Sustained-release formulation for injection

1. A composition comprising the following (1) to (5),

(1) N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-(2R,3R)-2,3-tetramethylene-butyl]-(1′R, 2′S, 3′R, 4′S)-2,3-bicyclo[2,2,1]heptanedicarboximide or a pharmaceutically acceptable acid addition salt thereof as an active ingredient,

wherein the active ingredient is in crystal form, and the mean particle size of the crystal is about 4 μm - about 26 μm,

(2) a surfactant comprising at least one ingredient selected from the group consisting of polysorbate 80, polysorbate 20, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, poloxamer 188 and polyoxyethylene castor oil,

(3) a buffer comprising at least one ingredient selected from the group consisting of sodium phosphate, disodium hydrogenphosphate, sodium dihydrogenphosphate, potassium phosphate, dipotassium hydrogenphosphate, potassium dihydrogenphosphate, trometamol, sodium carbonate, sodium bicarbonate, meglumine, arginine, triethanolamine and citric acid,

(4) an isotonic agent comprising at least one ingredient selected from the group consisting of sodium chloride and D-mannitol, and

(5) water for injection.

2. The composition of claim 1 wherein the mean particle size of the crystal is about 4 μm - about 20 μm, about 4 μm - about 18 μm, about 4 μm - about 16 μm, about 5 μm - about 26 μm, about 5 μm - about 20 μm, about 5 μm - about 18 μm, about 5 μm - about 16 μm, about 8 μm - about 20 μm, about 10 μm - about 26 μm, about 10 μm - about 20 μm, about 10 μm - about 18 μm, or about 10 μm-about 16 μm.

3. The composition of claim 1 wherein the crystal is a cubic crystal.

4. The composition of claim 3 wherein the ratio between length and width of the cubic crystal is about 1:1, and the ratio between length and height thereof is about 1:0.8 to about 1:1.2.

5. The composition of claim 1 wherein the active ingredient in crystal form is contained in about 5% (w/v) to about 60% (w/v) per the whole of the composition.

6. The composition of claim 1 wherein the surfactant is polysorbate 80.

7. The composition of claim 1 wherein the surfactant is contained in about 0.005% (w/v) to about 2% (w/v) per the whole of the composition.

8. The composition of claim 1 wherein the buffer is sodium dihydrogenphosphate and/or disodium hydrogenphosphate.

9. The composition of claim 1 wherein the buffer is contained in about 0.01% (w/v) to about 2% (w/v) per the whole of the composition.

10. The composition of claim 1 wherein the isotonic agent is sodium chloride.

11. The composition of claim wherein the isotonic agent is contained in about 0.1% (w/v) to about 10% (w/v) per the whole of the composition.

12. A sustained release formulation for injection which comprises the composition according to claim 1 .

13. The formulation of claim 12 wherein the active ingredient is contained in a concentration of about 50 mg/mL to about 600 mg/mL.

14. The formulation of claim 12 wherein the surfactant is contained in a concentration of about 0.05 mg/mL to about 20 mg/mL.

15. The formulation of claim 12 wherein the buffer is contained in a concentration of about 0.1 mg/mL to about 20 mg/mL.

16. The formulation of claim 12 wherein the isotonic agent is contained in a concentration of about 1 mg/mL to about 100 mg/mL.

17. The formulation of claim 12 which contains about 50 mg to about 1200 mg of the active ingredient per a container.

18. The formulation of claim 12 which can pass through a needle of 18 to 23 gauges.

19. The formulation of claim 12 wherein the sustained release formulation for injection is a depot formulation for injection.

