TW202100157A - Aqueous suspension pharmaceutical preparation with controlled particle size - Google Patents

Abstract

The present invention provides an aqueous suspension pharmaceutical preparation comprising (1) (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione (Compound 1), a pharmaceutically acceptable acid addition salt thereof, or a mixture thereof and (2) one or more chlorides selected from an inorganic chloride or quaternary ammonium chloride having 4 to 12 carbon atoms, which has the following feature (I) or (II): (I) D90 of the suspended particle in the preparation is 1 to 50 μm when the particle size distribution of the suspended particle is unimodal; (II) D90 of the suspended particle in the preparation is 1 to 90 μm when the particle size distribution of the suspended particle is bimodal or more multimodal, which produces not only no bitter taste and improved administration feeling but also good absorbability of the drug.

Description

Aqueous suspension type pharmaceutical preparation with controlled particle diameter

The present invention relates to an aqueous suspension type pharmaceutical preparation. Specifically, the present invention relates to a method of making (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piper𠯤 -1-ylmethyl]cyclohexylmethyl)hexahydro-4,7-methyl bridge-2H-isoindole-1,3-dione (hereinafter also referred to as "compound 1"), its pharmaceutical institute An aqueous suspension type pharmaceutical preparation in which an allowable acid addition salt or a mixture thereof (hereinafter also referred to as "compound 1 or its salt") is suspended in a solvent containing water. Preferably, it relates to a preparation for use as a medicine.

Known (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperidin-1-ylmethyl] ring Hexylmethyl}hexahydro-4,7-methyl bridge-2H-isoindole-1,3-dione (compound 1) is a compound that can be used as an unspecified antipsychotic, and is effective for schizophrenia, bipolar disorder, The treatment of mental illnesses such as depression is effective (for example, Patent Document 1 to Patent Document 3).

Generally, in most diseases, oral solid preparations such as tablets or capsules can be taken at home, and they are widely used as easy-to-take dosage forms. However, in schizophrenia and other mental diseases, the symptoms involve multiple aspects according to the conditions of each patient. For example, there are many conditions that cannot be adequately dealt with by oral solid preparations: To patients with acute schizophrenia The administration of the drug, the administration to patients such as children or the elderly who especially need to adjust the dosage, the administration to the patients who refuse to take the medication, and the administration to the patients with difficulty swallowing. Especially in recent years, the number of elderly people has been increasing. Therefore, the medical field strongly expects to provide oral liquids or injections as medicines that are less burdensome for these patients and improve the adaptability of taking medication.

So far, as an oral liquid preparation of compound 1, a solution-type preparation has been reported, which is characterized in that N-[4-[4-(1,2-benzisothiazole- 3-yl)-1-piperidyl)-(2R,3R)-2,3-tetramethylene-butyl)-(1'R,2'S,3'R,4'S)-2,3-bicyclic [2,2,1]Heptane dicarboxyimidine hydrochloride as an active ingredient and contains at least one selected from benzyl alcohol, N,N-dimethylacetamide, lactic acid or propylene glycol (patent Literature 4). However, in Patent Document 4, although an effort is made to make the compound solubilized at a high concentration, and the solubility or stability as a solution-type preparation is characteristic, it has not been studied from the perspective of drug dynamics. Furthermore, in Patent Document 4, there is no disclosure or suggestion regarding a suspension type preparation.

In Patent Document 5, it is disclosed that N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperidyl]- as compound 1 is contained in the form of suspended particles. (2R,3R)-2,3-tetramethylene-butyl)-(1'R,2'S,3'R,4'S)-2,3-bicyclo[2,2,1]heptane dicarboxyl The composition of imine or its pharmaceutically acceptable acid addition salt, in more detail, discloses a sustained-release preparation for injection that can maintain the effective blood concentration of the compound. However, Patent Document 5 does not disclose oral administration of the preparation. That is, in Patent Document 5, there is no disclosure or suggestion regarding the feeling of ingestion, absorbability, etc. when the preparation is orally administered. [Prior Technical Literature] [Patent Literature]

[Patent Document 1] Japanese Patent No. 2800953 (US 5532372 A) [Patent Document 2] International Publication No. 2005/009999 [Patent Document 3] International Publication No. 2006/126681 [Patent Document 4] International Publication No. 2006/134864 [Patent Document 5] International Publication No. 2012/053654

[The problem to be solved by the invention]

In the manufacture of suspension liquids, the setting of the particle diameter range of the suspended particles of the drug is very important. In order to slow down the dissolution rate of the drug in the oral cavity, increasing the suspended particles (that is, reducing the specific surface area of the suspended particles) can be expected to make it difficult to feel the bitter taste of the drug. In particular, for drugs that cause a strong bitter taste such as compound 1 or its salt, it is desirable to enlarge the suspended particles as much as possible to mask the bitter taste. On the other hand, the dissolution rate of larger suspended particles after entering the digestive tract is also slower, so there is a problem that the possibility of hindering the absorption of the drug becomes higher.

