinylpyrrolidone concentration increased, the viscosity decreased up to about 20 to 50 mg / mL, but as the concentration increased to about 100 mg / mL or more, the viscosity tended to increase again.

[0204] Test Example 2 In the same manner as in Examples 1 to 7 above (i.e., ingredients other than the active ingredient were mixed and the pH was adjusted to 7.0 First, a vehicle solution adjusted to the above is prepared, the active ingredient is suspended in the vehicle solution, and then crushed. Injection preparations (Production Examples B, C, and D) having the compositions shown in Table 6 were prepared. These injection preparations gelled when left to stand at 25°C or 40°C. Even if these injection preparations gelled, they could be turned into a sol by simply shaking them lightly by hand. The average particle size measurement results of aripiprazole monohydrate were as follows. The average primary particle size of Production Example B was 2.2 μm, and the average secondary particle size was 2.4 μm. The average primary particle size of Production Example C was 4.2 μm, and the average secondary particle size was 4.3 μm. The average primary particle size of Production Example D was 3.9 μm, and the average secondary particle size was 3.9 μm.

[0205] [Table 6]

[0206] The injection preparations of Production Examples B to D stored at 5°C were shaken by hand to form a sol, and then subjected to a rheometer to measure the viscosity at 5°C, 25°C, or 40°C (measurement temperature). Note that the injection preparations of Production Examples B and C were in a sol state after storage at 5°C. The injection preparation of Production Example D was in a gel state after storage at 5°C.

[0207] The measurement results are shown in Figures 6 to 8. Specific values ​​for the viscosity measured at a shear rate of 0.01 to 0.02 (1 / s) and the viscosity measured at a shear rate of 900 to 1,000 (1 / s) are shown in Tables 7 to 9, respectively (the measurement results for Production Example B are shown in Figures 6 and Tables 7, the measurement results of Production Example C are shown in FIG. 7 and Table 8, and the measurement results of Production Example D are shown in FIG. 8 and Table 9.

[0208] [Table 7]

[0209] [Table 8]

[0210] [Table 9]

[0211] Test Example 3 In the same manner as in Examples 1 to 7 above (i.e., ingredients other than the active ingredient were mixed and the pH was adjusted to 7.0 First, a vehicle solution adjusted to the above is prepared, the active ingredient is suspended in the vehicle solution, and then crushed. An injection preparation (Production Example E) having the composition shown in Table 10 was prepared. Even if the injection preparation of Production Example E gelled, it turned into a sol by simply shaking it lightly by hand. The measurement results of the average particle size of aripiprazole monohydrate were as follows. The average primary particle size of Production Example E was 5.4 μm, and the average secondary particle size was 9.5 μm.

[0212] [Table 10]

[0213] The injection preparation of Preparation Example E was stored at 5°C, and then vigorously shaken by hand to form a sol, which was then subjected to a rheometer to measure the viscosity at each of the temperatures of 5°C, 25°C, and 40°C (measurement temperature). The results are shown in Figure 9a. Table 11 shows specific values ​​for the viscosity measured at a shear rate of 0.01 to 0.02 (1 / s) and at a shear rate of 900 to 1,000 (1 / s).

[0214] [Table 11]

[0215] In addition, after the preparation of the injection preparation of Production Example E, it was left to stand for 5 days at 5°C, 25°C or 40°C. Under all conditions, the injection preparation of Production Example E gelled (the injection preparation was placed in a container and left for 5 days). FIG. 9b is a photograph of the container after being left to stand for 10 days, and FIG. 9c is a photograph of the container containing the injection formulation which was slowly tilted to a horizontal position after storage.

[0216] The viscosity measurement results of Manufacturing Examples A1 to E show that if the viscosity of the injectable formulation measured at a shear rate of 0.01 to 0.02 (1 / s) is approximately 40 (Pa s) or more, the formulation is in a gel state, and if the shear rate increases, the formulation becomes a sol state. In particular, if the viscosity of the injectable formulation measured at a shear rate of 900 to 1,000 (1 / s) is approximately 0.2 Pa s or less, it can be said that the formulation can be injected as is.

