HK40065261B - Injectable preparation - Google Patents

Description

Injectable formulations

This application is a divisional application of Chinese invention patent application 201810143716.5, filed on April 23, 2013, entitled "Injectable Preparation".

Technical Field

This invention relates to injectable formulations comprising a poorly soluble drug (such as aripiprazole or a salt thereof), a specific suspending agent, and a dispersion medium in a dispersion medium, and also to pre-filled syringes containing said injectable formulations.

Background Technology

Aripiprazole, used as the active ingredient in pharmaceutical compositions, is a compound represented by the following structural formula:

Drug compositions containing aripiprazole are known as atypical antipsychotics and are used to treat schizophrenia.

Pharmaceutical compositions containing aripiprazole as an active ingredient are known to be used, for example, in the following manner. Prior to use, a block composition (which is prepared by suspending aripiprazole and an excipient therefor in a dispersion medium and freeze-drying the suspension) is mixed with a desired dispersant (preferably water for injection) and resuspended, and the resuspended (injectable formulation) is injected intramuscularly or subcutaneously into the patient (see, for example, Patent Documents 1 and 2).

The forms of pharmaceutical compositions disclosed in patent documents (PTLs) 1 and 2 require vials containing the block composition, containers containing a dispersing medium, and syringes for administration to patients. Therefore, there is a need for pharmaceutical formulations that simplify the structure of the medical device used, reduce its size and weight, and are easier to use.

Reference List

Patent documents

PTL 1: US Patent No. 5006528

PTL 2: JP2007-509148A

Summary of the Invention

Technical issues

To obtain a pharmaceutical formulation that simplifies the structure of the medical device used, reduces its size and weight, and is more convenient to use, it is possible to develop pre-filled syringes, for example, by directly filling the suspension (injectable formulation) into a syringe. However, when the suspension contains a poorly soluble drug (hereinafter also referred to as "poorly soluble drug") such as aripiprazole or its salt as the active ingredient, the active ingredient particles precipitate over time, leading to clumping and making it difficult to redisperse the suspension. Even if the suspension can be redispersed, redispersibility requires vigorous shaking, for example, by using a device, which is inconvenient clinically. Therefore, there is a need for an injectable formulation that contains a poorly soluble drug as the active ingredient and has storage stability that prevents clumping due to particle precipitation over time.

One object of the present invention is to provide a highly storage-stable injectable formulation comprising a poorly soluble drug as an active ingredient and a dispersion medium. More specifically, an object of the present invention is to provide an injectable formulation that readily provides a suspension in which the active ingredient is well dispersed upon use (administration to a patient) and does not clump due to precipitation of the poorly soluble drug even after prolonged storage.

Another object of the present invention is to provide a more compact and lightweight pre-filled syringe by filling the syringe with the above-described injectable formulation. More preferably, an object of the present invention is to provide a more compact and lightweight pre-filled syringe that achieves the effect of applying a low-viscosity suspension by simply squeezing the plunger rod of the syringe through the syringe needle after gentle agitation of the syringe, or without agitation.

Solution to the problem

To achieve the above objectives, the inventors of this invention conducted intensive research. As a result, the inventors discovered that when an injectable formulation containing a poorly soluble drug as an active ingredient also contains a dispersing medium and a specific suspending agent (hereinafter also referred to as suspending agent A), clumping due to precipitation of the active ingredient can be prevented even during prolonged storage after production (e.g., until administration to a patient). The inventors of this invention conducted further research and completed this invention.

This invention includes the subject matter presented in the following terms.

Item 1. An injectable formulation comprising a poorly soluble drug, a dispersing medium, and a suspending agent,

The suspending agent is selected from at least one of (i) and (ii):

(i) polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts.

When measured by a rheometer, the viscosity of the composition is 40 Pa·s or higher at at least one point in the shear rate range of 0.01 to 0.02 ^s⁻¹ , and 0.2 Pa·s or lower at at least one point in the shear rate range of 900 to 1000 ^s⁻¹ .

Item 2. An injectable formulation comprising a poorly soluble drug, a dispersing medium, and a suspending agent,

The suspending agent is selected from at least one of (i) and (ii):

(i) Polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts.

When measured by a rheometer at 25°C, the viscosity of the composition is 40 Pa·s or higher at at least one point in the shear rate range of 0.01 to 0.02 ^s⁻¹ , and 0.2 Pa·s or lower at at least one point in the shear rate range of 900 to 1000 ^s⁻¹ , for example.

Item 3. An injectable formulation comprising a composition according to Item 1 or 2, wherein the composition comprises at least water as a dispersion medium.

Item 4. The injectable formulation 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]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof.

Item 4a. The injectable formulation 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.

Item 4b. An injectable formulation according to any one of items 1 to 4 and 4a, wherein the average secondary particle size of said poorly soluble drug may be up to but not exceed 3 times its average primary particle size.

Item 5. A gel composition, said composition comprising:

Poorly soluble drugs, namely aripiprazole or its salts, or 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or its salts,

Water, and

At least one suspending agent selected from (i) and (ii):

(i) Polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts.

The poorly soluble drug has an average primary particle size of 0.5 to 30 μm and is contained at a concentration of 200 to 600 mg/mL.

Item 5a. The gel composition according to item 5, comprising:

aripiprazole or its salts

Water, and

At least one suspending agent selected from (i) and (ii):

(i) Polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts.

The aripiprazole or its salt thereof has an average primary particle size of 0.5 to 30 μm and is contained at a concentration of 200 to 600 mg/mL.

Item 5b. The gel composition according to item 5, comprising

7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof,

Water, and

At least one suspending agent selected from (i) and (ii):

(i) polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts.

The 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or its salts thereof have an average primary particle size of 0.5 to 30 μm and are contained at a concentration of 200 to 600 mg/mL.

Item 6. The composition according to Item 5, 5a or 5b, wherein (i) polyvinylpyrrolidone is contained as a suspending agent at a concentration of 0.1 to 100 mg/mL.

Item 7. The composition according to any one of items 5 to 6, wherein (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof are contained as a suspending agent.

The concentration of polyethylene glycol is 0.05 to 2 mg/mL, and the concentration of carboxymethyl cellulose or its salt is 0.5 to 50 mg/mL.

(The phrase "according to any one of items 5 to…" includes items 5, 5a, and 5b. The same applies below.)

Item 8. The composition according to any one of items 5 to 7, wherein (i) polyvinylpyrrolidone and (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof are contained as a suspending agent.

Item 8a. The composition according to item 5 or 6, wherein (i) polyvinylpyrrolidone and (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof are contained as a suspending agent, and the concentration of polyethylene glycol is from 0.05 to 100 mg/mL.

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 may be up to but not exceed 3 times its average primary particle size.

Item 10. The composition according to any one of items 5 to 9, when measured by a rheometer, has a viscosity of 40 Pa·s or higher at at least one point in the shear rate range of 0.01 to 0.02 ^s⁻¹ , and a viscosity of 0.2 Pa·s or lower at at least one point in the shear rate range of 900 to 1000 ^s⁻¹ , as is the case.

Item 11. The composition according to any one of items 5 to 9, when measured by a rheometer at 25°C, has a viscosity of 40 Pa·s or higher at at least one point in the shear rate range of 0.01 to 0.02 ^s⁻¹ , and a viscosity of 0.2 Pa·s or lower at at least one point in the shear rate range of 900 to 1000 ^s⁻¹ .

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

Item 13. A method for producing a gel composition comprising aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof, the method comprising:

The following liquid mixture is allowed to stand at 5 to 70°C for 5 minutes or longer, wherein the liquid mixture contains aripiprazole or a salt thereof at a concentration of 200 to 600 mg/mL, or 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof, water, and at least one suspending agent selected from (i) and (ii):

(i) Polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts.

Furthermore, the average primary particle size of aripiprazole or its salts, or 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or its salts, is 0.5 to 30 μm.

Item 13a. A method for producing a gel composition comprising aripiprazole or a salt thereof according to item 13, said method comprising:

The following liquid mixture is allowed to stand at 5 to 70°C for 5 minutes or longer, wherein the liquid mixture contains aripiprazole or a salt thereof at a concentration of 200 to 600 mg/mL, water, and at least one suspending agent selected from (i) and (ii):

(i) polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts.

Furthermore, the average primary particle size of aripiprazole or its salts is 0.5 to 30 μm.

Item 13b. The method according to Item 13 for producing a gel composition comprising 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof, said method comprising:

The following liquid mixture is allowed to stand at 5 to 70°C for 5 minutes or longer, wherein the liquid mixture contains 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof at a concentration of 200 to 600 mg/mL, water, and at least one suspending agent selected from (i) and (ii):

(i) polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts.

Furthermore, the average primary particle size of 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or its salts is 0.5 to 30 μm.

Item 14. The method according to Item 13, comprising: pulverizing aripiprazole or a salt thereof or 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof to an average primary particle size of 0.5 to 30 μm in a liquid mixture comprising aripiprazole or a salt thereof or 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof at a concentration of 200 to 600 mg/mL, water, and at least one suspending agent selected from (i) and (ii):

(i) Polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts.

Additionally, the pulverized liquid mixture should be allowed to stand at 5 to 70°C for 5 minutes or longer.

Item 14a. A method for producing a gel composition comprising aripiprazole or a salt thereof according to Item 14, comprising: pulverizing aripiprazole or a salt thereof to an average primary particle size of 0.5 to 30 μm in a liquid mixture comprising aripiprazole or a salt thereof at a concentration of 200 to 600 mg/mL, water, and at least one suspending agent selected from (i) and (ii):

(i) Polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts.

Additionally, allow the pulverized liquid mixture to stand at 5 to 70°C for 5 minutes or longer.

Item 14b. A method according to Item 14 for producing a gel composition comprising 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof, comprising: pulverizing 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof to an average primary particle size of 0.5 to 30 μm in a liquid mixture comprising 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof at a concentration of 200 to 600 mg/mL, water, and at least one suspending agent selected from (i) and (ii):

(i) polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts.

Additionally, allow the pulverized liquid mixture to stand at 5 to 70°C for 5 minutes or longer.

Item 15. The method according to Items 13, 13a, 13b, 14, 14a or 14b, wherein the liquid mixture comprises (i) polyvinylpyrrolidone at a concentration of 0.1 to 100 mg/mL.

Item 16. The method according to items 13, 13a, 13b, 14, 14a, 14b or 15, wherein the liquid mixture comprises (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof.

The concentration of the polyethylene glycol is from 0.05 to 2 mg/mL, and the concentration of the carboxymethyl cellulose or its salt is from 0.5 to 50 mg/mL.

Item 17. The method according to any one of items 13 to 16, wherein the liquid mixture comprises: (i) polyvinylpyrrolidone, and (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof.

Item 17a. The method according to any one of items 13 to 15, wherein the liquid mixture comprises: (i) polyvinylpyrrolidone, and (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof.

The concentration of polyethylene glycol is 0.05 to 100 mg/mL.

(The phrases “items 13 to 15” and “items 13 to 16” above include items 13a, 13b, 14a, and 14b.)

Item 18. A gel composition comprising aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof, said composition being obtained by the method according to any one of items 13 to 17.

(The phrase “items 13 to 17” also includes items 13a, 13b, 14a, 14b and 17a.)

Item 19. A method for producing a pre-filled syringe pre-filled with a gel composition comprising aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof.

The method includes:

The following liquid mixture is filled into a syringe, the liquid mixture comprising aripiprazole or a salt thereof or 7-[4-(4-benzo[b]thiophene-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 (i) and (ii):

(i) polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts.

The aripiprazole or its salt, or 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or its salt, has an average primary particle size of 0.5 to 30 μm; and

The liquid mixture is allowed to stand at 5 to 70°C for 5 minutes or longer.

Item 19a. The method for producing a pre-filled syringe pre-filled with a gel composition containing aripiprazole or a salt thereof, according to item 19.

The method includes:

The following liquid mixture is filled into a syringe, the liquid mixture comprising aripiprazole or its saline at a concentration of 200 to 600 mg/mL, water, and at least one suspending agent selected from (i) and (ii):

(i) polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts.

The aripiprazole or its salts thereof have an average primary particle size of 0.5 to 30 μm; and

The liquid mixture is allowed to stand at 5 to 70°C for 5 minutes or longer.

Item 19b. The method for producing a pre-filled syringe pre-filled with a gel composition comprising 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof, according to Item 19.

The method includes:

The following liquid mixture is filled into a syringe, the liquid mixture comprising 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof at a concentration of 200 to 600 mg/mL, water, and at least one suspending agent selected from (i) and (ii):

(i) polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts.

The 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof has an average primary particle size of 0.5 to 30 μm; and

The liquid mixture is allowed to stand at 5 to 70°C for 5 minutes or longer.

Item 20. The method according to item 19, comprising:

In a liquid mixture, aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof, is pulverized to an average primary particle size of 0.5 to 30 μm, wherein the liquid mixture comprises aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof, at a concentration of 200 to 600 mg/mL, water, and at least one suspending agent selected from (i) and (ii):

(i) polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts; and

The pulverized liquid mixture is loaded into a syringe and left to stand at 5 to 70°C for 5 minutes or longer.

Item 20a. The method for producing a pre-filled syringe pre-filled with a gel composition containing aripiprazole or a salt thereof, according to item 20.

The method includes:

Aripiprazole or its salt is pulverized to an average primary particle size of 0.5 to 30 μm in a liquid mixture comprising aripiprazole or its salt at a concentration of 200 to 600 mg/mL, water, and at least one suspending agent selected from (i) and (ii):

(i) polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts; and

The pulverized liquid mixture is loaded into a syringe and left to stand at 5 to 70°C for 5 minutes or longer.

Item 20b. The method for producing a pre-filled syringe pre-filled with a gel composition comprising 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof, according to Item 20.

The method includes:

In a liquid mixture, 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof is pulverized to an average primary particle size of 0.5 to 30 μm, said liquid mixture comprising 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof at a concentration of 200 to 600 mg/mL, water, and at least one suspending agent selected from (i) and (ii):

(i) Polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts; and

The pulverized liquid mixture is loaded into a syringe and left to stand at 5 to 70°C for 5 minutes or longer.

Item 21. The method according to Items 19, 19a, 19b, 20, 20a or 20b, wherein the liquid mixture comprises (i) polyvinylpyrrolidone, and (i) the concentration of polyvinylpyrrolidone is from 0.1 to 100 mg/mL.

Item 22. The method according to any one of items 19 to 21, wherein the liquid mixture comprises (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof, wherein the concentration of polyethylene glycol is from 0.05 to 2 g/mL and the concentration of carboxymethyl cellulose or a salt thereof is from 0.5 to 50 mg/mL.

Item 23. The method according to any one of items 19 to 22, wherein the liquid mixture comprises: (i) polyvinylpyrrolidone, and (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof.

Item 23a. The method according to any one of items 19 to 21, wherein the liquid mixture comprises: (i) polyvinylpyrrolidone and (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof, wherein the concentration of polyethylene glycol is from 0.05 to 100 mg/mL.

(The phrases “items 19 to 21” and “items 19 to 22” also include items 19a, 19b, 20a, and 20b.)

Item 24. A pre-filled syringe containing a gel composition comprising aripiprazole or a salt thereof or 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof, said syringe being obtained by the method according to any one of items 19 to 23 and 23a.