Generally speaking, when studying the absorption in the digestive tract of suspension liquids, in most cases, the digestive tract is evaluated using the dissolution test method (paddle method) described in the 17th revised edition of the Japanese Pharmacopoeia. For the dissolution performance under the internal pH value (for example, if it is gastric juice, the pH value is about 1 to 3), for example, set the particle diameter showing a stable dissolution rate as the management range. However, when the dissolution rate is significantly reduced as the particle diameter increases like a suspension of compound 1 or its salt, the study of increasing the particle diameter to mask the bitter taste is very difficult and is considered to be substantially impossible.

The present invention has been made in view of the above circumstances, and its subject is to provide a suspension type liquid formulation that uses compound 1 or its salt as suspended particles to form a suspension, and is set to not inhibit the drug. The upper limit of the suspended particle diameter that can be absorbed can even cover up the bitter taste to improve the feeling of taking, and the absorption of the drug is also good. [Technical means to solve the problem]

The inventors of the present invention conducted intensive research to solve the above-mentioned problems. As a result, they found that an aqueous suspension type pharmaceutical preparation containing a specific relatively large particle diameter of Compound 1 or its salt, or a specific large particle diameter and The aqueous suspension type pharmaceutical preparation of compound 1 or its salt of a mixture of smaller particle diameters improves the ability to mask the bitter taste from the drug, and although the dissolution is reduced, it is also shown to be the same as the LATUDA (Lurasidone HCl) Tablet sold in the US in 2018 (40 mg) (Sunovion) the same level of absorption, thus completing the present invention.

That is, the present invention is as follows. [Item 1] An aqueous suspension type pharmaceutical preparation containing (1)(3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzoiso Thiazol-3-yl)piperidin-1-ylmethyl)cyclohexylmethyl)hexahydro-4,7-methyl bridge-2H-isoindole-1,3-dione (compound 1), its pharmacy Acid addition salts or mixtures of the above allowable acid addition salts, and (2) one or more chlorides selected from inorganic chlorides or quaternary ammonium chlorides with 4 to 12 carbon atoms, and having the following ( Features of I) or (II): (I) When the particle size distribution of the suspended particles in the formulation is unimodal, the D90 of the suspended particles is 1-50 μm; (II) When the particle size distribution of the suspended particles in the formulation is bimodal or more multimodal, the D90 of the suspended particles is 1-100 μm.

[Item 2] The aqueous suspension type pharmaceutical preparation as described in Item 1, wherein the suspended particles in the preparation contain suspended particles containing compound 1, its pharmaceutically acceptable acid addition salt or a mixture of these, And the suspended particles containing compound 1, its pharmacologically acceptable acid addition salt or a mixture of these have the characteristics of (I) or (II) above.

[Item 3] The aqueous suspension type pharmaceutical preparation according to Item 2, wherein the suspended particles in the preparation are suspended particles containing compound 1, its pharmaceutically acceptable acid addition salt, or a mixture thereof.

[Item 4] The aqueous suspension type pharmaceutical preparation as described in Item 2 or Item 3, wherein the preparation does not contain a suspension containing compound 1, its pharmaceutically acceptable acid addition salt or a mixture thereof Suspended particles other than particles.

[Item 5] The aqueous suspension type pharmaceutical preparation according to any one of items 1 to 4, wherein the suspended particles in the preparation have the characteristics of (I).

[Item 6] The aqueous suspension type pharmaceutical preparation as described in Item 5, wherein the suspended particles in the preparation have a D50 of 3-15 μm.

[Item 7] The aqueous suspension type pharmaceutical preparation as described in Item 5, wherein the suspended particles in the preparation have a D50 of 3 to 11 μm.

[Item 8] The aqueous suspension type pharmaceutical preparation as described in Item 5, wherein the suspended particles in the preparation have a D50 of 3-8 μm.

[Item 9] The aqueous suspension type pharmaceutical preparation as described in Item 5, wherein the suspended particles in the preparation have a D50 of 3 to 6 μm.

[Item 10] The aqueous suspension type pharmaceutical preparation as described in Item 5, wherein the suspended particles in the preparation have a D50 of 4-6 μm.

[Item 11] The aqueous suspension type pharmaceutical preparation as described in Item 5, wherein the suspended particles in the preparation have a D50 of 5 to 11 μm.

[Item 12] The aqueous suspension type pharmaceutical preparation as described in Item 5, wherein the suspended particles in the preparation have a D50 of 5 to 8 μm.

[Item 13] The aqueous suspension type pharmaceutical preparation described in Item 5, wherein the suspended particles in the preparation have a D50 of 5 to 7 μm.

[Item 14] The aqueous suspension type pharmaceutical preparation as described in Item 5, wherein the suspended particles in the preparation have a D50 of 6 to 11 μm.

[Item 15] The aqueous suspension type pharmaceutical preparation as described in Item 5, wherein the suspended particles in the preparation have a D50 of 6 to 8 μm.

[Item 16] The aqueous suspension type pharmaceutical preparation as described in Item 5, wherein the suspended particles in the preparation have a D50 of 7 to 11 μm.

[Item 17] The aqueous suspension type pharmaceutical preparation as described in Item 5, wherein the suspended particles in the preparation have a D50 of 9-11 μm.