[0217] Test Example 4 In the same manner as in Examples 1 to 7 above (i.e., ingredients other than the active ingredient were mixed and the pH was adjusted to 7.0 First, a vehicle solution adjusted to the above is prepared, the active ingredient is suspended in the vehicle solution, and then crushed. Injection preparations (Production Examples F1 and F2) having the compositions shown in Table 12 were prepared. The injection preparations of Production Examples F1 and F2 did not gel. The measurement results of the average particle size of aripiprazole monohydrate were as follows. The average primary particle size of Production Example F1 was 3.2 μm, and the average secondary particle size was 5.6 μm. The average primary particle size of Production Example F2 was 2.7 μm, and the average secondary particle size was 2.7 μm.

[0218] [Table 12]

[0219] The injection preparations of Preparation Examples F1 and F2 were stored at 5° C., shaken well by hand, and then subjected to a rheometer to measure the viscosity at 5° C. or 25° C. (measurement temperature). The results are shown in FIG. 10a.

[0220] Table 13 shows specific values ​​for the viscosity measured at a shear rate of 0.01 to 0.02 (1 / s) and the viscosity measured at a shear rate of 900 to 1,000 (1 / s).

[0221] [Table 13]

[0222] After preparation, the injectable formulations of Production Examples F1 and F2 were stored at 5°C, 25°C, or 40°C for 5 days. Under any of the conditions, the injectable formulations of Production Examples F1 and F2 did not gel. Figure 10b shows a photograph of the container after the injectable formulation was placed in a container and stored for 5 days, and Figure 10c shows a photograph of the container containing the injectable formulation that was slowly tilted over and then horizontalized after storage. In the explanation of Test Example 4 (particularly in the figures and tables), Production Example F1 may be written as "Povidone K17 0.1 mg / mL" and Production Example F2 may be written as "Povidone K17 4.0 mg / mL". In particular, from FIG. 10b, it was found that under all conditions, in Production Examples F1 and F2, sedimentation of particles was observed. It was found that Production Examples F1 and F2 were unsuitable for the injectable preparation of the present invention, which maintains uniform dispersion of particles by gelation.

[0223] From the results of Test Examples 1 to 4 above, it was found that by using polyvinylpyrrolidone as a suspending agent to prepare an injectable formulation of a poorly soluble drug, the drug gels when left standing and is easily resistant to light shock (e.g., by touching the It has been found that it is possible to prepare an injectable formulation that returns to a sol state simply by subjecting it to agitation, etc. Understood.

[0224] In addition, when aripiprazole is used as the poorly soluble drug, an injection preparation in which aripiprazole has a specific average primary particle size and a concentration of 200 mg / mL to 600 mg / mL is prepared, which gels when left standing and is resistant to light impact (e.g., by hand). It has been found that it is possible to prepare an injectable formulation that returns to a sol state simply by subjecting it to agitation, etc. It was also found that the gelation was favorable when the solution was left to stand at a temperature of about 20 to 70° C., and that the solution returned to a sol state when subjected to a slight impact.

[0225] Test Example 5 In the same manner as in Examples 1 to 7 above (i.e., ingredients other than the active ingredient were mixed and the pH was adjusted to 7.0 First, a vehicle solution adjusted to the above is prepared, the active ingredient is suspended in the vehicle solution, and then crushed. Injection preparations (Production Examples G, H, and I) having the compositions shown in Table 14 were prepared. In the preparation of these Production Examples, poorly soluble drugs other than aripiprazole were used (see Table 14). After preparation, the viscosity of the injection preparations of Production Examples G, H, and I and the average particle size of the poorly soluble drug were measured in the same manner as in the above Production Examples. The preparations of Production Examples G, H, and I prepared here turned into a sol-like state by simply shaking them lightly by hand even if they gelled.

[0226] [Table 14]

[0227] After preparation, the formulations of each manufacturing example were placed in a transparent container and stored for 5 days at 5° C., 25° C., or 40° C. A photograph of the container containing the injection formulation after storage was slowly tilted and then turned horizontally is shown in Figure 11.

[0228] Furthermore, the preparations of each Production Example stored at 5°C were shaken well by hand and then subjected to a rheometer, and the viscosity was measured at 5°C, 25°C, or 40°C (measurement temperature) in the same manner as above. The viscosity measurement results of Production Example G are shown in Figure 12, those of Production Example H in Figure 13, and those of Production Example I in Figure 14. Furthermore, specific values ​​of the viscosities measured at shear rates of 0.01 to 0.02 (1 / s) and those measured at shear rates of 900 to 1,000 (1 / s) are summarized in Tables 15 to 17. Table 15 corresponds to the data in Figure 12, Table 16 corresponds to the data in Figure 13, and Table 17 corresponds to the data in Figure 14, respectively.