Item 25. A kit comprising a pre-filled syringe as described in Item 24.

Item 26. A sustained-release injectable formulation comprising the following composition, wherein the composition comprises:

Poorly soluble drugs, namely aripiprazole or its salts, or 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or its salts,

Water, and

At least one suspending agent selected from (i) and (ii):

(i) Polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts.

The poorly soluble drug has an average primary particle size of 1 to 10 μm and is contained at a concentration of 200 to 400 mg/mL.

The composition exists in gel form when left to stand, and changes into a sol upon impact.

The preparation is applied once a month.

Item 27. The injectable formulation according to Item 26, wherein the poorly soluble drug has an average primary particle size of 2 to 7 μm.

Item 28. A sustained-release injectable formulation comprising the following composition, wherein the composition comprises:

Poorly soluble drugs, namely aripiprazole or its salts, or 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or its salts,

Water, and

At least one suspending agent selected from (i) and (ii):

(i) Polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts.

The poorly soluble drug has an average primary particle size of 4 to 30 μm and is contained at a concentration of 300 to 600 mg/mL.

The composition exists in gel form when left to stand, and changes into a sol upon impact.

The preparation is applied once every 2 or 3 months.

Item 29. The injectable formulation according to Item 28, wherein the poorly soluble drug has an average primary particle size of 5 to 20 μm.

Item 30. The injectable formulation according to any one of items 26 to 29, wherein the suspending agent comprises (i) polyvinylpyrrolidone at a concentration of 0.1 to 100 mg/mL.

Item 31. The injectable formulation according to any one of items 26 to 30, wherein it comprises (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof as a suspending agent, wherein the concentration of polyethylene glycol is 0.05 to 2 mg/mL and the concentration of carboxymethyl cellulose or a salt thereof is 0.5 to 50 mg/mL.

Item 32. The injectable formulation according to any one of items 26 to 31, wherein it comprises (i) polyvinylpyrrolidone and (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof as a suspending agent.

Item 33. The injectable formulation according to any one of items 26 to 32, wherein the average secondary particle size of the poorly soluble drug may be up to but not exceed three times its average primary particle size.

Item 34. The injectable formulation according to any one of items 26 to 33, wherein, when measured by a rheometer, the viscosity of the composition is 40 Pa·s or higher at at least one point in the shear rate range of 0.01 to 0.02 ^s⁻¹ , and the viscosity is 0.2 Pa·s or lower at at least one point in the shear rate range of 900 to 1000 ^s⁻¹ .

Item 35. The injectable formulation according to any one of items 26 to 33, wherein, when measured by a rheometer at 25°C, the viscosity of the composition is 40 Pa·s or higher at at least one point in the shear rate range of 0.01 to 0.02 ^s⁻¹ , and the viscosity is 0.2 Pa·s or lower at at least one point in the shear rate range of 900 to 1000 ^s⁻¹ .

Item 36. A method for treating schizophrenia, bipolar disorder, or depression, or for preventing relapse of schizophrenia, bipolar disorder, or depression, said method comprising administering an injectable formulation according to any one of items 1 to 4, 12, and 26 to 35.

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

Item A-1. A storage-stable aqueous suspension injectable formulation comprising a poorly soluble drug, a specific suspending agent (suspending agent A), and a dispersion medium; said suspension having a high viscosity when left to stand and a low viscosity when shaken or extruded through a syringe needle.

Item A-2. The injectable formulation according to Item A-1 has a viscosity of 1000 mPa·s or higher when left to stand, and a viscosity of 300 mPa·s or lower when vibrated or extruded through a syringe needle.

Item A-3. The injectable formulation according to Item A-1 or A-2 has a viscosity of 5000 mPa·s or higher when left to stand, and a viscosity of 300 mPa·s or lower when vibrated or extruded through a syringe needle.

Item A-4. The injectable formulation according to any one of items A-1 to A-3, having a viscosity of 10,000 mPa·s or higher when standing, and a viscosity of 300 mPa·s or lower when vibrated or extruded through a syringe needle.

Item A-5. The injectable formulation according to Item A-1 or A-2 has a viscosity of 1000 mPa·s or higher when left to stand, and a viscosity of 200 mPa·s or lower when vibrated or extruded through a syringe needle.

Item A-6. The injectable formulation according to Items A-1, A-2, A-3 or A-5 has a viscosity of 5000 mPa·s or higher when left to stand, and a viscosity of 200 mPa·s or lower when vibrated or extruded through a syringe needle.

Item A-7. The injectable formulation according to any one of items A-1 to A-6, having a viscosity of 10,000 mPa·s or higher when standing, and a viscosity of 200 mPa·s or lower when vibrated or extruded through a syringe needle.

Item A-8. The injectable preparation according to any one of items A-1 to A-7, comprising a poorly soluble drug at a concentration of 100 to 500 mg/mL.

Item A-9. The injectable preparation according to any one of items A-1 to A-8, comprising a poorly soluble drug at a concentration of 200 to 480 mg/mL.

Item A-10. The injectable preparation according to any one of items A-1 to A-9, comprising a poorly soluble drug at a concentration of 250 to 450 mg/mL.

Item A-11. An injectable formulation according to any one of items A-1 to A-10, comprising a poorly soluble drug at a concentration of about 300 mg/mL or higher, and which, when left to stand, becomes a gel, wherein the gel composition becomes a liquid sol upon stirring, shaking, external impact, etc.

Item A-12. The injectable formulation according to any one of items A-1 to A-11, wherein the poorly soluble drug has an average primary particle size of about 0.5 to 30 μm.

Item A-13. The injectable formulation according to any one of items A-1 to A-12, wherein the poorly soluble drug has an average primary particle size of about 1.0 to 10 μm.

Item A-14. The injectable formulation according to any one of items A-1 to A-13, wherein the poorly soluble drug has an average primary particle size of about 1.0 to 5 μm.

Item A-15. An injectable formulation according to any one of items A-1 to A-14, wherein the poorly soluble drug is aripiprazole or a salt thereof, the formulation comprising a composition containing a dispersing medium and at least one suspending agent selected from polyvinylpyrrolidone and polyethylene glycol.

Item A-16. The injectable formulation according to item A-15, wherein the poorly soluble drug is aripiprazole monohydrate.

Item A-17. The injectable formulation according to Item A-15 or A-16, wherein the poorly soluble drug is aripiprazole or a salt thereof, the formulation is storage stable, and comprises a composition containing sodium carboxymethyl cellulose, a dispersing medium, and at least one suspending agent selected from polyvinylpyrrolidone and polyethylene glycol.

Item A-18. A pre-filled syringe comprising an injectable formulation according to any one of items A-1 to A-17.

The expression "to comprise" as used in this article also includes the meanings of "basically composed of" and "composed of".

This application relates to the following:

1. An injectable formulation comprising a composition comprising a poorly soluble drug, a dispersing medium, and a suspending agent, wherein the suspending agent is at least one selected from the group consisting of (i) and (ii):

(i) Polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts.

The viscosity of the composition, as measured by a rheometer, is 40 Pa·s or higher at at least one point in the shear rate range of 0.01 to 0.02 ^s⁻¹ , and 0.2 Pa·s or lower at at least one point in the shear rate range of 900 to 1000 ^s⁻¹ .

2. An injectable formulation comprising a composition comprising a poorly soluble drug, a dispersing medium, and a suspending agent, wherein the suspending agent is at least one selected from the group consisting of (i) and (ii):

(i) Polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts.

The viscosity of the composition, measured by a rheometer at 25°C, is 40 Pa·s or higher at at least one point in the shear rate range of 0.01 to 0.02 ^s⁻¹ , and 0.2 Pa·s or lower at at least one point in the shear rate range of 900 to 1000 ^s⁻¹ .

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

4. An injectable formulation 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]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof.

5. A gel composition comprising:

Poorly soluble drugs, namely aripiprazole or its salts, or 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or its salts,

Water, and

At least one suspending agent, said suspending agent being selected from the group consisting of (i) and (ii):

(i) Polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts.

The poorly soluble drug has an average primary particle size of 0.5 to 30 μm and is contained at a concentration of 200 to 600 mg/mL.

6. The composition according to claim 5, wherein (i) polyvinylpyrrolidone is contained as a suspending agent at a concentration of 0.1 to 100 mg/mL.

7. The composition according to item 5 or 6, wherein (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof are contained as a suspending agent.

The concentration of polyethylene glycol is 0.05 to 2 mg/mL, and the concentration of carboxymethyl cellulose or its salt is 0.5 to 50 mg/mL.

8. The composition according to any one of items 5 to 7, wherein (i) polyvinylpyrrolidone and (ii) polyethylene glycol and carboxymethyl cellulose or their salts are contained as suspending agents.

9. The composition according to any one of items 5 to 8, wherein the average secondary particle size of the poorly soluble drug is up to but does not exceed three times its average primary particle size.

10. The composition according to any one of items 5 to 9, as measured by a rheometer, has a viscosity of 40 Pa·s or higher at at least one point in a shear rate range of 0.01 to 0.02 ^s⁻¹ , and a viscosity of 0.2 Pa·s or lower at at least one point in a shear rate range of 900 to 1000 ^s⁻¹ .

11. The composition according to any one of items 5 to 9, when measured by a rheometer at 25°C, has a viscosity of 40 Pa·s or higher at at least one point in a shear rate range of 0.01 to 0.02 ^s⁻¹ , and a viscosity of 0.2 Pa·s or lower at at least one point in a shear rate range of 900 to 1000 ^s⁻¹ .

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

13. A method for producing a gel composition comprising aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof, the method comprising:

The liquid mixture is allowed to stand at 5 to 70°C for 5 minutes or longer, the liquid mixture comprising aripiprazole or a salt thereof or 7-[4-(4-benzo[b]thiophene-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):

(i) Polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts.

Furthermore, aripiprazole or its salts or 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or their salts have an average primary particle size of 0.5 to 30 μm.

14. The method according to item 13, comprising:

In the following liquid mixture, aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof, is pulverized to an average primary particle size of 0.5 to 30 μm, the liquid mixture comprising aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-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):

(i) Polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts.

Additionally, the pulverized liquid mixture should be left to stand at 5 to 70°C for 5 minutes or longer.

15. The method according to item 13 or 14, wherein the liquid mixture comprises (i) polyvinylpyrrolidone, and (i) the concentration of polyvinylpyrrolidone is from 0.1 to 100 mg/mL.

16. The method according to any one of items 13 to 15, wherein the liquid mixture comprises (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof.

The concentration of polyethylene glycol is 0.05 to 2 mg/mL, and the concentration of carboxymethyl cellulose or its salt is 0.5 to 50 mg/mL.

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

18. A gel composition comprising aripiprazole or a salt thereof, said composition being obtained by the method according to any one of items 13 to 17.

19. A method for producing a pre-filled syringe pre-filled with a gel composition comprising aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof.

The method includes:

The following liquid mixture is filled into a syringe, the liquid mixture comprising aripiprazole or a salt thereof or 7-[4-(4-benzo[b]thiophene-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):

(i) Polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts.

The aripiprazole or its salt, or 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or its salt, has an average primary particle size of 0.5 to 30 μm; and

The liquid mixture is allowed to stand at 5 to 70°C for 5 minutes or longer.

20. The method according to item 19, comprising:

In the following liquid mixture, aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof, is pulverized to an average primary particle size of 0.5 to 30 μm, said liquid mixture comprising aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-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):

(i) Polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts; and

The pulverized liquid mixture is loaded into a syringe and left to stand at 5 to 70°C for 5 minutes or longer.

21. The method according to item 19 or 20, wherein the liquid mixture comprises (i) polyvinylpyrrolidone, and (i) the concentration of polyvinylpyrrolidone is from 0.1 to 100 mg/mL.

22. The method according to any one of items 19 to 21, wherein the liquid mixture comprises (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof, wherein the concentration of polyethylene glycol is from 0.05 to 2 g/mL and the concentration of carboxymethyl cellulose or a salt thereof is from 0.5 to 50 mg/mL.

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

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

25. A kit comprising a pre-filled syringe as described in item 24.

26. A sustained-release injectable formulation, wherein the formulation comprises the following composition:

Poorly soluble drugs, namely aripiprazole or its salts, or 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or its salts,

Water, and

Choose at least one suspending agent from the group consisting of (i) and (ii):

(i) Polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts.

The poorly soluble drug has an average primary particle size of 1 to 10 μm and is contained at a concentration of 200 to 400 mg/mL.

The composition exists in gel form when left to stand, and changes into a sol upon impact.

The preparation is applied once a month.

27. The injectable formulation according to item 26, wherein the poorly soluble drug has an average primary particle size of 2 to 7 μm.

28. A sustained-release injectable formulation, wherein the formulation comprises the following composition:

Poorly soluble drugs, namely aripiprazole or its salts, or 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or its salts,

Water, and

Choose at least one suspending agent from the group consisting of (i) and (ii):

(i) Polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts.

The poorly soluble drug has an average primary particle size of 4 to 30 μm and is contained at a concentration of 300 to 600 mg/mL.

The composition exists in gel form when left to stand, and changes into a sol upon impact.

The preparation is applied once every 2 or 3 months.

29. The injectable formulation according to item 28, wherein the poorly soluble drug has an average primary particle size of 5 to 20 μm.

30. An injectable formulation according to any one of items 26 to 29, wherein (i) polyvinylpyrrolidone is contained as a suspending agent at a concentration of 0.1 to 100 mg/mL.

31. An injectable formulation according to any one of items 26 to 30, wherein (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof are contained as a suspending agent.

The concentration of the polyethylene glycol is from 0.05 to 2 mg/mL, and the concentration of the carboxymethyl cellulose or its salt is from 0.5 to 50 mg/mL.

32. An injectable formulation according to any one of items 26 to 31, wherein (i) polyvinylpyrrolidone and (ii) polyethylene glycol and carboxymethyl cellulose or salts thereof are contained as suspending agents.

33. An injectable formulation according to any one of items 26 to 32, wherein the average secondary particle size of the poorly soluble drug is up to but does not exceed three times its average primary particle size.

34. The injectable formulation according to any one of items 26 to 33, wherein, as measured by a rheometer, the viscosity of the composition at at least one point in a shear rate range of 0.01 to 0.02 ^s⁻¹ is 40 Pa·s or higher, and the viscosity at at least one point in a shear rate range of 900 to 1000 ^s⁻¹ is 0.2 Pa·s or lower.

35. An injectable formulation according to any one of claims 26 to 33, wherein, measured by a rheometer at 25°C, the viscosity of the composition at at least one point in a shear rate range of 0.01 to 0.02 ^s⁻¹ is 40 Pa·s or higher, and the viscosity at at least one point in a shear rate range of 900 to 1000 ^s⁻¹ is 0.2 Pa·s or lower.

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

37. The method according to item 36, wherein the injectable formulation is administered intramuscularly or subcutaneously.

Beneficial effects of the present invention

The injectable formulation of the present invention has excellent storage stability and does not clump due to the precipitation of poorly soluble drug (i.e., active ingredient) particles.

Therefore, there is no need to prepare a suspension during use, and syringe needle clogging is less likely to occur.