20. A process for preparation of a sustained-release sterile formulation of claim 12 comprising the following steps (1) to (5):

step (1): dissolving a mixture comprising N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-(2R,3R)-2,3-tetra-methylene-butyl]-(1′R, 2′S, 3′R, 4′S)-2,3-bicyclo[2,2,1]-heptanedicarboximide or a pharmaceutically acceptable acid addition salt thereof and a surfactant with an organic solvent or a mixture of an organic solvent and water, and then sterilely-filtering the solution through a sterile filter,

wherein the surfactant in this step (1) is independently at least one ingredient selected from the group consisting of polysorbate 80, polysorbate 20, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, poloxamer 188, polyoxyethylene castor oil, benzalkonium chloride and sodium lauryl sulfate,

step (2): preparing a water solution comprising a surfactant and a buffer, sterilely filtering the water solution through a sterile filter, and then sterilely putting the water solution into a sealed vessel whose inside is sterilized,

wherein the surfactant in this step (2) is independently at least one ingredient selected from the group consisting of polysorbate 80, polysorbate 20, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, poloxamer 188, polyoxyethylene castor oil, benzalkonium chloride and sodium lauryl sulfate,

step (3): sterilely adding the sterile solution prepared in step (1) into the sealed vessel containing the water solution in step (2),

step (4): collecting a crystal precipitated in step (3) through a filter in the sealed vessel, and

step (5): preparing a water solution comprising a surfactant, a buffer, an isotonic agent and water for injection, sterilely filtering the water solution through a sterile filter, and then sterilely putting the water solution into the sealed vessel containing the crystal in step (4) and mixing the water solution and the crystal.

21. A process for preparation of a sustained-release formulation of claim 12 comprising the following steps (1) to (5):

step (1): dissolving a mixture comprising N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-(2R,3R)-2,3-tetra-methylene-butyl]-(1′R,2′S,3′R,4′S)-2,3-bicyclo[2,2,1]-heptanedicarboximide or a pharmaceutically acceptable acid addition salt thereof and a surfactant with an organic solvent or a mixture of an organic solvent and water to prepare a solution of the active ingredient,

wherein the surfactant in this step (1) is independently at least one ingredient selected from the group consisting of polysorbate 80, polysorbate 20, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, poloxamer 188, polyoxyethylene castor oil, benzalkonium chloride and sodium lauryl sulfate,

step (2): preparing a water solution comprising a surfactant and a buffer (i.e. a crystallizing agent),

wherein the surfactant in this step (2) is independently at least one ingredient selected from the group consisting of polysorbate 80, polysorbate 20, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, poloxamer 188, polyoxyethylene castor oil, benzalkonium chloride and sodium lauryl sulfate,

step (3): adding the solution of the active ingredient prepared in step (1) into the crystallizing agent in step (2),

step (4): collecting a crystal precipitated in step (3) through a filter, and

step (5): preparing a water solution comprising a surfactant, a buffer, an isotonic agent and water for injection (i.e. a vehicle solution), and then mixing the water solution and the crystal of the active ingredient prepared in step (4) to prepare a suspension formulation.

22. The process of claim 20 or 21 further followed by the following steps (6) to (8):

step (6): aseptically filling a formulation container with the suspension formulation prepared in step (5) to prepare a filled suspension formulation,

step (7): sterilizing the filled suspension formulation prepared in step (6) by a process of steaming under pressure, and

step (8): ultrasonicating the filled suspension formulation prepared in step (7).

23. The process of claim 20 or 21 , in step (3) the solution of the active ingredient is added to the crystallizing agent in the vessel for crystallization (or the sealed vessel) while circulating the solution (or the suspension solution), in the vessel for crystallization (or the sealed vessel) via a bypass pathway equipped with a pump which can pressure a solution.

24. The process of claim 23 wherein the pump in the bypass pathway is a roller pump.

25. A process for preparation of a sustained-release formulation of claim 12 comprising the following steps (1) to (5):

step (1): dissolving a mixture comprising N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-(2R,3R)-2,3-tetra-methylene-butyl]-(1′R,2′S,3′R,4′S)-2,3-bicyclo[2,2,1]-heptanedicarboximide or a pharmaceutically acceptable acid addition salt thereof and a surfactant with an organic solvent or a mixture of an organic solvent and water to prepare a solution of the active ingredient,

wherein the surfactant in this step (1) is independently at least one ingredient selected from the group consisting of polysorbate 80, polysorbate 20, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, poloxamer 188, polyoxyethylene castor oil, benzalkonium chloride and sodium lauryl sulfate,