[0229] [Table 15]

[0230] [Table 16]

[0231] [Table 17]

[0232] Test Example 6 In the same manner as in Examples 1 to 7 above (i.e., ingredients other than the active ingredient were mixed and the pH was adjusted to 7.0 First, a vehicle solution adjusted to the above is prepared, the active ingredient is suspended in the vehicle solution, and then crushed. An injection preparation (Production Example J) having the composition shown in Table 18 was prepared. The injection preparation of Formulation Example J gelled when left to stand at 5°C, 25°C or 40°C. The injection preparation of Production Example J, even if gelled, turned into a sol by simply shaking it lightly by hand. The results of measuring the average particle size of aripiprazole monohydrate were as follows. The average primary particle size of Production Example J was 5.5 μm, and the average secondary particle size was 6.9 μm.

[0233] [Table 18]

[0234] The injectable formulation of Production Example J was stored at 5°C, then vigorously shaken by hand to form a sol, and then subjected to a rheometer to measure the viscosity at each of the temperatures of 5°C, 25°C, and 40°C (measurement temperature). The results are shown in Figure 15. Specific values ​​for the viscosity measured at a shear rate of 0.01 to 0.02 (1 / s) and at a shear rate of 900 to 1,000 (1 / s) are shown in Table 19. The injectable formulation of Production Example J had gelled after being stored stationary at 5°C for 5 days.

[0235] [Table 19]

[0236] Test Example 7 In the same manner as in Examples 1 to 7 above (i.e., ingredients other than the active ingredient were mixed and the pH was adjusted to 7.0 First, a vehicle solution adjusted to the above is prepared, the active ingredient is suspended in the vehicle solution, and then crushed. Injection preparations (Production Examples K and L) having the compositions shown in Table 20 were prepared. After preparation, the injection preparations were allowed to stand at 60°C for 12 hours for aging treatment. In addition, freeze-dried injection preparations containing 200 mg / mL or 400 mg / mL of aripiprazole were prepared according to the method described in the Examples of WO2005 / 041937 (Comparative Example 200 and Comparative Example 200, respectively). (Example: 400) The results of measuring the average particle size of aripiprazole monohydrate are as follows: The average primary particle diameter of Production Example K was 2.8 μm, and the average secondary particle diameter was 4.3 μm. The average primary particle diameter of Production Example L was 6.1 μm, and the average secondary particle diameter was 7.9 μm. The average primary particle diameter of Comparative Example 200 was 2.1 μm, and the average secondary particle diameter was 2.1 μm. The average primary particle diameter of Comparative Example 400 was 2.0 μm, and the average secondary particle diameter was 2.1 μm.

[0237] These injection preparations were injected into the leg muscle of male rats at a dose of 50 mg / kg for Preparation Example K and Comparative Example 200, and at a dose of 100 mg / kg for Preparation Example L and Comparative Example 400. To evaluate the blood transfer of aripiprazole after administration, blood samples were collected 0.25, 1, 3, 6, 9, 14, 21, 28, 42, and 56 days after administration, and the concentration of aripiprazole in the serum was measured. Note that the injection preparations of Preparation Examples K and L were put into a vial after preparation, left to gel, and gently shaken before administration to change from a gel to a sol, and then administered. The injection preparations of Comparative Examples 200 and 400 were lyophilized and reconstituted with water before administration.

[0238] The results obtained are shown in graph form in FIG.

[0239] [Table 20]

[0240] Preparation K showed a pharmacokinetic (PK) profile almost equivalent to that of Comparative Example 200, and The PK profile was favorable for a long-acting injection formulation administered once. Compared with Comparative Example 400, C max The PK profile was more favorable for a long-acting injection administered once every 2 to 3 months because the drug had a lower PK and the duration of action was equal or greater. Ta.

[0241] Test Example 8 The viscosity of the injection preparations (Production Examples A3 to A6) stored at 5° C. in Test Example 1 was measured again. Specifically, although the injection preparations of Production Examples A3 to A6 left at 5° C. were in a sol state, they were shaken by hand to confirm that they were in a sol state before being subjected to the rheometer, left at 40° C. for 5 minutes, and then returned to 25° C. before measurement. The viscosity was measured in the same manner as in Test Example 1.