More specifically, because (α) the injectable formulations of the present invention form a gel upon standing, precipitation and clumping of poorly soluble drug particles can be suppressed, thereby providing excellent storage stability. Furthermore, because (β) the injectable formulations of the present invention, even in gel form, readily acquire fluidity upon mild impact, they can be easily injected during use (at injection). In particular, since the gelled injectable formulation (gel composition) acquires fluidity (forming a sol state) by simply squeezing the syringe plunger and extruding the formulation through the syringe needle, the formulation can be smoothly extruded directly through the needle. Therefore, at injection time, the formulation can be well dispersed intramuscularly or subcutaneously with relatively little local disturbance and pain.

As described above, the injectable formulation of the present invention exhibits excellent storage stability. This enables the direct filling of the injectable formulation into syringes to prepare pre-filled syringes, thus providing medical devices with reduced size and weight.

Attached Figure Description

Figure 1 shows a photograph taken immediately after production of the injectable formulation obtained in Example 1.

Figure 2 shows a photograph of the injectable formulation obtained in Example 1 being slowly tilted after being left to stand for a certain period of time.

Figure 3 shows a photograph of the injectable formulation obtained in Example 1 after it has been left to stand for a period of time, and then the container is tapped and tilted.

Figure 4a shows photographs of the injectable formulations of production examples A1 to A6, which were stored in transparent containers and left to stand at 5°C for 5 days, after which the containers were slowly tilted and placed horizontally.

Figure 4b shows photographs of the injectable formulations of production examples A1 to A6, which were stored in transparent containers and left to stand at 25°C for 5 days, after which the containers were slowly tilted and placed horizontally.

Figure 4c shows photographs of the injectable formulations of production examples A1 to A6, which were stored in transparent containers and left to stand at 40°C for 5 days, after which the containers were slowly tilted and placed horizontally.

Figure 5a shows the viscosity of the injectable formulations of production examples A1 to A6 as measured using a rheometer (measurement temperature: 5°C).

Figure 5b shows the viscosity of the injectable formulations of production examples A1 to A6 as measured using a rheometer (measurement temperature: 25°C).

Figure 5c shows the viscosity of the injectable formulations of production examples A1 to A6 measured using a rheometer (measurement temperature: 40°C).

Figure 6 shows the viscosity of the injectable formulation of Production Example B, measured using a rheometer at 5°C, 25°C, or 40°C.

Figure 7 shows the viscosity of the injectable formulation of Production Example C, measured using a rheometer at 5°C, 25°C, or 40°C.

Figure 8 shows the viscosity of the injectable formulation of Production Example D, measured using a rheometer at 5°C, 25°C, or 40°C.

Figure 9a shows the viscosity of the injectable formulation of Production Example E, measured using a rheometer at 5°C, 25°C, or 40°C. In this figure, 5d, 25d, and 40d represent measurement temperatures of 5°C, 25°C, and 40°C, respectively.

Figure 9b shows the injectable formulation of Production Example E, stored for 5 days under stable conditions at 5°C, 25°C, or 40°C.

Figure 9c shows the injectable formulation of Production Example E, which was stored for 5 days under stable conditions at 5°C, 25°C, or 40°C (i.e., each shown in Figure 9b), and then the container was slowly tilted and placed horizontally.

Figure 10a shows the viscosity of the injectable formulations of Production Example F1 (povidone K17, 0.1 mg/mL) and Production Example F2 (povidone K17, 4 mg/mL), measured using a rheometer at 5°C or 25°C. In this figure, 5d and 25d represent the measurement temperatures of 5°C and 25°C, respectively.

Figure 10b shows the injectable formulations of Production Example F1 (povidone K17, 0.1 mg/mL) and Production Example F2 (povidone K17, 4 mg/mL) stored under stable conditions at 5°C, 25°C or 40°C for 5 days.

Figure 10c shows the injectable formulations of Production Example F1 (povidone K17, 0.1 mg/mL) and Production Example F2 (povidone K17, 4 mg/mL) after being stored for 5 days under stable conditions at 5°C, 25°C or 40°C (i.e., each shown in Figure 10b), and then the containers were slowly tilted and placed horizontally.

Figure 11 shows the injectable formulations of Production Example G (containing 400 mg/mL ethyl 4-aminobenzoate), Production Example H (containing 300 mg/mL probucol), and Production Example I (containing 300 mg/mL cilostazol), which were stored in transparent containers and allowed to stand for 5 days at 5°C, 25°C, or 40°C, and then the containers were slowly tilted and placed horizontally.

Figure 12 shows the viscosity of the injectable formulation of Production Example G, measured using a rheometer at 5°C, 25°C, or 40°C.

Figure 13 shows the viscosity of the injectable formulation of Production Example H, measured using a rheometer at 5°C, 25°C, or 40°C.

Figure 14 shows the viscosity of the injectable formulation of Production Example I, measured using a rheometer at 5°C, 25°C, or 40°C.

Figure 15 shows the viscosity of the injectable formulation of Production Example J, measured using a rheometer at 5°C, 25°C, or 40°C. In this figure, 5d, 25d, and 40d represent measurement temperatures of 5°C, 25°C, and 40°C, respectively.

Figure 16 is a graph showing the mean serum concentration-time curves after administration of the injectable formulations of Production Example K, Production Example L, Comparative Example 200, and Comparative Example 400 to the cruural muscle of rats (n=4, mean ± standard deviation).

Figure 17 shows the viscosity of the injectable formulations of Production Examples A3 to A6, measured in a rheometer after standing at 40°C for 5 minutes and then returning to 25°C.

Figure 18 shows the viscosity of the injectable formulations of Production Examples B and C, measured in a rheometer after standing at 40°C for 5 minutes and then returning to 25°C. Figure 18 also shows the viscosity measured in Test Example 2 at 5°C or 25°C.

Figure 19a shows the viscosity of the injectable formulations of Production Example E and Production Example E' measured in a rheometer after standing at 40°C for 5 minutes and then returning to 25°C. Figure 19a also shows the viscosity of the injectable formulation of Production Example E' measured at 5°C or 25°C in the same manner as in Test Example 3. Figure 19a also shows the viscosity of the injectable formulation of Production Example E measured at 5°C or 25°C in Test Example 3.

Figure 19b shows the injectable formulation of production example E' (povidone K17, 4 mg/mL) after being stored for 5 days under stable conditions at 5°C, 25°C, or 40°C, and then the container was slowly tilted and placed horizontally. The injectable formulation stored only at 40°C was gelled.

Figure 20a shows the viscosity of the injectable formulations of Production Example M1 and Production Example M2 as measured by a rheometer at 5°C, 25°C, or 40°C.

Figure 20b shows the injectable formulations of Production Example M1 and Production Example M2 after being stored for 5 days under stable conditions at 5°C, 25°C or 40°C, and then the containers were slowly tilted and placed horizontally.

Detailed Implementation

The injectable formulation of the present invention comprises a composition containing a poorly soluble drug, a specific suspending agent (suspending agent (A)), and a dispersion medium. Therefore, in the following explanation, the interpretation of the injectable formulation of the present invention is equivalent to the interpretation of the composition. For example, when explaining that the injectable formulation of the present invention contains a specific component, this means that the injectable formulation of the present invention contains a specific composition containing that specific component. As used herein, "poorly soluble drug" refers to a drug that is poorly soluble in water, corresponding to a drug that is "very slightly soluble" or "hardly soluble" according to the 16th edition of the Japanese Pharmacopoeia. Specifically, the degree of solubility is studied over 30 minutes after placing the drug in water (or, if the drug is in solid form, pulverizing it and then placing it in water) and vigorously shaking it at 20±5°C for 30 seconds. A drug is considered "very slightly soluble" when it requires more than 1000 mL but less than 10000 mL of water to dissolve 1 g or 1 mL of the drug. A drug is considered "hardly soluble" when it requires 10000 mL or more of water.

Poorly soluble drugs included in the injectable formulations of the present invention include, for example, aripiprazole or a salt thereof. Other examples of poorly soluble drugs include 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-ylbutoxy)-1H-quinoline-2-one (hereinafter also referred to as "brexpiprazole") or a salt thereof. Other examples of poorly soluble drugs include rebamipide, cilostazol, probucol, ethyl4-aminobenzoate, etc. These compounds may be in salt form. Aripiprazole or a salt thereof, or 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof, are particularly preferred.

When a poorly soluble drug is in the form of a salt, there are no particular limitations on the salt as long as it is a pharmaceutically usable salt. Examples include alkali metal salts (e.g., sodium and potassium salts); alkaline earth metal salts (e.g., calcium and magnesium salts) and similar metal salts; ammonium salts; alkali metal carbonates (e.g., lithium carbonate, potassium carbonate, sodium carbonate, and cesium carbonate); alkali metal bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate); alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide), and salts of similar inorganic bases; tri(lower)alkylamines (e.g., trimethylamine, triethylamine, and N-ethyldiisopropylamine), pyridine, quinoline, piperidine, imidazole, methylpyridine, dimethylaminopyridine, dimethylaniline, and N-(lower)alkylmorpholine (e.g., N-methylmorpholine). Salts of 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), and similar organic bases; salts of hydrochlorides, hydrobromates, hydroiodates, sulfates, nitrates, phosphates, and similar inorganic acid salts; salts of formates, acetates, propionates, oxalates, malonates, succinates, fumarates, maleates, lactates, malates, citrates, tartrates, carbonates, picrates, methanesulfonates, ethanesulfonates, p-toluenesulfonates, glutamates, dihydroxynaphthyl salts, and similar organic acids. As used herein, the term "(lower) alkyl" means "an alkyl group having 1 to 6 carbon atoms."

When the poorly soluble drug contained in the injectable formulation of the present invention is aripiprazole or a salt thereof, the crystalline form of aripiprazole or a salt thereof is not particularly limited. Aripiprazole or a salt thereof may be in monohydrate form (aripiperazole hydrate A) or in various anhydrous forms, known to exist in the form of anhydrous crystals B, C, D, E, F, and G. All these crystalline forms may be used as aripiprazole or a salt thereof in the injectable formulation of the present invention. The monohydrate form is preferred.

These poorly soluble drugs are known compounds and can be readily produced by known methods, or commercially available products can be used.

The injectable formulation of the present invention preferably contains at least water as a dispersion medium. Water, or an aqueous solvent containing water and an organic solvent, can preferably be used as a dispersion medium containing at least water. The organic solvents that can be used are those miscible with water, such as methanol, ethanol, propanol, isopropanol and similar alcohols; acetone and similar ketones; tetrahydrofuran and similar ethers; dimethylformamide; and mixtures thereof. Alcohols are preferred, and ethanol is particularly preferred. Although not particularly limiting, the amount of water in the aqueous solvent is preferably, for example, about 50 wt% or higher.

Water is preferred as a dispersion medium, and sterile water for injection is particularly preferred.

The specific suspending agent (suspending agent A) included in the injectable formulation of the present invention comprises at least one suspending agent selected from (i) and (ii):

(i) Polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts.

The polyvinylpyrrolidone used preferably has a K value (Fikentscher K value) of about 10 to 90, more preferably about 12 to 30, and even more preferably about 12 to 20. The polyvinylpyrrolidone used preferably has an average molecular weight of about 2,000 to 700,000, more preferably about 2,000 to 40,000, and even more preferably about 2,000 to 10,000. Using polyvinylpyrrolidone with a K value and average molecular weight within the above range is advantageous for the gelation of poorly soluble drug suspensions upon standing, for the inhibition of agglomeration due to particulate precipitation, and for providing injectable formulations with excellent storage stability. Examples of polyvinylpyrrolidone include povidone K12, povidone K17, povidone K25, povidone K30, etc. Povidone K17 is the most preferred. These various polyvinylpyrrolidones can be used alone or in combination of two or more.

The polyethylene glycols (polyethylene glycols) used as suspending agent A preferably have an average molecular weight of about 100 to 10,000, more preferably about 150 to 8,000, and even more preferably about 200 to 5,000. The use of polyethylene glycols with an average molecular weight within the above range can suppress clumping due to particulate precipitation and provide injectable formulations with excellent storage stability. Examples of polyethylene glycols include commercially available polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000, etc. Polyethylene glycol 400 is the most preferred. These polyethylene glycols can be used alone or in combination of two or more.

Examples of carboxymethyl cellulose or its salts include carboxymethyl cellulose and carboxymethyl cellulose salts, preferably, for example, alkali metal salts and ammonium salts of carboxymethyl cellulose. Specific examples include sodium carboxymethyl cellulose, potassium carboxymethyl cellulose, lithium carboxymethyl cellulose, ammonium carboxymethyl cellulose, etc. Among these, carboxymethyl cellulose and sodium carboxymethyl cellulose are preferred, with sodium carboxymethyl cellulose being particularly preferred. These carboxymethyl celluloses or their salts can be used alone or in combination of two or more.

When left to stand for a period of time after manufacturing, the injectable formulation of the present invention exhibits high viscosity and loses its fluidity (i.e., gels). However, after gelling, the injectable formulation will regain fluidity when subjected to minor impacts (e.g., stirring, shaking, tapping, external impact, or pressure from extrusion through a syringe needle). While not intended to be limiting, the injectable formulation of the present invention can be considered to exhibit structural viscosity. Structural viscosity is a type of non-Newtonian flow characterized by the property that, when gradually increasing shear stress is applied, weaker bonds in the internal structure of the liquid are broken, the apparent viscosity decreases, and the flow behavior becomes closer to Newtonian flow.

When this liquid injectable formulation is allowed to stand for a period of time, it returns to a gel state; upon slight impact (e.g., stirring, shaking, etc.), the gelled injectable formulation becomes liquid; and when it is allowed to stand again, the formulation becomes a gel. Therefore, this injectable formulation is considered to exhibit thixotropy.

This property can be verified by measuring the viscosity of the injectable formulation using a rheometer. A rheometer is an advanced viscometer that can use a variety of parameters and accurately measure viscosity under each parameter condition. When the viscosity of the injectable formulation of the present invention is measured by a rheometer while gradually increasing the shear rate, the viscosity tends to gradually decrease. A rotational rheometer is preferred. Such rheometers include, for example, the Discovery Hybrid Rheometer-2 (DHR-2) and the Discovery Hybrid Rheometer-3 (DHR-3) (manufactured by TA Instruments).

In particular, because (α) the injectable formulation of the present invention forms a gel upon standing, it can inhibit the precipitation and clumping of poorly soluble drug particles, thereby providing excellent storage stability. Furthermore, because (β) the injectable formulation of the present invention, even in gel form, readily acquires fluidity upon gentle impact, it can be easily injected during use (at injection). Specifically, since the gel injectable formulation (gel composition) acquires fluidity (forming a sol state) by simply squeezing the syringe plunger and extruding the formulation through the syringe needle, the formulation can be smoothly extruded directly through the needle. Therefore, the formulation can be well dispersed intramuscularly or subcutaneously upon injection, with relatively little local disturbance and pain.