step (2): preparing a water solution comprising a surfactant and a buffer (i.e. a crystallizing agent) and injecting the water solution into a vessel for crystallization equipped with a stirring system,

wherein the surfactant in this step (2) is independently at least one ingredient selected from the group consisting of polysorbate 80, polysorbate 20, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, poloxamer 188, polyoxyethylene castor oil, benzalkonium chloride and sodium lauryl sulfate,

step (3): adding the solution of the active ingredient to the crystallizing agent in the vessel for crystallization while circulating the solution (or the suspension solution) in the vessel for crystallization via a bypass pathway equipped with a pump which (i) is connected to the vessel for crystallization, (ii) can make the solution in the vessel for crystallization circulated, and (iii) can pressure the solution,

step (4): collecting a crystal precipitated in the vessel for crystallization from the solution (or the suspension solution) in step (3) through a filter, and

step (5): preparing a water solution comprising a surfactant, a buffer, an isotonic agent and water for injection (i.e. a vehicle solution), and then injecting the water solution into the crystal of the active ingredient prepared in step (4) and mixing them to prepare a suspension formulation.

26. A process for preparation of a sustained-release formulation of claim 12 comprising the following steps (4) to (8):

step (4): preparing a vehicle solution comprising a surfactant, a buffer, an isotonic agent and water for injection,

step (5): injecting the vehicle solution in step (4) into a crystal of N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-(2R,3R)-2,3-tetramethylene -butyl]-(1′R,2′S,3′R,4′S)-2,3-bicyclo[2,2,1]heptanedicarboximide and mixing them to prepare a suspension formulation,

step (6): aseptically filling a formulation container with the suspension formulation prepared in step (5) to prepare a filled suspension formulation

step (7): sterilizing the filled suspension formulation prepared in step (6) by a process of steaming under pressure, and

step (8): ultrasonicating the filled suspension formulation prepared in step (7).

27. The process of any one of claims 20 , 21 , or 25 wherein the organic solvent is a single solvent or a mixture of two or more solvents selected from the group consisting of 1-propanol, methanol, ethanol, 2-propanol, acetone, dimethylsulfoxide and N,N-dimethylacetamide.

28. The process of any one of claim 20 , 21 , or 25 wherein the solvent used in step (1) is a mixture of an organic solvent and water.

29. The process of claim 28 wherein the mixture solvent is a water-containing alcohol.

30. The process of claim 28 wherein the mixture of an organic solvent and water is a water-containing ethanol and the content of ethanol in the water-containing ethanol is 40% to 90%.

31. The process of any one of claim 20 , 21 , 25 or 26 wherein each the buffer is independently at least one ingredient selected from the group consisting of sodium dihydrogenphosphate, disodium hydrogenphosphate, potassium dihydrogenphosphate, dipotassium hydrogenphosphate, sodium carbonate, triethanolamine, arginine and meglumine.

32. The process of any one of claim 20 , 21 , 25 or 26 wherein the isotonic agent is sodium chloride and/or D-mannitol.

33. A sustained release formulation for injection which is prepared through the process of any one of claim 20 , 21 , 25 or 26 .

34. A method for treating psychiatric disease which comprises administering the composition of claim 1 .

35. The method of claim 34 wherein the psychiatric disease is schizophrenia.

36. The method of claim 34 wherein the psychiatric disease is bipolar disorder.

37. The method of claim 34 wherein the psychiatric disease is depression.

38. A sustained release formulation of claim 12 which is prepared through a process for preparation of a sustained-release formulation for injection comprising the following steps (1) to (5):

step (1): dissolving a mixture comprising N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-(2R,3R)-2,3-tetramethylene-butyl]-(1′R,2′S,3′R,4′S)-2,3-bicyclo[2,2,1]-heptanedicarboximide or a pharmaceutically acceptable acid addition salt thereof and a surfactant with an organic solvent or a mixture of an organic solvent and water to prepare a solution of the active ingredient,

wherein the surfactant in this step (1) is independently at least one ingredient selected from the group consisting of polysorbate 80, polysorbate 20, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, poloxamer 188, polyoxyethylene castor oil, benzalkonium chloride and sodium lauryl sulfate,