[0242] The results of the viscosity measurements are shown in Figure 17. Table 21 shows specific values ​​of the viscosities measured at shear rates of 0.01 to 0.02 (1 / s) and at shear rates of 900 to 1,000 (1 / s).

[0243] [Table 21]

[0244] Test Example 9 In Test Example 2, the viscosity of the injection preparations (Production Examples B and C) stored at 5° C. was measured again. Specifically, although the injection preparations of Production Examples B and C left at 5° C. were in a sol state, they were shaken by hand to confirm that they were in a sol state before being subjected to the rheometer, left at 40° C. for 5 minutes, and then returned to 25° C. before measurement. Except for this, the viscosity was measured in the same manner as in Test Example 2.

[0245] The results of the viscosity measurements are shown in Figure 18. Figure 18 also shows the results of viscosity measurements at measurement temperatures of 5°C and 25°C in Test Example 2. Table 22 shows a summary of specific values ​​for the viscosities measured at shear rates of 0.01 to 0.02 (1 / s) and those measured at shear rates of 900 to 1,000 (1 / s) in Figure 18. In Table 22, "40→25" in the measurement temperature column indicates that the formulation was left to stand in the rheometer at 40°C for 5 minutes and then returned to 25°C before measurement (the same applies to the following tables).

[0246] [Table 22]

[0247] Test Example 10 An injection preparation (Production Example E') was prepared in the same manner as in the preparation of Production Example E in Test Example 3, except that the blending amount of povidone K17 was 4 mg / mL instead of 0.1 mg / mL, and stored at 5°C, 25°C, or 40°C. Then, the formulations of Production Examples E and E' stored at 5°C were subjected to viscosity measurement in the same manner as in Test Example 3. Specifically, the injection preparation of Production Example E' left at 5°C was in a sol state, but the formulations of Production Examples E and E' were shaken by hand to confirm that they were in a sol state, and then subjected to a rheometer, left at 40°C for 5 minutes, and then returned to 25°C before measurement. The formulation of Production Example E' was also subjected to viscosity measurement in the same manner as in Test Example 3 ( Measurement temperature: 5℃ or 25℃).

[0248] The results of the viscosity measurement are shown in Figure 19a. Figure 19a also shows the results of viscosity measurement of Production Example E at measurement temperatures of 5°C and 25°C in Test Example 3. Table 23 shows specific values ​​of the viscosities measured in the shear rate range of 0.01 to 0.02 (1 / s) and the viscosities measured in the shear rate range of 900 to 1,000 (1 / s) in Figure 19a.

[0249] [Table 23]

[0250] In addition, when the injection preparation of Preparation Example E' was left to stand for 5 days at 5°C, 25°C or 40°C, only the preparation stored at 40°C gelled (the injection preparation that was slowly turned horizontal after storage A photograph of the container containing the above is shown in Figure 19b. In the diagram, Example E' is sometimes referred to as "Povidone K17 4.0 mg / mL."

[0251] Test Example 11 Using 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one dihydrate as an active ingredient, an injectable preparation (preparation) having the composition shown in Table 24 below was prepared in the same manner as in Preparation Examples A1 and A2 in Test Example 1. Examples M1 and M2) were prepared. The [1H-piperazin-1-yl]butoxy-1H-quinolin-2-one dihydrate used was that prepared in Synthesis Example 1 below.

[0252] The injection preparations of Production Examples M1 and M2, even if gelled, turned into a sol by simply shaking lightly by hand. The average particle size measurement results of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one dihydrate were as follows. The average primary particle size of Production Example M1 was 8.8 μm, and the average secondary particle size was 10.8 μm. The average primary particle size of Production Example M2 was 8.3 μm, and the average secondary particle size was 10.2 μm.

[0253] [Table 24]

[0254] After standing at 5° C., the viscosity of the injection preparations of Production Examples M1 and M2 was measured. Specifically, the preparation of Production Example M2 that was stood at 5° C. was in a sol state, but both the preparations of Production Examples M1 and M2 were shaken by hand to confirm that they were in a sol state, and then subjected to a rheometer, and viscosity measurements were performed at 5° C., 25° C., or 40° C. (measurement temperature) in the same manner as in Test Example 1.

[0255] The results of the viscosity measurement are shown in Figure 20a. Table 25 shows specific values ​​of the viscosity measured in the shear rate range of 0.01 to 0.02 (1 / s) and the viscosity measured in the shear rate range of 900 to 1,000 (1 / s) in Figure 20a.