Whether an injectable formulation has gelled (i.e., whether the formulation provides the aforementioned effect (α ⁾ ) can be confirmed by whether the formulation exhibits a viscosity of about 40 Pa·s or higher (as measured by a rheometer) at at least one point in the shear rate range of 0.01 to 0.02 ^s⁻¹ . Specifically, a viscosity of about 40 Pa·s or higher in the shear rate range of 0.01 to 0.02 s⁻¹ indicates that the measured injectable formulation has lost its flowability and is in gel form. In particular, a viscosity of about 100 Pa·s or higher in the shear rate range of 0.01 to 0.02 ^s⁻¹ indicates that the measured injectable formulation has definitely lost its flowability and is in gel form. At at least one point in the shear rate range of 0.01 to 0.02 ^s⁻¹ , the measured viscosity value is preferably about 40 to 20,000 Pa·s, more preferably about 50 to 10,000 Pa·s, even more preferably about 75 to 5,000 Pa·s, and particularly preferably about 100 to 3,000 Pa·s. Further, in the shear rate range of 0.01 to 0.02 ^s⁻¹ , the viscosity is preferably about 40 Pa·s or higher (specifically about 100 Pa·s or higher), more preferably about 40 to 20,000 Pa·s, more preferably about 50 to about 10,000 Pa·s, even more preferably about 75 to 5,000 Pa·s, and particularly preferably about 100 to 3,000 Pa·s.

Whether an injectable formulation provides the aforementioned effect (β) can be confirmed by whether the formulation exhibits a viscosity of 0.2 Pa·s or lower (as measured by a rheometer) at at least one point in a shear rate range of 900 to 1000 ^s⁻¹ . Specifically, a viscosity of about 0.2 Pa·s or lower at at least one point in a shear rate range of 900 to 1000 ^s⁻¹ indicates that the measured injectable formulation has achieved flowability and is in sol form. At at least one point in a shear rate range of 900 to 1000 ^s⁻¹ , the measured viscosity value is preferably about 0.1 Pa·s or lower, more preferably about 0.05 Pa·s or lower. Further, in a shear rate range of 900 to 1000 ^s⁻¹ , the viscosity is preferably about 0.2 Pa·s or lower, more preferably about 0.1 Pa·s or lower, and even more preferably about 0.05 Pa·s or lower.

Specifically, whether an injectable formulation has gelled (i.e., whether the formulation provides the aforementioned effect ⁽ α)) can be confirmed by whether the formulation exhibits a viscosity of about 40 Pa·s or higher at at least one point in the shear rate range of 0.01 to 0.02 ^s⁻¹ (as measured by a rheometer at 25 °C). Specifically, a viscosity of about 40 Pa·s or higher at at least one point in the shear rate range of 0.01 to 0.02 ^{s⁻¹ indicates that the measured injectable formulation has lost its flowability and is in gel form. Specifically, a viscosity of about 100 Pa·s or higher in the shear rate range of 0.01 to 0.02 s⁻¹} indicates that the measured injectable formulation has definitely lost its flowability and is in gel form. The viscosity value measured at at least one point in the shear rate range of 0.01 to 0.02 ^s⁻¹ is preferably about 40 to 20,000 Pa·s, more preferably about 50 to 10,000 Pa·s, even more preferably about 75 to 5,000 Pa·s, and particularly preferably about 100 to 3,000 Pa·s. Further, in the shear rate range of 0.01 to 0.02 ^s⁻¹ , the viscosity is preferably about 40 Pa·s or higher (specifically about 100 Pa·s or higher), more preferably about 40 to 20,000 Pa·s, more preferably about 50 to about 10,000 Pa·s, even more preferably about 75 to 5,000 Pa·s, and particularly preferably about 100 to 3,000 Pa·s.

Specifically, whether an injectable formulation provides the aforementioned effect ( ^β ) can be confirmed by whether the formulation exhibits a viscosity of 0.2 Pa·s or lower (as measured by a rheometer at 25°C) at at least one point in the shear rate range of 900 to 1000 ^s⁻¹ . Specifically, a viscosity of about 0.2 Pa·s or lower in the shear rate range of 900 to 1000 ^s⁻¹ indicates that the measured injectable formulation has achieved flowability and is in sol form. At at least one point in the shear rate range of 900 to 1000 s⁻¹, the measured viscosity value is preferably about 0.1 Pa·s or lower, more preferably about 0.05 Pa·s or lower. Further, in the shear rate range of 900 to 1000 ^s⁻¹ , the viscosity is preferably about 0.2 Pa·s or lower, more preferably about 0.1 Pa·s or lower, and even more preferably about 0.05 Pa·s or lower.

Preferably, viscosity measurements are performed in these shear rate ranges (0.01 to 0.02 ^s⁻¹ and 900 to 1000 ^s⁻¹ ) by sequentially measuring viscosity while gradually increasing the shear rate, starting from the lowest shear rate. Preferably, for example, viscosity is measured sequentially in the shear rate range of 0.001 to 1000 ^s⁻¹ using a rheometer.

When the sequential viscosity measurements of the gel composition are plotted with shear rate ( ^s⁻¹ ) as the ordinate (x-axis) and viscosity (Pa·s) as the ordinate (y-axis), a generally decreasing figure is obtained. Using this figure, the above can be further explained as follows. For example, a viscosity of 40 Pa·s or higher at at least one point in the shear rate range of 0.01 to 0.02 ^s⁻¹ indicates that at least a portion of the graph in the shear rate range of 0.01 ≤ x ≤ 0.02 satisfies y ≥ 40.

As another example, a viscosity of 40 Pa·s or higher in the shear rate range of 0.01 to 0.02 ^s⁻¹ indicates that the entire graph satisfies y ≥ 40 in the shear rate range of 0.01 ≤ x ≤ 0.02.

As another example, a viscosity of 0.2 Pa·s or less at at least one point in the shear rate range of 900 to 1000 ^s⁻¹ indicates that at least a portion of the graph satisfies y ≤ 0.2 in the shear rate range of 900 ≤ x ≤ 1000. As another example, a viscosity of 0.2 Pa·s or less in the shear rate range of 900 to 1000 ^s⁻¹ indicates that the entire graph satisfies y ≤ 0.2 in the shear rate range of 900 ≤ x ≤ 1000.

As a rheometer, for example, the Discovery Hybrid Rheometer-2 (DHR-2) or the Discovery Hybrid Rheometer-3 (DHR-3) (manufactured by TA Instruments) can be used.

The combined use of the specific suspending agent (suspending agent A) with the poorly soluble drug is one of the main reasons why the injectable formulation of the present invention can provide the aforementioned effects (α) and (β). More specifically, although a very wide range of suspending agents are known for poorly soluble drugs, most suspending agents cannot provide compositions that can produce the aforementioned effects (α) and (β); while the aforementioned suspending agent A is very suitable for obtaining injectable formulations with the aforementioned effects (α) and (β). Therefore, the injectable formulation of the present invention can be obtained by preparing a suspension using a combination of the poorly soluble drug and the dispersing medium with suspending agent A, measuring the viscosity, and selecting a suspension that meets the above conditions.

Other important factors for achieving the aforementioned effects (α) and (β) include, for example, the particle size and concentration of poorly soluble drugs.

The poorly soluble drug contained in the injectable formulation of the present invention typically has an average primary particle size of about 0.5 to 100 μm, preferably about 0.5 to 50 μm, more preferably about 0.5 to 30 μm, even more preferably about 1 to 20 μm, still more preferably about 1 to 10 μm, even more preferably about 1 to 5 μm, and particularly preferably about 2 to 5 μm. The average secondary particle size of the poorly soluble drug is preferably up to but not more than 3 times its average primary particle size, more preferably up to but not more than 2 times its average primary particle size.

The term "primary particle size" refers to the diameter of individual, unaggregated particles that are separated from each other. The "average primary particle size" is calculated from the volume average diameter derived from the average primary particle size distribution measured using laser diffraction scattering. In this invention, the average primary particle size is measured while the injectable formulation is circulated in an aqueous medium using ultrasonic irradiation. "Secondary particle size" refers to the size of aggregated particles. The "average secondary particle size" is calculated from the volume average diameter derived from the average secondary particle size distribution measured using laser diffraction scattering. In this invention, the average secondary particle size is measured while the injectable formulation is circulated in an aqueous medium without using ultrasonic irradiation.

For example, the SALD-3000J (manufactured by Shimadzu Corporation) can be used to measure the average particle size using laser diffraction scattering.

The average secondary particle size is not less than the average primary particle size (excluding measurement error). Injectable formulations containing poorly soluble drugs with nearly identical average primary and average secondary particle sizes (i.e., whose particles hardly aggregate) are also included within the scope of the injectable formulations of this invention. Poorly soluble drugs with an average secondary particle size greater than their average primary particle size are preferred unless specific operations (operations for pulverizing secondary particles into primary particles) such as ultrasonic irradiation are performed.

When the average primary particle size of a poorly soluble drug is set to 1 μm or larger and is used for injection, a long-term sustained release property can be advantageously obtained. The average primary particle size of the poorly soluble drug is preferably set to 100 μm or smaller, more preferably about 50 μm or smaller, even more preferably about 30 μm or smaller, still more preferably 10 μm or smaller, and particularly preferably about 2 to 5 μm, because this inhibits precipitation of the poorly soluble drug during the production of the compositions of the present invention or from their production until administration to the patient, and also prevents clogging of the syringe needle during injection.

As a method for preparing poorly soluble drugs having the above-mentioned average primary particle size, wet milling is preferably used. Preferred wet milling methods include wet ball milling, high-pressure homogenization, and high-shear homogenization. In addition to these methods, other low-energy and high-energy mills (such as roller mills) can also be used.

Controlled crystallization and other methods can be used as alternative approaches.

Furthermore, as a method for producing poorly soluble drugs having the aforementioned average primary particle size, the impact jet crystallization method (see JP2007-509153A), which has been patented by Bristol-Myers Squibb, can be used, or the wet milling method using a high-pressure homogenizer (see JP2007-200088A), which has been patented by Otsuka Pharmaceutical Co., Ltd. The wet milling method using a high-pressure homogenizer (specifically, the two-step wet milling method), which has been patented by Otsuka Pharmaceutical Co., Ltd., is more preferred.

The injectable formulation of the present invention preferably contains a poorly soluble drug at a concentration of about 200 to 600 mg/mL, more preferably about 200 to 500 mg/mL, even more preferably about 200 to 480 mg/mL, and still more preferably about 250 to 450 mg/mL.

An injectable formulation containing the aforementioned suspending agent A and a poorly soluble drug that meets the aforementioned average particle size and concentration conditions can more advantageously provide the aforementioned effects (α) and (β).

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

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

In addition to poorly soluble drugs, suspending agent A, and dispersing media, the injectable formulations of the present invention may also contain suspending agents other than suspending agent A (hereinafter also referred to as "suspending agent B"), buffers, pH adjusters, excipients, lubricants, plasticizers, disintegrants, binders, surfactants, preservatives, flavorings, fragrances, tensioning agents, and similar additives.

For example, the additives disclosed in JP2007-509148A can be used as these additives.

Other examples of suspending agents suitable for use as suspending agent B include a variety of polymers, low molecular weight oligomers, natural products, and surfactants (including nonionic and ionic surfactants). Specific examples include hexadecyl pyridine chloride, gelatin, casein, lecithin (phospholipids), dextran, glycerol, gum arabic, cholesterol, astragalus gum, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetearyl alcohol, cetomacrogol emulsifying wax, sorbitol esters, polyoxyethylene alkyl ethers (e.g., polyethylene glycol ethers, such as polycetomacrogol 1000), polyoxyethylene castor oil derivatives; dodecyltrimethylammonium bromide, polyoxyethylene stearate, colloidal silica, phosphates/esters, sodium dodecyl sulfate, methylcellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose phthalate, amorphous cellulose, magnesium aluminum silicate, triethanolamine, and polyvinyl alcohol (PVA). Polymers of 4-(1,1,3,3-tetramethylbutyl)phenol with ethylene oxide and formaldehyde (also known as tylosap, superione, and triton); poloxamine (e.g., Tetronic 908 (registered trademark), also known as Poloxamines 908 (registered trademark), which is a tetrafunctional block copolymer derived by sequentially adding propylene oxide and ethylene oxide to ethylenediamine (BASF Wyandotte Corporation, Parsippany, N.J.)); charged phospholipids, such as dimyristoyl phosphatidylglycerol and dioctyl succinate sulfonate (DOSS); Tetronic 1508 (registered trademark) (T-1508) (BASF Wyandotte Corporation, Parsippany, N.J.) ndotte Corporation), dialkyl esters of sodium succinate sulfonate (e.g., Aloxo OT (registered trademark), which is dioctyl succinate sulfonate (American Cyanamid)); Duponol P (registered trademark), which is sodium lauryl sulfate (DuPont); Tritons X-200 (registered trademark), which is alkylaryl polyether sulfonate (Rohm and Haas); Crodestas F-110 (registered trademark), which is a mixture of sucrose stearate and sucrose distearate (Croda Inc.); p-Isononylphenoxy poly- (glycidyl), also known as Olin-10G (registered trademark) or surfactant 10-G (registered trademark) (Olin Chemicals, St. Amford, Conn.); Crodestas SL-40 (Croda, Inc.); and SA9OHCO, which is (Eastman Kodak Co.); N-methylglucosyldecanoamide; n-decyl-β-D-glucopyranoside; n-decyl-β-D-maltopyranoside; n-dodecyl-β-D-glucopyranoside; n-dodecyl-β-D-maltopyranoside; N-methylglucosylheptamide; n-heptyl-β-D-glucopyranoside; n-heptyl-β-D-thioglucoside; n-hexyl-β-D-glucopyranoside; N-methylglucosylnonamide; n-nonyl-β-D-glucopyranoside; N-methylglucosyloctamide; n-octyl-β-D-glucopyranoside; octyl-β-D-thioglucopyranoside; etc.

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

The concentration of suspending agent B is preferably from about 0.1 to 50 mg/mL, more preferably from about 0.1 to 20 mg/mL, and even more preferably from about 0.3 to 15 mg/mL.

Except for (i) polyvinylpyrrolidone, polyethylene glycol is preferably used in mixtures thereof. In this case, the concentration of polyvinylpyrrolidone is preferably about 0.1 mg/mL or higher, more preferably about 0.1 to 100 mg/mL, and the concentration of polyethylene glycol is preferably about 0.05 to 100 mg/mL, more preferably about 0.1 to 50 mg/mL. When polyethylene glycol 400 is used as polyethylene glycol, the concentration of polyethylene glycol 400 is preferably about 0.1 to 100 mg/mL, more preferably about 0.1 to 10 mg/mL, and even more preferably about 0.5 to 5 mg/mL. When polyethylene glycol 4000 is used as polyethylene glycol, the concentration of polyethylene glycol 4000 is preferably about 0.1 to 40 mg/mL.

When (ii) polyethylene glycol and carboxymethyl cellulose or their salts are used as suspending agent A, the concentration of polyethylene glycol is preferably from about 0.05 to 2 mg/mL, more preferably from about 0.1 to 1 mg/mL.

When carboxymethyl cellulose or its salt is used in a mixture with (i) polyvinylpyrrolidone or when (ii) polyethylene glycol and carboxymethyl cellulose or its salt are used as suspending agent A, the concentration of carboxymethyl cellulose or its salt 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.

By containing carboxymethyl cellulose or its salts, the increase in viscosity during production can be suppressed. This allows poorly soluble drugs (such as aripiprazole or its salts) to be efficiently pulverized to the desired particle size, and is therefore preferred. Furthermore, by containing polyethylene glycol, dehydration shrinkage is preferably prevented even during long-term storage of the resulting injectable formulation.