step (2): preparing a water solution comprising a surfactant and a buffer (i.e. a crystallizing agent) and injecting the water solution into a vessel for crystallization equipped with a stirring system,

wherein the surfactant in this step (2) is independently at least one ingredient selected from the group consisting of polysorbate 80, polysorbate 20, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, poloxamer 188, polyoxyethylene castor oil, benzalkonium chloride and sodium lauryl sulfate,

step (3): adding the solution of the active ingredient to the crystallizing agent in the vessel for crystallization while circulating the solution (or the suspension solution) in the vessel for crystallization via a bypass pathway equipped with a pump which (i) is connected to the vessel for crystallization, (ii) can make the solution in the vessel for crystallization circulated, and (iii) can pressure the solution,

step (4): collecting a crystal precipitated in the vessel for crystallization from the solution (or the suspension solution) in step (3) through a filter, and

step (5): preparing a water solution comprising a surfactant, a buffer, an isotonic agent and water for injection (i,e, a vehicle solution), and then injecting the water solution into the crystal of the active ingredient prepared in step (4) and mixing them to prepare a suspension formulation

wherein the formulation comprises a composition comprising the following (1) to (5),

(1) N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-(2R,3R)-2,3-tetramethylene-butyl]-(1′R,2′S,3′R,4′S)-2,3-bicyclo[2,2,1]heptanedicarboximide or a pharmaceutically acceptable acid addition salt thereof as an active ingredient,

wherein the active ingredient is in crystal form, the mean particle size of the crystal is about 4 μm-about 26 μm, and the crystal is a cubic crystal,

(2) a surfactant comprising at least one ingredient selected from the group consisting of polysorbate 80, polysorbate 20, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, poloxamer 188 and polyoxyethylene castor oil,

(3) a buffer comprising at least one ingredient selected from the group consisting of sodium phosphate, disodium hydrogenphosphate, sodium dihydrogenphosphate, potassium phosphate, dipotassium hydrogenphosphate, potassium dihydrogenphosphate, trometamol, sodium carbonate, sodium bicarbonate, meglumine, arginine, triethanolamine and citric acid,

(4) an isotonic agent comprising at least one ingredient selected from the group consisting of sodium chloride and D-mannitol, and

(5) water for injection.

39. The formulation of claim 38 wherein the solvent used in step (1) is a mixture of an organic solvent and water,

wherein the mixture of an organic solvent and water is a water-containing ethanol and the content of ethanol in the water-containing ethanol is 40% to 90%.

40. A sustained release formulation of claim 12 which is prepared through a process for preparation of a sustained-release formulation for injection comprising the following steps (1) to (5):

step (1): dissolving a mixture comprising N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-(2R,3R)-2,3-tetramethylene-butyl]-(1′R,2′S,3′R,4′S)-2,3-bicyclo[2,2,1]heptanedicarboximide or a pharmaceutically acceptable acid addition salt thereof and a surfactant with an organic solvent or a mixture of an organic solvent and water, and then sterilely-filtering the solution through a sterile filter,

wherein the surfactant in this step (1) is independently at least one ingredient selected from the group consisting of polysorbate 80, polysorbate 20, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, poloxamer 188, polyoxyethylene castor oil, benzalkonium chloride and sodium lauryl sulfate,

step (2): preparing a water solution comprising a surfactant and a buffer, sterilely filtering the water solution through a sterile filter, and then sterilely putting the water solution into a sealed vessel whose inside is sterilized,

wherein the surfactant in this step (2) is independently at least one ingredient selected from the group consisting of polysorbate 80, polysorbate 20, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, poloxamer 188, polyoxyethylene castor oil, benzalkonium chloride and sodium lauryi sulfate,

step (3): sterilely adding the sterile solution prepared in step (1) into the sealed vessel containing the water solution in step (2),

step (4): collecting a crystal precipitated in step (3) through a filter in the sealed vessel, and

step (5): preparing a water solution comprising a surfactant, a buffer, an isotonic agent and water for injection, sterilely filtering the water solution through a sterile filter, and then sterilely putting the water solution into the sealed vessel containing the crystal in step (4) and mixing the water solution and the crystal;

wherein the formulation comprises a composition comprising the following (1) to (5),