[0256] [Table 25]

[0257] In addition, after the preparation of the injectable formulations of Manufacturing Examples M1 and M2, they were stored at 5°C, 25°C, or 40°C for 5 days. All of them gelled except for the formulation of Manufacturing Example M2 stored at 5°C (Figure 20b shows a photograph of the container containing the injectable formulation that was slowly turned over and then horizontally placed after being left to stand for 5 days). In the explanation of Test Example 11, Production Example M1 is referred to as "Povidone K17 0.1 mg / mL" and Production Example M2 is sometimes written as "Povidone K17 1.0 mg / mL."

[0258] Synthesis Example 1 Methanol (149 L), 7-hydroxy-1H-quinolin-2-one (14.87 kg), and potassium hydroxide (6.21 kg) were mixed in a reaction vessel, and the resulting mixture was stirred. After dissolution, 1-bromo-4-chlorobutane (47.46 kg) was added and stirred under reflux for 7 hours. Then, the mixture was stirred at 10°C for 1 hour. The precipitated crystals were centrifuged and washed with methanol (15 L), and the wet crystals were taken out and placed in a tank. Water (149 L) was added, and the mixture was stirred at room temperature. The mixture was stirred at 10°C. After centrifugation and washing with water (30 L), the wet crystals were taken out and charged into a tank. Methanol (74 L) was added and the mixture was stirred under reflux for 1 hour, then cooled to 10°C and stirred. The precipitated crystals were centrifuged and washed with methanol (15 L). The separated crystals were dried at 60°C to obtain 7-(4-chlorobutoxy)-1H-quinolin-2-one (15.07 kg).

[0259] Next, water (20 L), potassium carbonate (1.84 kg), 1-benzo[b]thiophen-4-yl-piperazine hydrochloride (3.12 kg), and ethanol (8 L) were mixed in a reaction vessel and stirred at 50° C., and 7-(4-chlorobutoxy)-1H-quinolin-2-one (2.8 The mixture was mixed with 100 kg of water and stirred under reflux for 9 hours. The solvent was concentrated to 8 L at normal pressure, and the mixture was stirred at 90°C for 1 hour. After cooling to 9°C, the precipitated crystals were centrifuged and then mixed with water (8 L) and ethanol (6 L). The separated crystals were dried at 60°C to obtain a crude product. The crude product (4.82 kg) and ethanol (96 L) were mixed in a reaction vessel, and acetic acid (4.8 L) was poured in. The mixture was refluxed for 1 hour. The crude product was dissolved by stirring for 1 hour. Hydrochloric acid (1.29 kg) was added and the mixture was cooled to 10°C. The mixture was heated again and refluxed for 1 hour, and then cooled to 7°C. The precipitated crystals were centrifuged and separated into ethanol (4. The separated crystals were dried at 60°C and washed with 7-[4-(4-benzo[b]thiophene The resulting 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one hydrochloride (5.00 kg) was obtained. g), ethanol (45 L), and 30 L of water were mixed in a reaction vessel and stirred under reflux to obtain 7-[4-( 4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one·hydrochloride was dissolved in the mixture. Activated carbon (500g) and water (5L) were added and the mixture was treated with activated carbon under reflux for 30 minutes. After hot filtration, the filtrate was stirred under reflux and a solution of sodium hydroxide (511g) in water (1.5L) was poured into the reaction vessel. After stirring for 30 minutes under reflux, water (10L) was poured in, and the mixture was cooled to around 40°C. The precipitated crystals were centrifuged and washed with water (125L). The separated crystals were dried at 80°C to obtain 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one (3.76kg).

[0260] The obtained 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one (3.2 kg), ethanol (64 L), water (7 The mixture was mixed with acetic acid (1.77 kg) and 4 L of acetic acid in a reaction vessel to prepare an acidic mixture. The 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one was dissolved by refluxing while stirring (reflux temperature: 8 After cooling to -5°C, the resulting solution was poured into a solution of 25% sodium hydroxide (5.9 kg) and water (54 L) cooled to 0°C over 30 minutes while stirring to prepare a mixed solution with a pH of 10. After stirring at 5°C or less for 1 hour, the mixed solution was heated to 20°C to 30°C and stirred for an additional 7 hours to separate the solid and liquid. The mixture was stirred until the alkali in the obtained solid disappeared (specifically The solid was air-dried to constant weight (i.e., no further weight change) and isolated as a white solid 7-[ 4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one dihydrate (unground, 3.21 kg) was obtained.