The dispersing medium is added in an amount suitable for bringing the content of the poorly soluble drug within the aforementioned range. For example, the amount of dispersing medium added results in a final injectable formulation volume of about 0.2 to 5.0 mL, more specifically about 0.4 to 3.0 mL, and even more preferably about 0.5 to 2.0 mL.

When a composition (injectable formulation) produced using a poorly soluble drug, a dispersing medium, and suspending agent A does not gel upon standing, it can be gelled by heat treatment (aging). Even in this case, the resulting formulation can still be preferably used as an injectable formulation of the present invention, provided that the effects of the present invention are advantageously provided. Specifically, an injectable formulation gelled in this manner can be suitably used as an injectable formulation of the present invention, provided that it meets the above-described conditions, and in particular, has a viscosity of 40 Pa·s or higher at at least one point in the shear rate range of ^0.01 to 0.02 s⁻¹, and a viscosity of 0.2 Pa·s or lower at at least one point in the shear rate range of 900 to 1000 ^s⁻¹ (as measured by a rheometer at 25 °C). For example, gelation of the injectable formulation can preferably be promoted by setting the temperature conditions during standing to a higher temperature, or by temporarily allowing the formulation to stand at a higher temperature and then allowing it to stand at ambient temperature (about 25 °C), thereby producing an injectable formulation of the present invention.

Aging is performed, for example, by heating at a temperature of about 30°C or higher (preferably about 30°C to 70°C, more preferably about 40°C to 60°C, and even more preferably about 45°C to 55°C) for several minutes to several days (e.g., preferably about 5 minutes to 5 days, more preferably about 1 hour to 3 days, and even more preferably about 12 to 24 hours). However, heating at 90°C or higher is undesirable as this will cause water evaporation. Aging tends to increase the secondary particle size of poorly soluble drugs. However, even when aging is performed, as mentioned above, the average secondary particle size of poorly soluble drugs is preferably up to but not more than 3 times their average primary particle size, and more preferably up to but not more than 2 times their average primary particle size. It is also undesirable to leave injectable formulations to stand at temperatures as low as those at which the injectable formulation would freeze.

As can be understood from the above, when the injectable formulation is allowed to stand to allow the formulation to gel, the standing temperature is preferably about 5°C to 70°C, more preferably about 20°C to 70°C, and even more preferably about 25°C to 65°C.

The settling time depends on the amount of injectable formulation to be gelled and the settling temperature, and can be any length of time as long as it is not less than the time required for the formulation to gel. For example, a settling time is preferably 5 minutes or longer, more preferably 10 minutes or longer, even more preferably 30 minutes or longer, and still more preferably 1 hour or longer. When the settling time is 1 hour or longer, a settling time of 4 hours or longer is preferred, more preferably 12 hours or longer, and even more preferably 24 hours or longer. There is no specific upper limit to the settling time, and the time can be, for example, about several days (2, 3, 4, or 5 days).

As mentioned above, aging can be introduced during the settling period (preferably at the beginning of the settling).

The injectable formulation of the present invention may contain a tonicity agent. Examples of tonicity agents include, but are not limited to, sodium chloride, potassium chloride, mannitol, glycerol, sorbitol, glucose, xylitol, trehalose, maltose, and maltitol. These tonicity agents may be used alone or in combination of two or more. Sodium chloride is preferred. Such tonicity agents are added in an isotonic amount to make the composition present.

The pH of the suspension is adjusted to approximately 6 to 8, preferably approximately 7, using a buffer. To achieve this pH, the concentration of the buffer can be appropriately set depending on the type of buffer. The concentration of the buffer is preferably approximately 0.02 to 2 mg/mL, more preferably approximately 0.03 to 1 mg/mL.

Specific examples of buffers include, but are not limited to, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, their hydrates, TRIS buffer, etc. These buffers can be used alone or in combination of two or more. Sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, and their hydrates are preferred.

The pH adjuster is used in an amount to adjust the aqueous suspension of the poorly soluble drug to a pH of about 6 to 7.5, preferably about 7. The acid or base used depends on the pH of the injectable formulation of the present invention. When adjusting the injectable formulation to a lower pH, an acidic pH adjuster, such as hydrochloric acid or acetic acid, can be used. Hydrochloric acid is preferred. When adjusting the injectable formulation to a higher pH, an alkaline pH adjuster, such as sodium hydroxide, potassium hydroxide, calcium carbonate, magnesium oxide, or magnesium hydroxide, can be used. Sodium hydroxide is preferred. These pH adjusters can be used alone or in combination of two or more.

Although the method for preparing the injectable formulation of the present invention is not specifically limited, the injectable formulation can be prepared by mixing a poorly soluble drug, suspending agent A, and a dispersing medium, optionally with additives. More specifically, after mixing suspending agent A and the dispersing medium optionally with additives, the resulting carrier solution is mixed with the poorly soluble drug, and the resulting mixture is wet-milled using the method described above, thus providing the injectable formulation of the present invention. To prevent gelation of the injectable formulation, it is preferably produced at a low temperature (e.g., about 2 to 10°C, particularly about 5°C).

The above methods can be used to obtain storage-stable injectable formulations containing poorly soluble drugs with a desired average particle size.

The injectable formulation of the present invention is suitably formulated into a dosage form that can be administered once a month, once every two months, or once every three months. Although intramuscular administration is preferred, subcutaneous injection is also acceptable.

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 is preferably used to treat schizophrenia and related conditions (such as bipolar disorder, depression and dementia) in human patients or to prevent recurrence of symptoms of these diseases.

As described above, the injectable formulation of the present invention containing a specific suspending agent A can inhibit clumping caused by the precipitation of poorly soluble drugs from its production to its administration to the patient, and thus has excellent storage stability, and can be smoothly expelled from the syringe through a fine syringe needle during injection.

In particular, when the injectable formulation of the present invention has a structural viscosity, the injectable formulation is immediately in a sol state exhibiting fluidity after its preparation (see Figure 1). When the sol injectable formulation is allowed to stand, it becomes a gel and no longer flows even when slowly tilted (see Figure 2). The injectable formulation in gel form is stable enough that even after prolonged standing, clumping of poorly soluble drug particles due to particle precipitation does not occur. Due to stirring, shaking, tapping, external impact, or pressure when extruded through a syringe needle, the gel injectable formulation rapidly forms a sol state (see Figure 3). In the sol state of the injectable formulation, poorly soluble drugs do not clump due to precipitation but are uniformly dispersed, thus reproducing the injectable formulation immediately after manufacturing.

While not wishing to make a restrictive interpretation, it can be assumed that the following mechanisms lead to the structural viscosity and thixotropy of the above-mentioned injectable formulations.

It is believed that injectable formulations have a structure that allows a portion of the suspending agent A to bind to poorly soluble drug particles in the dispersion medium; therefore, the bound suspending agent A leads to interactions between the poorly soluble drug particles.

It is hypothesized that intermolecular and interparticle interactions exist between suspending agent A molecules attached to the surface of poorly soluble drug particles, or between suspending agent A molecules attached to the surface of poorly soluble drug particles and suspending agent A molecules existing in an unattached state in the dispersion medium, or within the poorly soluble drug particles themselves, thereby forming a network structure. It is assumed that injectable formulations become gels due to this network structure.

The intermolecular interactions induced by suspending agent A, which forms the network structure, are weak binding forces. Therefore, due to stirring, shaking, tapping, external impact, or pressure during extrusion through a syringe needle, this network structure breaks down, resulting in the injectable gel formulation turning into a sol. When the injectable formulation is in a sol state, the network structure is rebuilt, and upon resting again, the injectable formulation becomes a gel.

The injectable formulation of the present invention is also advantageous because it can be directly filled into vials or syringes.

An example of a conventional dosage form of aripiprazole or its salts is as follows: a suspension containing aripiprazole or its salts as the active ingredient is prepared, and the suspension is freeze-dried in a vial. Before use, water for injection is added to the vial, and the resulting formulation is drawn into a syringe and then administered to the patient.

According to the form of use of the present invention, the injectable formulation is directly filled into vials or syringes and used. Therefore, the injectable formulation of the present invention can be readily obtained without freeze-drying in the manufacturing process.

In particular, the injectable formulation of the present invention can be directly filled into a syringe for use as a pre-filled syringe. This simplifies the syringe structure and reduces size and weight. In a preferred embodiment, when the injectable formulation of the present invention is filled into a syringe, the sol suspension can be administered by simply squeezing the plunger rod of the syringe, without vibrating the syringe, through the syringe needle. This provides a pre-filled syringe with clinical convenience and operability, and is therefore highly useful in medicine and industry. A preferred example of producing such a pre-filled syringe is to manufacture the injectable formulation as described above, pre-fill the formulation into a syringe, and then allow it to stand as described above to allow the injectable formulation to gel. The present invention also includes a kit equipped with the pre-filled syringe described above.

Aripiprazole or its salts, or 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or its salts, are particularly preferred as poorly soluble drugs contained in the injectable formulations of the present invention. Therefore, the following explanation describes more preferred embodiments of injectable formulations containing aripiprazole or its salts as poorly soluble drugs, or more preferred embodiments of injectable formulations containing 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or its salts as poorly soluble drugs. However, unless otherwise defined below, the above explanation also applies to injectable formulations containing aripiprazole or its salts, or 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or its salts as poorly soluble drugs.

The injectable formulations of the present invention containing aripiprazole or a salt thereof preferably comprise aripiprazole or a salt thereof, water, and at least one suspending agent selected from (i) and (ii):

(i) Polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts.

The aripiprazole or its salts have an average primary particle size of about 0.5 to 30 μm and a concentration of aripiprazole or its salts of 200 to 600 mg/mL.

In particular, when the injectable formulation of the present invention contains aripiprazole or a salt thereof (which may be referred to below as "the injectable aripiprazole formulation of the present invention"), the concentration of aripiprazole or a salt thereof is important. When its concentration is outside the range of 200 to 600 mg/mL, it is difficult to obtain an injectable formulation that can achieve both (α) and (β) as described above. In particular, when its concentration is 100 mg/mL or lower, it is still difficult to manufacture an injectable formulation that can form a gel, even with the use of suspending agent A (or further aging treatment). Therefore, when the injectable formulation of the present invention contains aripiprazole or a salt thereof, the combination of the use of a specific suspending agent (suspending agent A) and a specific concentration of aripiprazole or a salt thereof (200 to 600 mg/mL, and more preferably 250 to 450 mg/mL) is particularly important. When the injectable formulation of the present invention contains a salt of aripiprazole, the concentration described above is preferably the concentration calculated as aripiprazole.

The injectable formulation of the present invention containing 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof comprises 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof, water, and at least one suspending agent selected from (i) and (ii):

(i) Polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts.

The 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or its salts have an average primary particle size of about 0.5 to 30 μm, and the concentration of 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or its salts is 200 to 600 mg/mL.

In particular, when the injectable formulation of the present invention comprises 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof (hereinafter, it may be referred to as "the brexpiprazole injectable formulation of the present invention"), the concentration of 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof is important. When its concentration is outside the range of 200 to 600 mg/mL, it is difficult to obtain an injectable formulation that can achieve both (α) and (β) the effects described above. In particular, when its concentration is 100 mg/mL or lower, it is still difficult to manufacture an injectable formulation that can form a gel, even with the use of suspending agent A (or further aging treatment). Therefore, when the injectable formulation of the present invention comprises 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof, the use of a specific suspending agent (suspending agent A) and a specific concentration (200 to 600 mg/mL, and more preferably 250 to 450 mg/mL) of 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof are particularly important. When the injectable formulation of the present invention comprises a salt of brexpiprazole, the concentration described above is preferably the concentration calculated as brexpiprazole.

In the aripiprazole injectable formulation or the brexpiprazole injectable formulation of the present invention, when polyvinylpyrrolidone is included as suspending agent A, 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.

When the aripiprazole injectable formulation of the present invention or the brexpiprazole injectable formulation of the present invention comprises (i) polyvinylpyrrolidone as suspending agent A and further comprises one or more other suspending agents, preferably, it comprises at least one member selected from polyethylene glycol and carboxymethyl cellulose or salts thereof as one or more other suspending agents. More specifically, these injectable formulations of the present invention comprise (i) polyvinylpyrrolidone as suspending agent A, and when they further comprise one or more other suspending agents, they preferably comprise any combination of suspending agents from (i-1) to (i-3) as shown below.

(i-1) Polyvinylpyrrolidone and polyethylene glycol

(i-2) Polyvinylpyrrolidone and carboxymethyl cellulose or their salts, and

(i-3) Polyvinylpyrrolidone, polyethylene glycol, and carboxymethyl cellulose or their salts

Regardless of the combination of (i-1) to (i-3) in these injectable formulations of the present invention, as described above, 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. In (i-1) or (i-3), the concentration of polyethylene glycol is preferably about 0.05 to 100 mg/mL, more preferably about 0.1 to 50 mg/mL. In (i-2) or (i-3), the concentration of carboxymethyl cellulose 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.

By containing carboxymethyl cellulose or its salts, the increase in viscosity during production can be suppressed. This allows aripiprazole or its salts, brexpiprazole or its salts, to be efficiently pulverized to the desired particle size, and is therefore preferred. Furthermore, by containing polyethylene glycol, dehydration shrinkage is preferably prevented even during long-term storage of the resulting injectable formulation. Of (i-1) to (i-3), (i-3) is particularly preferred because it achieves both of the effects described above.

When the aripiprazole injectable formulation of the present invention or the brexpiprazole injectable formulation of the present invention comprises (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof as A, the concentration of polyethylene glycol is preferably from about 0.05 to 2 mg/mL, more preferably from about 0.1 to 1 mg/mL. The concentration of carboxymethyl cellulose or a salt thereof is preferably from about 0.5 to 50 mg/mL, more preferably from 1 to 30 mg/mL, and even more preferably from 2 to 20 mg/mL.

When the aripiprazole injectable formulation of the present invention or the brexpiprazole injectable formulation of the present invention comprises (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof as suspending agent A, and further comprises one or more other suspending agents, it preferably comprises polyvinylpyrrolidone as one or more other suspending agents. Specifically, the injectable formulation of the present invention comprises (ii) polyethylene glycol and carboxymethyl cellulose or a salt thereof as suspending agent A, and when it further comprises one or more other suspending agents, it more preferably comprises suspending agent (i-3). In this case, the concentrations of polyethylene glycol, carboxymethyl cellulose or a salt thereof, and polyvinylpyrrolidone are the same as described in (i-3) above.

In the aripiprazole injectable formulation of the present invention or the brexpiprazole injectable formulation of the present invention, when the suspending agent (i-3) is used, a particularly preferred composition contains 0.5 to 20 mg/mL of polyvinylpyrrolidone, 0.1 to 100 mg/mL of polyethylene glycol, 0.5 to 50 mg/mL of carboxymethyl cellulose or a salt thereof, and 250 to 450 mg/mL (more preferably 300 to 400 mg/mL) of aripiprazole or a salt thereof. In this case, more preferably, the polyethylene glycol is polyethylene glycol 400 or polyethylene glycol 4000. More preferably, the polyvinylpyrrolidone has a K value of about 12 to 20. Even more preferably, the aripiprazole or a salt thereof has an average primary particle size of about 1 to 10 μm.