(1) N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-(2R,3R)-2,3-tetramethylene-butyl]-(1′R,2′S,3′R,4′S)-2,3-bicyclo[2,2,1]heptanedicarboximide or a pharmaceutically acceptable acid addition salt thereof as an active ingredient,

wherein the active ingredient is in crystal form, the mean particle size of the crystal is about 4 μm-about 26 μm, and the crystal is a cubic crystal,

(2) a surfactant comprising at least one ingredient selected from the group consisting of polysorbate 80, polysorbate 20, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, poloxamer 188 and polyoxyethylene castor oil,

(3) a buffer comprising at least one ingredient selected from the group consisting of sodium phosphate, disodium hydrogenphosphate, sodium dihydrogenphosphate, potassium phosphate, dipotassium hydrogenphosphate, potassium dihydrogenphosphate, trometamol, sodium carbonate, sodium bicarbonate, meglumine, arginine, triethanolamine and citric acid,

(4) an isotonic agent comprising at least one ingredient selected from the group consisting of sodium chloride and D-mannitol, and

(5) water for injection.

41. A sustained release formulation of claim 12 which is prepared through a process for preparation of a sustained-release formulation for injection comprising the following steps (1) to (5):

step (1): dissolving a mixture comprising N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-(2R,3R)-2,3-tetramethylene-butyl]-(1′R,2′S,3′R,4′S)-2,3-bicyclo[2,2,1]-heptanedicarboximide or a pharmaceutically acceptable acid addition salt thereof and a surfactant with an organic solvent or a mixture of an organic solvent and water to prepare a solution of the active ingredient,

wherein the surfactant in this step (1) is independently at least one ingredient selected from the group consisting of polysorbate 80, polysorbate 20, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, poloxamer 188, polyoxyethylene castor oil, benzalkonium chloride and sodium lauryl sulfate,

step (2): preparing a water solution comprising a surfactant and a buffer (i.e. a crystallizing agent),

wherein the surfactant in this step (2) is independently at least one ingredient selected from the group consisting of polysorbate 80, polysorbate 20, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, poloxamer 188, polyoxyethylene castor oil, benzalkonium chloride and sodium lauryl sulfate,

step (3): adding the solution of the active ingredient prepared in step (1) into the crystallizing agent in step (2),

step (4): collecting a crystal precipitated in step (3) through a filter, and

step (5): preparing a water solution comprising a surfactant, a buffer, an isotonic agent and water for injection (i.e. a vehicle solution), and then mixing the water solution and the crystal of the active ingredient prepared in step (4) to prepare a suspension formulation;

wherein the formulation comprises a composition comprising the following (1) to (5),

(1) N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-(2R,3R)-2,3-tetramethylene-butyl]-(1′R,2′S,3′R,4′S)-2,3-bicyclo[2,2,1]heptanedicarboximide or a pharmaceutically acceptable acid addition salt thereof as an active ingredient,

wherein the active ingredient is in crystal form, the mean particle size of the crystal is about 4 μm-about 26 μm, and the crystal is a cubic crystal,

(2) a surfactant comprising at least one ingredient selected from the group consisting of polysorbate 80, polysorbate 20, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, poloxamer 188 and polyoxyethylene castor oil,

(3) a buffer comprising at least one ingredient selected from the group consisting of sodium phosphate, disodium hydrogenphosphate, sodium dihydrogenphosphate, potassium phosphate, dipotassium hydrogenphosphate, potassium dihydrogenphosphate, trometamol, sodium carbonate, sodium bicarbonate, meglumine, arginine, triethanolamine and citric acid,

(4) an isotonic agent comprising at least one ingredient selected from the group consisting of sodium chloride and D-mannitol, and

(5) water for injection.