Claims

1. A poorly soluble drug, a dispersion medium, and a suspending agent are included, The suspending agent is at least one suspending agent selected from the group consisting of: (i) and (ii) (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof When the viscosity is measured by a rheometer, Shearing rate 0.01~0.02s －1 At least one point in the range of 40 Pa·s or more The value is measured, Shearing rate 900-1,000s －１ A value of 0.2 Pa s or less is measured at at least one point in the range. composition 13. An injectable formulation comprising:

2. A poorly soluble drug, a dispersion medium, and a suspending agent are included, The suspending agent is at least one suspending agent selected from the group consisting of: (i) and (ii) (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof The viscosity was measured at 25°C using a rheometer. Shearing rate 0.01~0.02s －１ A value of 40 Pa s or more is measured at at least one point in the range, Shearing rate 900-1,000s －１ A value of 0.2 Pa s or less is measured at at least one point in the range. composition 13. An injectable formulation comprising:

3. The injectable formulation according to claim 1 or 2, comprising a composition comprising at least water as a dispersion medium.

4. The injectable preparation according to any one of claims 1 to 3, wherein the poorly soluble drug is aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof.

5. As the poorly soluble drug, aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof, Water, and At least one suspending agent selected from the group consisting of (i) and (ii) below: (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof Including, The poorly soluble drug has an average primary particle size of 0.5 to 30 μm; The concentration of the poorly soluble drug is 200 to 600 mg / mL; Gel composition.

6. (i) polyvinylpyrrolidone as a suspending agent; The concentration of polyvinylpyrrolidone is 0.1 to 100 mg / mL; The composition of claim 5.

7. As a suspending agent, (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof are included; The concentration of polyethylene glycol is 0.05 to 2 mg / mL; The concentration of carboxymethylcellulose or a salt thereof is 0.5 to 50 mg / mL.

7. The composition according to claim 5 or 6.

8. The composition according to any one of claims 5 to 7, comprising as suspending agents (i) polyvinylpyrrolidone, and (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof.

9. The composition according to any one of claims 5 to 8, wherein the average secondary particle size of the poorly soluble drug is no more than three times the average primary particle size.

10. When the viscosity is measured by a rheometer, Shearing rate 0.01~0.02s －１ A value of 40 Pa s or more is measured at at least one point in the range, Shearing rate 900-1,000s －１ A value of 0.2 Pa·s or less is measured at at least one point in the range The composition according to any one of claims 5 to 9.

11. The viscosity was measured at 25°C using a rheometer. Shearing rate 0.01~0.02s －１ A value of 40 Pa s or more is measured at at least one point in the range, Shearing rate 900-1,000s －１ A value of 0.2 Pa·s or less is measured at at least one point in the range The composition according to any one of claims 5 to 9.

12. An injectable formulation comprising the composition according to any one of claims 5 to 11.

13. 200 to 600 mg / mL of aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof, Water, and At least one suspending agent selected from the group consisting of (i) and (ii) below: (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof Including, The average primary particle size of the aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof is 0.5 to 30 μm. Mix the liquid Leave it at 5 to 70°C for at least 5 minutes. Including, A method for producing a gel composition containing aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof.

14. 200 to 600 mg / mL of aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof, Water, and At least one suspending agent selected from the group consisting of (i) and (ii) below: (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof In a mixture containing pulverizing aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof to an average primary particle size of 0.5 to 30 μm; and Allowing the mixed liquid after grinding to stand at 5 to 70°C for 5 minutes or more; Including, The method of claim 13.

15. The mixture contains (i) polyvinylpyrrolidone, The concentration of polyvinylpyrrolidone is 0.1 to 100 mg / mL; 15. The method according to claim 13 or 14.

16. The mixture contains (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof, The concentration of polyethylene glycol is 0.05 to 2 mg / mL; The concentration of carboxymethylcellulose or a salt thereof is 0.5 to 50 mg / mL. The method according to any one of claims 13 to 15.

17. The method according to any one of claims 13 to 16, wherein the mixture comprises (i) polyvinylpyrrolidone, and (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof.

18. A gel composition containing aripiprazole or a salt thereof, obtained by the method according to any one of claims 13 to 17.