Since an excessively large average primary particle size of aripiprazole or its salts, or 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or its salts, may lead to precipitation, the average primary particle size is preferably about 0.5 to 30 μm, more preferably about 1 to 20 μm. To maintain a sustained release effect, when the injectable formulation of the present invention is in a once-monthly dosage form, the average primary particle size of aripiprazole or its salts, or 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or its salts, is preferably about 1 to 10 μm, more preferably 2 to 7 μm, and even more preferably 2 to 4 μm. When the injectable formulation of the present invention is administered in a dose form once every 2 months or every 3 months, the average primary particle size of aripiprazole or its salts, or 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or its salts, is preferably about 1 to 50 μm, more preferably 4 to 30 μm, and even more preferably 5 to 20 μm. The average secondary particle size is preferably up to but not more than 3 times the average primary particle size, and more preferably up to but not more than 2 times its average primary particle size.

The aripiprazole injectable formulation of the present invention will be explained in more detail below. The concentration of aripiprazole or a salt thereof in the injectable formulation of the present invention, administered once monthly, is preferably about 200 to 600 mg/mL, more preferably about 200 to 400 mg/mL, and even more preferably about 300 mg/mL, when calculated as aripiprazole. In the injectable formulation of the present invention, administered once monthly, the average primary particle size of aripiprazole or a salt thereof is preferably about 1 to 10 μm, more preferably 1 to 5 μm, and even more preferably 2 to 4 μm. The dosage volume is preferably 0.3 to 3 mL, more preferably 0.6 to 2 mL, and even more preferably 1 to 1.5 mL.

The concentration of aripiprazole or its salt in the injectable formulation of the present invention, when calculated as aripiprazole, is preferably about 300 to 600 mg/mL, more preferably about 350 to 500 mg/mL, and even more preferably about 400 mg/mL. In the injectable formulation of the present invention, when administered once every two or three months, the average primary particle size of aripiprazole or its salt is preferably about 1 to 30 μm, more preferably 4 to 20 μm, and even more preferably 5 to 10 μm. When the injectable formulation is administered once every two months, the dose volume is preferably 0.5 to 5 mL, more preferably 1 to 3 mL, and even more preferably 1.5 to 2.5 mL. When the injectable formulation is administered once every three months, the dose volume is preferably 0.7 to 8 mL, more preferably 1.5 to 4.5 mL, and even more preferably 2 to 4 mL.

The injectable brexpiprazole formulation of the present invention will be explained in more detail below. The concentration of brexpiprazole or a salt thereof in the injectable formulation of the present invention, administered once monthly, is preferably about 200 to 600 mg/mL, more preferably about 200 to 400 mg/mL, and even more preferably about 300 mg/mL, when calculated as brexpiprazole. In the injectable formulation of the present invention, administered once monthly, the average primary particle size of brexpiprazole or a salt thereof is preferably about 1 to 10 μm, more preferably 1 to 5 μm, and even more preferably 2 to 4 μm. The dosage volume is preferably 0.3 to 3 mL, more preferably 0.6 to 2 mL, and even more preferably 1 to 1.5 mL.

The concentration of brexpiprazole or its salt in the injectable formulation of the present invention, when calculated as brexpiprazole, is preferably about 300 to 600 mg/mL, more preferably about 350 to 500 mg/mL, and even more preferably about 400 mg/mL. In the injectable formulation of the present invention, when administered once every two or three months, the average primary particle size of brexpiprazole or its salt is preferably about 1 to 30 μm, more preferably 4 to 20 μm, and even more preferably 5 to 10 μm. When the injectable formulation is administered once every two months, the dose volume is preferably 0.5 to 5 mL, more preferably 1 to 3 mL, and even more preferably 1.5 to 2.5 mL. When the injectable formulation is administered once every three months, the dose volume is preferably 0.7 to 8 mL, more preferably 1.5 to 4.5 mL, and even more preferably 2 to 4 mL.

The aripiprazole injectable formulations of the present invention or the brexpiprazole injectable formulations of the present invention can achieve the effects (α) and (β) described above. They can be in gel form, or they can be fluid (i.e., they can be in sol form). As described above, the achievement of effects (α) and (β) can be objectively confirmed using a rotational rheometer.

A preferred method for producing an injectable aripiprazole formulation or a brexpiprazole formulation according to the present invention comprises: preparing a liquid mixture of starting materials, and pulverizing the aripiprazole or a salt thereof or 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof contained in the liquid mixture to a desired average primary particle size, optionally followed by aging.

A particularly preferred method for producing an injectable gel aripiprazole formulation according to the invention comprises: allowing a liquid mixture to stand at 5 to 70°C for 5 minutes or longer, said liquid mixture comprising aripiprazole or a salt thereof having an average primary particle size of 0.5 to 30 μm and a concentration of 200 to 600 mg/mL, water, and at least one suspending agent selected from (i) and (ii):

(i) Polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts.

For example, a production method comprising the following steps may be preferred: pulverizing aripiprazole or a salt thereof to an average primary particle size of 0.5 to 30 μm in a liquid mixture comprising aripiprazole or a salt thereof at a concentration of 200 to 600 mg/mL, water, and at least one suspending agent selected from (i) and (ii):

(i) Polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts; and

Let the pulverized liquid mixture stand at 5 to 70°C for 5 minutes or longer.

A particularly preferred method for producing the injectable gel-type brexpiprazole formulation according to the invention comprises allowing a liquid mixture to stand at 5 to 70°C for 5 minutes or longer, said liquid mixture comprising 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof having an average primary particle size of 0.5 to 30 μm and a concentration of 200 to 600 mg/mL, water, and at least one suspending agent selected from (i) and (ii):

(i) Polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts.

For example, a production method comprising the following steps may be preferred: pulverizing 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof to an average primary particle size of 0.5 to 30 μm in a liquid mixture comprising 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof at a concentration of 200 to 600 mg/mL, water, and at least one suspending agent selected from (i) and (ii):

(i) Polyvinylpyrrolidone, and

(ii) polyethylene glycol and carboxymethyl cellulose or their salts; and

Let the pulverized liquid mixture stand at 5 to 70°C for 5 minutes or longer.

In the production of these injectable formulations, as described above, it is preferable to allow the injectable formulation to stand at 5 to 70°C for 5 minutes or longer, and more preferably, to undergo an aging treatment. By performing an aging treatment, gel compositions can be produced more reliably compared to conditions where, for example, the injectable formulation is left to stand at low temperatures or subjected to intermittent shocks. The aforementioned aging treatment conditions are less likely to cause problems such as moisture evaporation, tight gelation of the injectable formulation, and the inability of the injectable formulation to easily return to a sol even when subjected to shocks.

The concentration of the suspending agent contained in the liquid mixture is preferably the same as the concentration of the suspending agent contained in the injectable formulation. This is because the concentration of the suspending agent in the liquid mixture will directly become the concentration in the resulting injectable formulation.

As described above, the aripiprazole or its salt added to the liquid mixture for the production of the aripiprazole injectable formulation of the present invention can be, for example, in the form of a hydrate (aripiperazole hydrate A) and various anhydrous forms, namely anhydrous crystals B, anhydrous crystals C, anhydrous crystals D, anhydrous crystals E, anhydrous crystals F, or anhydrous crystals G. Preferably, aripiprazole or its salt is in the form of a hydrate, particularly preferably in the form of aripiprazole hydrate A. These can be used alone or in combination of two or more.

The addition of 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or a salt thereof to the liquid mixture used in the production of the brexpiprazole injectable formulation of the present invention is not limited, and may be, for example, in anhydrous or dihydrate form, preferably in dihydrate form. These may be used alone or in combination of two or more.

The method for pulverizing aripiprazole or its salts, or 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or its salts, contained in a liquid mixture is not particularly limited, and any known method may be used. For example, the method described above may be used. More specifically, wet milling is preferred. With regard to wet milling, wet ball milling, high-pressure homogenization, high-shear homogenization, etc., are preferred. In addition to the above-described pulverization methods, other low-energy mills and high-energy mills (such as roller mills) may also be used. Controlled crystallization and other methods may also be used. Furthermore, the impact jet crystallization method (see JP2007-509153A), for which a patent application has been filed by Bristol-Myers Squibb, may be used, or the wet milling method using a high-pressure homogenizer (see JP2007-200088A), for which a patent application has been filed by Otsuka Pharmaceutical Co., Ltd., may be used. Among them, the wet milling method using a high-pressure homogenizer (specifically, the two-step wet milling method), for which a patent application has been filed by Otsuka Pharmaceutical Co., Ltd., is more preferred.

In the production of gel aripiprazole injectable formulations or gel brexpiprazole injectable formulations by filling a liquid mixture into a syringe and allowing it to stand in the syringe, a pre-filled syringe containing gel aripiprazole injectable formulations or gel brexpiprazole injectable formulations can be obtained.

In the pre-filled syringe thus obtained, the injectable formulation (gel composition) contained therein acquires flowability (becomes a sol) by simply squeezing the plunger rod of the syringe and extruding it through the syringe needle. This allows the injectable formulation of the present invention to be extruded directly and smoothly from the syringe needle (i.e., the above-mentioned effect (β) can be achieved). Furthermore, precipitation and agglomeration of aripiprazole or its salts or 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one or its salts can be inhibited, thus achieving excellent storage stability (i.e., the above-mentioned effect (α) can be achieved). This makes the injectable formulation of the present invention highly useful in the clinical setting.

The present invention also includes a kit comprising a pre-filled syringe.

Example

The invention will now be explained in more detail. However, the invention is not limited to these embodiments. The abbreviation "q.s." stands for "quantum sufficiat," which means "sufficient quantity."

Examples 1 to 7

The suspending agent, sodium chloride, and sodium dihydrogen phosphate monohydrate shown in Table 1 were dissolved in water (water for injection). The solution was adjusted to pH 7.0 using sodium hydroxide to prepare the vehicle solution. The active ingredient (aripiperazole monohydrate) was suspended in the resulting vehicle solution. The resulting suspension was pre-pulverized using a CLEARMIX S1.5 (manufactured by M Technique Co., Ltd.) and then finely pulverized using a high-pressure homogenizer (Panda NS1001L2K model, manufactured by Niro Soavi) to prepare the injectable formulation. After the step of suspending the active ingredient in the vehicle solution, all steps of producing the injectable formulation were carried out at a temperature of 10°C or lower.

Immediately after production, all injectable formulations were in the form of a free-flowing sol-like suspension. Figure 1 shows a photograph of the injectable formulation of Example 1 taken immediately after production. When each of the resulting injectable formulations was placed in a transparent container and allowed to stand at 25°C for 1 hour, all injectable formulations lost their flowability, thus becoming gel-like injectable formulations. Figure 2 shows a photograph of a container containing the injectable formulation of Example 1, which, after standing, was slowly tilted and placed horizontally. Furthermore, when gently agitated, all gelled injectable formulations returned to a sol state and regained their flowability. Figure 3 shows a photograph of a container containing the injectable formulation of Example 1, after standing, gently tapped (i.e., applying a weak impact to the gel formulation), and placed horizontally.

After the injectable formulations produced in Examples 1 to 7 were gelled, these formulations were stored at 40°C for one week and then shaken. Table 1 shows the average particle size (average secondary particle size) of each formulation obtained. Table 1 also shows the average particle size (average primary particle size) when subjected to ultrasonic treatment and shaking. The particle size was measured by laser diffraction scattering using a SALD-3000J (manufactured by Shimadzu Corporation). The average particle size of the drugs contained in the injectable formulations (production examples) described below was also measured by laser diffraction scattering using a SALD-3000J.

After shaking the injectable formulations of Examples 1 to 7, 1.0 to 1.2 mL of each sample was collected. Viscosity was measured using a Type B rotational viscometer (TVE-30H laminar rotational viscometer, manufactured by Tokimec Inc.) at 25°C, 50 rpm, and 120 seconds. Table 1 shows the evaluation results. Viscosity was measured according to Method 2 (viscosity determination as defined in the Japanese Pharmacopoeia).

Test Example 1

Injectable formulations having the compositions shown in Table 2 below (Production Examples A1 to A6) were produced in the same manner as in Examples 1 to 7 described above (i.e., mixing components other than the active ingredient, adjusting the pH of the mixture to 7.0 to prepare a carrier solution, suspending the active ingredient in the carrier solution, and then pulverizing the suspension). The average primary and average secondary particle sizes of aripiprazole monohydrate in each production example were measured immediately after production. The results showed that all production examples had an average primary particle size of approximately 2.0 to 4.0 μm and an average secondary particle size of approximately 2.0 to 7.5 μm (Table 2).

Table 2

^* : Concentration of aripiprazole monohydrate (as anhydrous, 300 mg/mL)

^** : In production examples A1 to A6, measurements were taken in a circulating water medium without ultrasonic irradiation.

^*** : In production examples A1 to A6, measurements were taken in a circulating water medium under ultrasonic irradiation.

After production, the formulations of each production example were placed in transparent containers and then stored under stable conditions at 5°C, 25°C, or 40°C for 5 days. Figures 4a (stored at 5°C), 4b (stored at 25°C), and 4c (stored at 40°C) show photographs of the injectable formulations held in containers that were slowly tilted and placed horizontally after storage. In the explanation of Test Example 1 (specifically, in the figures and tables), Production Examples A1, A2, A3, A4, A5, and A6 can be referred to as “Povidone K17 0.1 mg/mL”, “Povidone K17 1.0 mg/mL”, “Povidone K17 4.0 mg/mL”, “Povidone K17 10.0 mg/mL”, “Povidone K17 50.0 mg/mL”, and “Povidone K17 100 mg/mL”, respectively.

The results shown in Figures 4a to 4c confirm that the tendency to gel increases with decreasing concentration of polyvinylpyrrolidone (Povidone K17) and also increases with increasing standing temperature. However, when the sample was left to stand at 90°C, moisture evaporated, making the sample unsuitable as an injectable formulation.

The formulations for each production example were stored at 5°C. After thoroughly shaking the formulations by hand to return them to a sol state (shaking was also performed on any formulations that remained in a sol state even after standing to confirm they were in a sol state), the viscosity of each formulation was measured using a rheometer. Viscosity measurements were performed under the following conditions.

• Measuring instrument: Rheometer (Discovery Hybrid Rheometer-2 (DHR-2) or Discovery Hybrid Rheometer-3 (DHR-3) (manufactured by TA Instruments))

• Shear rate: ^10⁻⁵ → 1000 (L/s)

• Temperature measurement: 5, 25, or 40℃

Concentric cylinders

• After storage at 5°C, shake the formulation of each production example by hand to form a sol, and place 10 mL of each formulation into a measuring instrument. After placing it into the measuring instrument, let each formulation stand at the measuring temperature for 5 to 10 minutes, and then begin the measurement (the purpose is to allow the injectable formulation to form a gel in the measuring instrument by letting it stand in the measuring instrument if it can form a gel).

In the following description, the viscosity of the injectable formulation (production example) was measured using the same measuring instrument with the same range of shear rate variation as described above, where concentric cylinders were also used. Furthermore, as mentioned above, the measurement was initiated after the sample was placed in the measuring instrument and allowed to stand at the measurement temperature for 5 to 10 minutes.

Figures 5a (measurement temperature: 5°C), 5b (measurement temperature: 25°C), and 5c (measurement temperature: 40°C) show the viscosity measurement results. Note that these figures show the results measured over a shear rate range of ^10⁻² to 1000 (L/s). Tables 3 to 5 summarize the specific viscosity data obtained for each measurement for viscosities measured at shear rates ranging from 0.01 to 0.02 (L/s) and from 900 to 1000 (L/s). Table 3 corresponds to the data in Figure 5a, Table 4 to the data in Figure 5b, and Table 5 to the data in Figure 5c.