42. A composition comprising the following (1) to (5),

(1) N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-(2R,3R)-2,3-tetramethylene-butyl]-(1′R,2′S,3′R,4′S)-2,3-bicyclo[2,2,1]heptanedicarboximide or a pharmaceutically acceptable acid addition salt thereof as an active ingredient,

wherein the active ingredient is in crystal form, and the mean particle size of the crystal is about 4 μm-about 26 μm,

(2) a surfactant comprising at least one ingredient selected from the group consisting of polysorbate 80, polysorbate 20, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, poloxamer 188 and polyoxyethylene castor oil,

(3) a buffer comprising at least one ingredient selected from the group consisting of sodium phosphate, disodium hydrogenphosphate, sodium dihydrogenphosphate, potassium phosphate, dipotassium hydrogenphosphate, potassium dihydrogenphosphate, trometamol, sodium carbonate, sodium bicarbonate, meglumine, arginine, triethanolamine and citric acid,

(4) an isotonic agent comprising at least one ingredient selected from the group consisting of sodium chloride and D-mannitol, and

(5) water for injection;

wherein the composition is prepared through a process comprising a process of crystallization using a surfactant, which is independently at least one ingredient selected from the group consisting of polysorbate 80, polysorbate 20, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, poloxamer 188, polyoxyethylene castor oil, benzalkonium chloride and sodium lauryl sulfate.

43. A composition comprising the following (1) to (5),

(1) N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-(2R,3R)-2,3-tetramethylene-butyl]-(1′R,2′S,3′R,4′S)-2,3-bicyclo[2,2,1]heptanedicarboximide or a pharmaceutically acceptable acid addition salt thereof as an active ingredient,

wherein the active ingredient is in crystal form, and the mean particle size of the crystal is about 4 μm-about 26 μm,

(2) a surfactant comprising at least one ingredient selected from the group consisting of polysorbate 80, polysorbate 20, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, poloxamer 188 and polyoxyethylene castor oil,

(3) a buffer comprising at least one ingredient selected from the group consisting of sodium phosphate, disodium hydrogenphosphate, sodium dihydrogenphosphate, potassium phosphate, dipotassium hydrogenphosphate, potassium dihydrogenphosphate, trometamol, sodium carbonate, sodium bicarbonate, meglumine, arginine, triethanolamine and citric acid,

(4) an isotonic agent comprising at least one ingredient selected from the group consisting of sodium chloride and D-mannitol, and

(5) water for injection;

wherein the composition is prepared through a process comprising the following steps (1) to (5):

step (1): dissolving a mixture comprising N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-(2R,3R)-2,3-tetramethylene-butyl]-(1′R,2′S,3′R,4′S)-2,3-bicyclo[2,2,1]-heptanedicarboximide or a pharmaceutically acceptable acid addition salt thereof and a surfactant with an organic solvent or a mixture of an organic solvent and water to prepare a solution of the active ingredient, wherein the surfactant in this step (1) is independently at least one ingredient selected from the group consisting of polysorbate 80, polysorbate 20, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, poloxamer 188, polyoxyethylene castor oil, benzalkonium chloride and sodium lauryl sulfate,

step (2): preparing a water solution comprising a surfactant and a buffer (Le, a crystallizing agent) and injecting the water solution into a vessel for crystallization equipped with a stirring system, wherein the surfactant in this step (2) is independently at least one ingredient selected from the group consisting of polysorbate 80, polysorbate 20, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, poloxamer 188, polyoxyethylene castor oil, benzalkonium chloride and sodium lauryl sulfate,

step (3): adding the solution of the active ingredient to the crystallizing agent in the vessel for crystallization while circulating the solution (or the suspension solution) in the vessel for crystallization via a bypass pathway equipped with a pump which (i) is connected to the vessel for crystallization, (ii) can make the solution in the vessel for crystallization circulated, and (iii) can pressure the solution,

step (4): collecting a crystal precipitated in the vessel for crystallization from the solution (or the suspension solution) in step (3) through a filter, and

step (5): preparing a water solution comprising a surfactant, a buffer, an isotonic agent and water for injection (i.e. a vehicle solution), and then injecting the water solution into the crystal of the active ingredient prepared in step (4) and mixing them to prepare a suspension formulation.

44. The composition of claim 42 or 43 wherein the crystal is a cubic crystal.