19. 200 to 600 mg / mL of aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof; Water, and At least one suspending agent selected from the group consisting of (i) and (ii) below: (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof Including, The average primary particle size of the aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof is 0.5 to 30 μm. Mix the liquid Filling into a syringe; Allowing the mixture to stand at 5 to 70°C for 5 minutes or more; Including, A method for producing a prefilled syringe prefilled with a gel composition containing aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof.

20. Aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof, 00-600mg / mL, Water, and At least one suspending agent selected from the group consisting of (i) and (ii) below: (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof In a mixture containing pulverizing aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof to an average primary particle size of 0.5 to 30 μm; and Filling the mixed liquid after the grinding into a syringe and leaving it at rest at 5 to 70°C for 5 minutes or more; Including, 20. The method of claim 19.

21. The mixture contains (i) polyvinylpyrrolidone, The concentration of polyvinylpyrrolidone is 0.1 to 100 mg / mL; 21. The method of claim 19 or 20.

22. The mixture contains (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof, The concentration of polyethylene glycol is 0.05 to 2 g / mL; The concentration of carboxymethylcellulose or a salt thereof is 0.5 to 50 mg / mL. The method according to any one of claims 19 to 21.

23. The method according to any one of claims 19 to 22, wherein the mixture comprises (i) polyvinylpyrrolidone, and (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof.

24. A pre-filled syringe pre-filled with a gel composition containing aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof, obtained by the method according to any one of claims 19 to 23.

25. A kit comprising the prefilled syringe of claim 24.

26. As the poorly soluble drug, aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof, Water, and At least one suspending agent selected from the group consisting of (i) and (ii) below: (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof The poorly soluble drug has an average primary particle size of 1 to 10 μm; The concentration of the poorly soluble drug is 200 to 400 mg / mL; When left standing, it is in a gel state, but when impacted, it turns into a sol. The composition comprises: A long-acting injectable formulation administered once per month.

27. The injectable preparation according to claim 26, wherein the average primary particle size of the poorly soluble drug is 2 to 7 μm.

28. As the poorly soluble drug, aripiprazole or a salt thereof, or 7-[4-(4-benzo[ b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof, Water, and At least one suspending agent selected from the group consisting of (i) and (ii) below: (i) Polyvinylpyrrolidone (ii) Polyethylene glycol and carboxymethylcellulose or a salt thereof The average primary particle size of the poorly soluble drug is 4 to 30 μm; The concentration of the poorly soluble drug is 300 to 600 mg / mL. The composition comprises: When left standing, it is in a gel state, but when impacted, it turns into a sol. A long-acting injectable formulation administered once every 2 or 3 months.

29. The injectable preparation according to claim 28, wherein the average primary particle size of the poorly soluble drug is 5 to 20 μm.

30. The composition contains the (i) polyvinylpyrrolidone as a suspending agent, The concentration of polyvinylpyrrolidone is 0.1 to 100 mg / mL; The injectable preparation according to any one of claims 26 to 29.

31. The suspension contains the above-mentioned (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof as a suspending agent, The concentration of polyethylene glycol is 0.05 to 2 mg / mL; The concentration of carboxymethylcellulose or a salt thereof is 0.5 to 50 mg / mL. The injectable preparation according to any one of claims 26 to 30.

32. The injectable formulation according to any one of claims 26 to 31, comprising, as a suspending agent, (i) polyvinylpyrrolidone, and (ii) polyethylene glycol and carboxymethylcellulose or a salt thereof.

33. The injectable preparation according to any one of claims 26 to 32, wherein the average secondary particle size of the poorly soluble drug is 3 times or less than the average primary particle size.

34. The composition, When the viscosity is measured by a rheometer, Shearing rate 0.01~0.02s －１ A value of 40 Pa s or more is measured at at least one point in the range, Shearing rate 900-1,000s －１ A value of 0.2 Pa·s or less is measured at at least one point in the range The injectable preparation according to any one of claims 26 to 33, which is a composition.

35. The composition, The viscosity was measured at 25°C using a rheometer. Shearing rate 0.01~0.02s －１ A value of 40 Pa s or more is measured at at least one point in the range, Shearing rate 900-1,000s －１ A value of 0.2 Pa·s or less is measured at at least one point in the range The injectable preparation according to any one of claims 26 to 33, which is a composition.

36. A method for treating or preventing recurrence of schizophrenia, bipolar disorder, or depression, comprising administering the injectable preparation according to any one of claims 1 to 4, 12, and 26 to 35.

37. 37. The method of claim 36, wherein the injectable formulation is administered intramuscularly or subcutaneously.

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