Table 3

(Measured temperature: 5℃)

Table 4

(Measurement temperature: 25℃)

Table 5

(Measurement temperature: 40℃)

The results above (particularly those in Figure 5b and Table 4 (measurements at 25°C)) indicate that the lowest viscosity is achieved at any shear rate when the concentration of polyvinylpyrrolidone (PVP) is approximately 2 to 50 mg/mL, and gelation is also achieved. The following trend was confirmed: the lower the concentration of PPVP, the higher the viscosity. At high concentrations of PPVP, the viscosity tends to decrease until the concentration reaches approximately 20 to 50 mg/mL; and when the concentration of PPVP reaches approximately 100 mg/mL or higher, the viscosity tends to increase again.

Test Example 2

Injectable formulations having the compositions shown in Table 6 (Production Examples B, C, and D) were produced in the same manner as in Examples 1 to 7 (i.e., mixing components other than the active ingredient, adjusting the pH of the mixture to 7.0 to prepare a carrier solution, suspending the active ingredient in the carrier solution, and then pulverizing the suspension). These injectable formulations gelled after standing at 25°C or 40°C. Even after gelling, these injectable formulations returned to a sol state when gently shaken by hand. The average particle size measurements of aripiprazole monohydrate are shown below. Production Example B had an average primary particle size of 2.2 μm and an average secondary particle size of 2.4 μm. Production Example C had an average primary particle size of 4.2 μm and an average secondary particle size of 4.3 μm. Production Example D had an average primary particle size of 3.9 μm and an average secondary particle size of 3.9 μm.

Table 6

^* : Concentration of aripiprazole monohydrate (as anhydrous, 300 mg/mL)

^** : Concentration of aripiprazole monohydrate (as anhydrous, 400 mg/mL)

^*** : Concentration of aripiprazole monohydrate (as anhydrous, 600 mg/mL)

^**** : In production examples B to D, measurements were taken in a circulating water medium without ultrasonic irradiation.

^***** : In production examples B to D, measurements were taken in a circulating water medium under ultrasonic irradiation.

After storage at 5°C, the injectable formulations of Production Examples B through D were shaken by hand and placed in a rheometer to measure the viscosity of each formulation at 5°C, 25°C, or 40°C (measurement temperature). After storage at 5°C, the injectable formulations of Production Examples B and C were in sol form. After storage at 5°C, the injectable formulation of Production Example D was in gel form.

Figures 6 to 8 show the measurement results. Tables 7 to 9 show the specific viscosity measured at shear rates in the range of 0.01 to 0.02 (L/s) and at shear rates in the range of 900 to 1000 (L/s). (Figures 6 and Tables 7 show the measurement results for Production Example B, Figures 7 and Tables 8 show the measurement results for Production Example C, and Figures 8 and Tables 9 show the measurement results for Production Example D.)

Table 7

(Production Example B)

Table 8

(Production Example C)

Table 9

(Production Example D)

Test Example 3

An injectable formulation having the composition shown in Table 10 (Production Example E) was produced in the same manner as in Examples 1 to 7 (i.e., mixing components other than the active ingredient, adjusting the pH of the mixture to 7.0 to prepare a carrier solution, suspending the active ingredient in the carrier solution, and then pulverizing the suspension). Even after gelation, the formulation of Production Example E returned to a sol when gently shaken by hand. The average particle size measurements of aripiprazole monohydrate are shown below. The average primary particle size of Production Example E was 5.4 μm, and the average secondary particle size was 9.5 μm.

Table 10

^* : Concentration of aripiprazole monohydrate (as anhydrous, 200 mg/mL)

^** : In production example E, measurements were taken in a circulating water medium without ultrasonic irradiation.

^*** : In production example E, measurements were taken in a circulating water medium under ultrasonic irradiation.

After storage at 5°C, the injectable formulation of Example E was produced by hand-vibration and placed in a rheometer to measure its viscosity at 5°C, 25°C, or 40°C (measurement temperature). Figure 9a shows the results. Table 11 shows the specific viscosity measured at shear rates ranging from 0.01 to 0.02 (L/s) and the specific viscosity measured at shear rates ranging from 900 to 1000 (L/s).

Table 11

(Production Example E)

After production, the injectable formulation of Production Example E was stored for 5 days under stable conditions at 5°C, 25°C, or 40°C. The injectable formulation of Production Example E gelled under all conditions. (Figure 9b shows photographs of the respective injectable formulations stored in containers under stable conditions for 5 days, and Figure 9c shows photographs of the respective containers containing the injectable formulations slowly tilted and placed horizontally after storage.)

Viscosity measurements in Production Examples A1 to E indicate that when the viscosity of the injectable formulation, measured at a shear rate in the range of 0.01 to 0.02 (L/s), is about 40 (Pa·s) or higher, the formulation is in a gel state, and forms a sol as the shear rate increases. Specifically, the results show that when the viscosity of the injectable formulation, measured at a shear rate in the range of 900 to 1000 (L/s), is about 0.2 Pa·s or lower, the formulation can be directly injected.

Test Example 4

Injectable formulations having the compositions shown in Table 12 (Production Examples F1 and F2) were produced in the same manner as in Examples 1 to 7 (i.e., mixing components other than the active ingredient, adjusting the pH of the mixture to 7.0 to prepare a carrier solution, suspending the active ingredient in the carrier solution, and then pulverizing the suspension). The injectable formulations of Production Examples F1 and F2 did not gel. The average particle size measurements of aripiprazole monohydrate are shown below. 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.

Table 12

^* : Concentration of aripiprazole monohydrate (as anhydrous, 100 mg/mL)

^** : In production examples F1 and F2, measurements were taken in a circulating water medium without ultrasonic irradiation.

^*** : In production examples F1 and F2, measurements were taken in a circulating water medium under ultrasonic irradiation.

After storage at 5°C, the injectable formulations of Production Examples F1 and F2 were thoroughly shaken by hand and placed in a rheometer to measure their viscosity at 5°C or 25°C (measurement temperature). Figure 10a shows the results.

Table 13 shows the specific viscosity measured at shear rates in the range of 0.01 to 0.02 (1/s) and at shear rates in the range of 900 to 1000 (1/s).

Table 13

(Production Examples F1 and F2)

After production, the injectable formulations of Production Examples F1 and F2 were stored for 5 days under stable conditions at 5°C, 25°C, or 40°C. As a result, the formulations of Production Examples F1 and F2 did not gel under any circumstances. Figure 10b shows photographs of the respective injectable formulations stored in containers under stable conditions for 5 days, and Figure 10c shows photographs of the containers containing the respective injectable formulations slowly tilted and placed horizontally after storage. In the explanation of Test Example 4 (specifically, in the figures and tables), Production Examples F1 and F2 can be represented as "Povidone K17 0.1 mg/mL" and "Povidone K17 4.0 mg/mL," respectively. Specifically, Figure 10b shows that particle precipitation occurred in both Production Examples F1 and F2. This indicates that Production Examples F1 and F2 are not suitable for the injectable formulations of the present invention that maintain a uniform particle dispersion system by forming a gel.

The results of Test Examples 1 to 4 reveal that when polyvinylpyrrolidone is used as a suspending agent to produce injectable formulations containing poorly soluble drugs, injectable formulations that can be gelled by static standing and returned to a sol by applying a gentle impact (e.g., by hand shaking) can be obtained.

It is also revealed that, in particular, when aripiprazole is used as a poorly soluble drug, an injectable formulation can be produced by forming it to have a specific aripiprazole average primary particle size and an aripiprazole concentration in the range of 200 mg/mL to 600 mg/mL, thereby producing an injectable formulation that gels upon standing and returns to a sol upon application of a slight impact (e.g., by hand shaking). It is further revealed that the formulation preferably gels by being stored under stable conditions at a temperature of about 20 to 70°C and returns to a sol upon application of a slight impact.

Test Example 5

Injectable formulations having the compositions shown in Table 14 (Production Examples G, H, and I) were produced in the same manner as in Examples 1 to 7 (i.e., mixing components other than the active ingredient, adjusting the pH of the mixture to 7.0 to prepare a carrier solution, suspending the active ingredient in the carrier solution, and then pulverizing the suspension). In the production examples, poorly soluble drugs other than aripiprazole were used (Table 14). After production, the viscosity and average particle size of the injectable formulations of Production Examples G, H, and I were measured in the same manner as in the production examples described above. Even though they had gelled, the formulations of Production Examples G, H, and I returned to a sol state when gently shaken by hand.

Table 14

^* : In production examples G to I, measurements were taken in a circulating water medium without ultrasonic irradiation.

^** : In production examples G to I, measurements were taken in a circulating water medium under ultrasonic irradiation.

After production, the formulations of each production example were placed in transparent containers and stored under stable conditions at 5°C, 25°C, or 40°C for 5 days. Figure 11 shows photographs of the containers containing the injectable formulations being slowly tilted and placed horizontally after storage.

After storage at 5°C, the formulations of each production example were thoroughly shaken by hand and placed in a rheometer in the same manner as described above to measure viscosity at 5°C, 25°C, or 40°C (measurement temperature). Figure 12 shows the viscosity measurement results for Production Example G. Figure 13 shows the results for Production Example H. Figure 14 shows the results for Production Example I. Tables 15 to 17 summarize the specific viscosity data measured at shear rates in the range of 0.01 to 0.02 (L/s) and at shear rates in the range of 900 to 1000 (L/s). 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.

Table 15

(Production Example G)

Table 16

(Production Example H)

Table 17

(Production Example I)

Test Example 6

Injectable formulations having the compositions shown in Table 18 (Production Example J) were produced in the same manner as in Examples 1 to 7 (i.e., mixing components other than the active ingredient, adjusting the pH of the mixture to 7.0 to prepare a carrier solution, suspending the active ingredient in the carrier solution, and then pulverizing the suspension). The injectable formulations of Production Example J gelled after standing at 5°C, 25°C, or 40°C, and even if they had gelled, they returned to a sol state when gently shaken by hand. The average particle size measurements of aripiprazole monohydrate are shown below. The average primary particle size of Production Example J was 5.5 μm, and the average secondary particle size was 6.9 μm.

Table 18

^* : Concentration of aripiprazole monohydrate (as anhydrous, 400 mg/mL)

^** : In production example J, measurements were taken in a circulating water medium without ultrasonic irradiation.

^*** : In production example J, measurements were taken in a circulating water medium under ultrasonic irradiation.

After storage at 5°C, the injectable formulation of Production Example J was thoroughly shaken by hand to form a sol state and placed in a rheometer to measure its viscosity at 5°C, 25°C, or 40°C (measurement temperature). Figure 15 shows the results. Table 19 shows the specific viscosity measured at shear rates in the range of 0.01 to 0.02 (L/s) and at shear rates in the range of 900 to 1000 (L/s). After storage at 5°C under stable conditions for 5 days, the injectable formulation of Production Example J gelled.

Table 19

(Production Example J)

Test Example 7

Injectable formulations having the compositions shown in Table 20 below (Production Examples K and L) were produced in the same manner as in Examples 1 to 7 (i.e., mixing components other than the active ingredient, adjusting the pH of the mixture to 7.0 to prepare a carrier solution, suspending the active ingredient in the carrier solution, and then pulverizing the suspension). After production, the injectable formulations were aged by standing at 60°C for 12 hours. Lyophilized injectable formulations containing 200 mg/mL or 400 mg/mL of aripiprazole (Comparative Example 200 or Comparative Example 400) were prepared in the same manner as disclosed in the examples of WO2005/041937. The average particle size measurements of aripiprazole monohydrate are shown below. The average primary particle size of Production Example K was 2.8 μm, and the average secondary particle size was 4.3 μm. The average primary particle size of Production Example L was 6.1 μm, and the average secondary particle size was 7.9 μm. The average primary particle size of Comparative Example 200 was 2.1 μm, and the average secondary particle size was 2.1 μm. The average primary particle size of Comparative Example 400 was 2.0 μm, and the average secondary particle size was 2.1 μm.

These injectable formulations were injected into the leg muscles of male rats at doses of 50 mg/kg (Production Example K and Comparative Example 200) and 100 mg/kg (Production Example L and Comparative Example 400). To evaluate the transfer of aripiprazole into the bloodstream after administration, blood samples were collected at 0.25, 1, 3, 6, 9, 14, 21, 28, 42, and 56 days post-administration, and the serum concentration of aripiprazole in each sample was measured. After production, the injectable formulation of Production Example K was packaged into vials and gelled by standing in them. Before administration, the injectable formulations were gently agitated to convert the gel to a sol state, and then administered. The injectable formulations of Comparative Example 200 and Comparative Example 400 were lyophilized and then reconstituted with water before administration.

Figure 16 shows the results in graphical form.

Table 20

^* : Concentration of aripiprazole monohydrate (as anhydrous, 300 mg/mL)

^** : Concentration of aripiprazole monohydrate (as anhydrous, 400 mg/mL)

^*** : Concentration of aripiprazole monohydrate (as anhydrous, 200 mg/mL)

^**** : Measurements were performed in a circulating water medium without ultrasonic irradiation.

^***** : Measurements are performed in a circulating water medium under ultrasonic irradiation.

Production Example K exhibited a pharmacokinetic (PK) profile that was nearly identical to that of Comparative Example 200. The PK profile of Production Example K is desirable for a sustained-release injectable formulation administered once monthly. Production Example L showed a lower _Cmax than Comparative Example 400, and equal or better sustained-release properties. In other words, the PK profile of Production Example L is more preferred for a sustained-release injectable formulation administered once every 2 to 3 months.

Test Example 8

The viscosity of the injectable formulations (Production Examples A3 to A6) stored at 5°C in Test Example 1 was remeasured. Specifically, the viscosity measurements were performed in the same manner as in Test Example 1, except for the following steps. After standing at 5°C, the injectable formulations of Production Examples A3 to A6 were in a sol state; however, they were shaken by hand to confirm their sol state before being placed in the rheometer. Subsequently, they were allowed to stand at 40°C for 5 minutes in the rheometer and then returned to 25°C to measure their viscosity.

Figure 17 shows the viscosity measurement results. Table 21 summarizes the specific viscosity data measured at shear rates ranging from 0.01 to 0.02 (1/s) and at shear rates ranging from 900 to 1000 (1/s).

Table 21

(Production Examples A3 to A6: After standing at 40°C for 5 minutes, measurements were taken at 25°C)

Test Example 9

The viscosity of the injectable formulations (Production Examples B to C) stored at 5°C in Test Example 2 was remeasured. Specifically, the viscosity measurements were performed in the same manner as in Test Example 2, except for the following steps. After standing at 5°C, the injectable formulations of Production Examples B and C were in a sol state; however, they were manually agitated before being placed in the rheometer to confirm that they were in a sol state. Subsequently, they were allowed to stand in the rheometer at 40°C for 5 minutes and then returned to 25°C to measure their viscosity.

Figure 18 shows the viscosity measurement results. Figure 18 also shows the viscosity measured at 5°C and 25°C in Test Example 2. Table 22 summarizes the specific viscosity data measured at shear rates ranging from 0.01 to 0.02 (L/s) and at shear rates ranging from 900 to 1000 (L/s) in the range shown in Figure 18. In Table 22, “40→25” indicates the viscosity measured after the formulation was allowed to stand in a rheometer at 40°C for 5 minutes and then returned to 25°C (this also applies to the tables below).

Table 22

Test Example 10

Except for changing the concentration of povidone K17 from 0.1 mg/mL to 4 mg/mL, the injectable formulation (Production Example E') was produced in the same manner as Production Example E in Test Example 3. The formulation of Production Example E' was then stored at 5°C, 25°C, or 40°C. After standing at 5°C, the viscosity of the formulations of Production Examples E and E' was measured in the same manner as in Test Example 3. Specifically, after standing at 5°C, the injectable formulation of Production Example E' was in a sol state; however, before placing it in the rheometer, the formulations of Production Examples E and E' were hand-shaken to confirm they were in a sol state. Subsequently, they were placed in the rheometer at 40°C for 5 minutes and then returned to 25°C to measure their viscosity. The viscosity of the formulation of Production Example E' was measured in the same manner as in Test Example 3 (measurement temperatures: 5°C and 25°C).

Figure 19a shows the viscosity measurement results. Figure 19a also shows the viscosity of Production Example E measured at 5°C and 25°C in Test Example 3. In the results shown in Figure 19a, Table 23 summarizes the data for specific viscosity measured at shear rates in the range of 0.01 to 0.02 (L/s) and at shear rates in the range of 900 to 1000 (L/s).

Table 23

The injectable formulation of Production Example E’ was stored under stable conditions for 5 days at 5°C, 25°C, or 40°C. Only the formulation stored at 40°C gelled (Figure 19b shows photographs of the containers containing the injectable formulation slowly tilted and placed horizontally after storage. In this figure, Production Example E’ can be referred to as “Povidone K17 4.0 mg/mL”).

Test Example 11

Using 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one dihydrate as the active ingredient, injectable formulations having the compositions shown in Table 24 below were produced (Production Examples M1 and M2) in the same manner as those produced in Test Example 1 for Production Examples A1 and A2. 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one dihydrate was obtained in Synthesis Example 1 as described below.

Even after gelation, the injectable formulations of Production Examples M1 and M2 were transformed into sols by gentle hand agitation. The average particle size measurements of 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one dihydrate are shown below. The primary average particle size of Production Example M1 was 8.8 μm, and the secondary average particle size was 10.8 μm. The primary average particle size of Production Example M2 was 8.3 μm, and the secondary average particle size was 10.2 μm.

Table 24

^* : As an anhydrous form, the concentration of 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one dihydrate (300 mg/mL)

^** : Measurements are performed in a circulating water medium without ultrasonic irradiation.

^*** : Measurements are taken in a circulating water medium under ultrasonic irradiation.

After standing at 5°C, the viscosity of the injectable formulations of Production Examples M1 and M2 was measured. Specifically, the formulation of Production Example M2 was in a sol state after standing at 5°C; however, before being placed in the rheometer, the formulations of Production Examples M1 and M2 were hand-shaken to confirm that they were in a sol state, and their viscosity was measured at 5°C, 25°C, or 40°C (measurement temperature) in the same manner as in Test Example 1.

Figure 20a shows the viscosity measurement results. In the results shown in Figure 20a, Table 25 summarizes the data for specific viscosity measured at shear rates in the range of 0.01 to 0.02 (1/s) and at shear rates in the range of 900 to 1000 (1/s).

Table 25

After production, the injectable formulations of Production Examples M1 and M2 were stored under stable conditions at 5°C, 25°C, or 40°C for 5 days. Except for the formulation of Production Example M2 stored at 5°C, all of them gelled. (Figure 20b shows photographs of the containers containing the injectable formulations after being slowly tilted and placed horizontally after standing for 5 days. In the explanation of Test Example 11, Production Example M1 and Production Example M2 can be referred to as "Povidone K17 0.1 mg/mL" and "Povidone K17 1.0 mg/mL", respectively).

Synthesis Example 1

Methanol (149 L), 7-hydroxy-1H-quinoline-2-one (14.87 kg), and potassium hydroxide (6.21 kg) were mixed in a reaction vessel and stirred. After dissolution, 1-bromo-4-chlorobutane (47.46 kg) was added, and the mixture was stirred under reflux for 7 hours. Subsequently, the mixture was stirred at 10°C for 1 hour. The precipitated crystals were centrifuged and washed with methanol (15 L). The wet crystals were collected and placed in a tank. Water (149 L) was added, and the mixture was stirred at room temperature. After centrifugation, the mixture was washed with water (30 L). The wet crystals were collected and placed in a tank. Methanol (74 L) was added, and the mixture was stirred under reflux for 1 hour, cooled to 10°C, and then 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-quinoline-2-one (15.07 kg).

Subsequently, water (20 L), potassium carbonate (1.84 kg), 1-benzo[b]thiophene-4-yl-piperazine hydrochloride (3.12 kg), and ethanol (8 L) were mixed in a reaction vessel and stirred at 50 °C. 7-(4-chlorobutoxy)-1H-quinoline-2-one (2.80 kg) was added to the mixture, and the mixture was stirred under reflux for 9 hours. The solvent was concentrated to 8 L at atmospheric pressure, and the mixture was stirred at 90 °C for 1 hour, then cooled to 9 °C. The precipitated crystals were centrifuged and washed successively with water (8 L) and ethanol (6 L). The separated crystals were dried at 60 °C to obtain the 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 introduced into the reaction vessel. The mixture was stirred under reflux for 1 hour to dissolve the crude product. After the introduction of hydrochloric acid (1.29 kg), the mixture was cooled to 10 °C. The mixture was reheated and refluxed for 1 hour, then cooled to 7°C. The precipitated crystals were centrifuged and washed with ethanol (4.8 L). The separated crystals were dried at 60°C to obtain 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one hydrochloride (5.09 kg). The obtained 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one hydrochloride (5.00 kg), ethanol (45 L), and water (30 L) were mixed in a reaction vessel. The mixture was stirred under reflux to dissolve 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one hydrochloride. Activated carbon (500 g) and water (5 L) were added, and the mixture was subjected to activated carbon treatment under reflux for 30 minutes. After hot filtration, a solution containing 511 g of sodium hydroxide dissolved in 1.5 L of water was introduced into the reaction vessel while the filtrate was stirred under reflux. After stirring under reflux for 30 minutes, water (10 L) was introduced and the mixture was cooled to approximately 40 °C. The precipitated crystals were centrifuged and washed with water (125 L). The separated crystals were dried at 80 °C to obtain 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one (3.76 kg).

The above-obtained 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one (3.2 kg), ethanol (64 L), water (74 L), and acetic acid (1.77 kg) were mixed in a reaction vessel to prepare an acidic liquid mixture. The liquid mixture was stirred under reflux to dissolve 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one (reflux temperature: 84 °C). After cooling to -5 °C, the solution obtained above was introduced over 30 minutes into a solution containing 25% sodium hydroxide (5.9 kg) and water (54 L) cooled to 0 °C to prepare a liquid mixture with pH 10. After stirring at 5 °C or below for 1 hour, the mixture was heated to 20 to 30 °C and stirred further for 7 hours for solid-liquid separation. Wash with water (320 L) until the alkali in the solid component disappears (i.e. until the pH of the filtrate becomes 7). Then, air-dry the solid component until its weight is constant (i.e. until the observed weight no longer changes) to obtain a white solid 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one dihydrate (unground, 3.21 kg).

Claims (30)

1. An injectable formulation comprising a composition comprising a poorly soluble drug, a dispersing medium, and a suspending agent, wherein the suspending agent comprises polyvinylpyrrolidone. The viscosity of the composition, measured by a rheometer at 5°C, 25°C, or 40°C, is 40 Pa·s or higher at at least one point in the shear rate range of 0.01 to 0.02 ^s⁻¹ , and 0.2 Pa·s or lower at at least one point in the shear rate range of 900 to 1000 ^s⁻¹ . The poorly soluble drug mentioned therein is aripiprazole or its salt. The poorly soluble drug has an average primary particle size of 30 μm or less and is contained at a concentration of 200 to 600 mg/mL on an anhydrous basis. Polyvinylpyrrolidone has a K value of 10 to 30, and The concentration of polyvinylpyrrolidone is 0.1 to 100 mg/mL. 2. An injectable formulation comprising a composition comprising a poorly soluble drug, a dispersing medium, and a suspending agent, wherein the suspending agent comprises polyvinylpyrrolidone. Measured by a rheometer at 25°C, the viscosity of the composition is 40 Pa·s or higher at at least one point in the shear rate range of 0.01 to 0.02 ^s⁻¹ , and 0.2 Pa·s or lower at at least one point in the shear rate range of 900 to 1000 ^s⁻¹ . The poorly soluble drug mentioned therein is aripiprazole or its salt. The poorly soluble drug has an average primary particle size of 30 μm or less and is contained at a concentration of 200 to 600 mg/mL on an anhydrous basis. Polyvinylpyrrolidone has a K value of 10 to 30, and The concentration of polyvinylpyrrolidone is 0.1 to 100 mg/mL. 3. The injectable formulation according to claim 1 or 2, comprising a composition wherein the composition comprises at least water as a dispersion medium. 4. The injectable formulation according to claim 1 or 2, wherein the suspending agent further comprises polyethylene glycol. 5. The injectable formulation according to claim 1 or 2, wherein the suspending agent further comprises polyethylene glycol and carboxymethyl cellulose or a salt thereof. 6. The injectable formulation according to claim 1 or 2, wherein the K value of polyvinylpyrrolidone is 12 to 30, and the concentration of polyvinylpyrrolidone is 0.2 to 50 mg/mL. 7. The injectable formulation according to claim 1 or 2, wherein aripiprazole or a salt thereof is aripiprazole monohydrate or a salt thereof. 8. A gel composition comprising: Poorly soluble drugs, namely aripiprazole or its salts. Water, and Suspending agents The suspending agent comprises polyvinylpyrrolidone. The poorly soluble drug has an average primary particle size of 0.5 to 30 μm and is contained at a concentration of 200 to 600 mg/mL on an anhydrous basis. Polyvinylpyrrolidone has a K value of 10 to 30, and The concentration of polyvinylpyrrolidone is 0.1 to 100 mg/mL. 9. The composition of claim 8, wherein the suspending agent further comprises polyethylene glycol. 10. The composition of claim 8, wherein the suspending agent further comprises polyethylene glycol and carboxymethyl cellulose or a salt thereof. 11. The composition according to claim 10, wherein the concentration of polyethylene glycol is from 0.05 to 2 mg/mL, and the concentration of carboxymethyl cellulose or a salt thereof is from 0.5 to 50 mg/mL. 12. The composition according to claim 8 or 9, wherein the average secondary particle size of the poorly soluble drug is up to but does not exceed three times its average primary particle size. 13. The composition according to claim 8 or 9, wherein the K value of polyvinylpyrrolidone is 12 to 30, and the concentration of polyvinylpyrrolidone is 0.2 to 50 mg/mL. 14. The composition according to claim 8 or 9, when measured by a rheometer at 5°C, 25°C or 40°C, has a viscosity of 40 Pa·s or higher at at least one point in a shear rate range of 0.01 to 0.02 ^s⁻¹ , and a viscosity of 0.2 Pa·s or lower at at least one point in a shear rate range of 900 to 1000 ^s⁻¹ . 15. The composition according to claim 8 or 9, when measured by a rheometer at 25°C, has a viscosity of 40 Pa·s or higher at at least one point in a shear rate range of 0.01 to 0.02 ^s⁻¹ , and a viscosity of 0.2 Pa·s or lower at at least one point in a shear rate range of 900 to 1000 ^s⁻¹ . 16. The composition according to claim 8 or 9, wherein aripiprazole or a salt thereof is a hydrate of aripiprazole or a salt thereof. 17. A sustained-release injectable formulation comprising the following composition, said composition comprising: Poorly soluble drugs, namely aripiprazole or its salts. Water, and Suspending agents The suspending agent comprises polyvinylpyrrolidone. The poorly soluble drug has an average primary particle size of 1 to 10 μm and is contained at a concentration of 200 to 400 mg/mL on an anhydrous basis. Polyvinylpyrrolidone has a K value of 10 to 30, and The concentration of polyvinylpyrrolidone is from 0.1 to 100 mg/mL. The composition exists in gel form when left to stand, and changes into a sol upon impact. The preparation is applied once a month. 18. The injectable formulation of claim 17, wherein the poorly soluble drug has an average primary particle size of 2 to 7 μm. 19. A sustained-release injectable formulation comprising the following composition, said composition comprising: Poorly soluble drugs, namely aripiprazole or its salts. Water, and Suspending agents The suspending agent comprises polyvinylpyrrolidone. The poorly soluble drug has an average primary particle size of 4 to 30 μm and is contained at a concentration of 300 to 600 mg/mL on an anhydrous basis. Polyvinylpyrrolidone has a K value of 10 to 30, and The concentration of polyvinylpyrrolidone is from 0.1 to 100 mg/mL. The composition exists in gel form when left to stand, and changes into a sol upon impact. The preparation is applied once every 2 to 3 months. 20. The injectable formulation of claim 19, wherein the poorly soluble drug has an average primary particle size of 5 to 20 μm. 21. The injectable formulation according to any one of claims 17 to 20, wherein the suspending agent further comprises polyethylene glycol. 22. The injectable formulation according to any one of claims 17 to 20, wherein the suspending agent further comprises polyethylene glycol and carboxymethyl cellulose or a salt thereof. 23. The injectable formulation according to claim 22, wherein, The concentration of the polyethylene glycol is from 0.05 to 2 mg/mL, and the concentration of the carboxymethyl cellulose or its salt is from 0.5 to 50 mg/mL. 24. The injectable formulation according to any one of claims 17 to 20, wherein the K value of polyvinylpyrrolidone is 12 to 30, and the concentration of polyvinylpyrrolidone is 0.2 to 50 mg/mL. 25. The injectable formulation according to any one of claims 17 to 20, wherein the average secondary particle size of the poorly soluble drug is up to but does not exceed three times its average primary particle size. 26. The injectable formulation according to any one of claims 17 to 20, wherein, measured by a rheometer at 5°C, 25°C or 40°C, the viscosity of the composition at at least one point in a shear rate range of 0.01 to 0.02 ^s⁻¹ is 40 Pa·s or higher, and the viscosity at at least one point in a shear rate range of 900 to 1000 ^s⁻¹ is 0.2 Pa·s or lower. 27. The injectable formulation according to any one of claims 17 to 20, wherein, measured by a rheometer at 25°C, the viscosity of the composition at at least one point in a shear rate range of 0.01 to 0.02 ^s⁻¹ is 40 Pa·s or higher, and the viscosity at at least one point in a shear rate range of 900 to 1000 ^s⁻¹ is 0.2 Pa·s or lower. 28. The injectable formulation according to any one of claims 17 to 20, wherein aripiprazole or a salt thereof is aripiprazole monohydrate or a salt thereof. 29. The use of the injectable formulation of any one of claims 1 to 7, 17 to 28 for the manufacture of a medicament for the treatment or prevention of relapse of schizophrenia, bipolar disorder or depression. 30. The use according to claim 29, wherein the injectable formulation is administered intramuscularly or subcutaneously.