[Item 18] The aqueous suspension type pharmaceutical preparation as described in Item 5, wherein the D90 of the suspended particles in the preparation is 6 to 29 μm.

[Item 19] The aqueous suspension type pharmaceutical preparation as described in Item 5, wherein the suspended particles in the preparation have a D90 of 6 to 18 μm.

[Item 20] The aqueous suspension type pharmaceutical preparation as described in Item 5, wherein the suspended particles in the preparation have a D90 of 6-12 μm.

[Item 21] The aqueous suspension type pharmaceutical preparation as described in Item 5, wherein the D90 of the suspended particles in the preparation is 10-12 μm.

[Item 22] The aqueous suspension type pharmaceutical preparation as described in Item 5, wherein the suspended particles in the preparation have a D90 of 11-29 μm.

[Item 23] The aqueous suspension type pharmaceutical preparation as described in Item 5, wherein the D90 of the suspended particles in the preparation is 11-24 μm.

[Item 24] The aqueous suspension type pharmaceutical preparation as described in Item 5, wherein the suspended particles in the preparation have a D90 of 11 to 18 μm.

[Item 25] The aqueous suspension type pharmaceutical preparation as described in Item 5, wherein the D90 of the suspended particles in the preparation is 16 to 18 μm.

[Item 26] The aqueous suspension type pharmaceutical preparation as described in Item 5, wherein the suspended particles in the preparation have a D90 of 17-29 μm.

[Item 27] The aqueous suspension type pharmaceutical preparation as described in Item 5, wherein the suspended particles in the preparation have a D90 of 17 to 24 μm.

[Item 28] The aqueous suspension type pharmaceutical preparation as described in Item 5, wherein the D90 of the suspended particles in the preparation is 23-29 μm.

[Item 29] The aqueous suspension type pharmaceutical preparation as described in Item 5, wherein the D90 of the suspended particles in the preparation is 27-29 μm.

[Item 30] The aqueous suspension type pharmaceutical preparation according to any one of items 1 to 4, wherein the suspended particles in the preparation have the feature (II).

[Item 31] The aqueous suspension type pharmaceutical preparation as described in Item 30, wherein the suspended particles in the preparation have a D50 of 1 to 6 μm.

[Item 32] The aqueous suspension type pharmaceutical preparation as described in Item 30 or Item 31, wherein the suspended particles in the preparation include particles having a D50 of 75 to 190 μm and a D90 of 120 to 420 μm and particles having a diameter of 0.8 to 3 μm D50 and D90 particles of 2-9 μm, and the mass ratio is 1:9-4:6.

[Item 33] The aqueous suspension type pharmaceutical preparation according to any one of items 1 to 32, which has a pH in the range of 2.5 to 5.5.

[Item 34] The aqueous suspension type pharmaceutical preparation as described in Item 33, which has a pH in the range of 3.0 to 5.5.

[Item 35] The aqueous suspension type pharmaceutical preparation as described in Item 33, which has a pH in the range of 3.0 to 5.0.

[Item 36] The aqueous suspension type pharmaceutical preparation according to any one of items 1 to 35, wherein the chloride is selected from sodium chloride, potassium chloride, ferrous chloride, calcium chloride, magnesium chloride, and chloride At least one of the group consisting of choline.

[Item 37] The aqueous suspension type pharmaceutical preparation described in Item 36, wherein the chloride is at least one selected from the group consisting of sodium chloride, potassium chloride, and choline chloride.

[Item 38] The aqueous suspension type pharmaceutical preparation as described in Item 36, wherein the chloride is at least one selected from the group consisting of sodium chloride and choline chloride.

[Item 39] The aqueous suspension type pharmaceutical preparation as described in Item 36, wherein the chloride is sodium chloride.

[Item 40] The aqueous suspension type pharmaceutical preparation according to any one of items 1 to 39, wherein the chloride ion concentration in the preparation is about 0.015 to about 1 mol/L (wherein, no salt derived from compound 1 The chloride ion).

[Item 41] The aqueous suspension type pharmaceutical preparation according to Item 40, wherein the chloride ion concentration is about 0.05 to about 1 mol/L.

[Item 42] The aqueous suspension type pharmaceutical preparation according to Item 40, wherein the chloride ion concentration is about 0.10 to about 1 mol/L.

[Item 43] The aqueous suspension type pharmaceutical preparation according to any one of items 1 to 42, which further contains a dispersant.

[Item 44] The aqueous suspension type pharmaceutical preparation according to Item 43, wherein the dispersant is at least one selected from the group consisting of cellulose derivatives, sucrose fatty acid esters, and polyvinyl alcohol.

[Item 45] The aqueous suspension type pharmaceutical preparation as described in Item 44, wherein the dispersant is a cellulose derivative.

[Item 46] The aqueous suspension type pharmaceutical preparation as described in Item 43, wherein the dispersant is hypromellose.

[Item 47] The aqueous suspension type pharmaceutical preparation according to any one of items 43 to 46, wherein the content of the dispersant in the preparation is about 0.1 to about 20 mg/mL.

[Item 48] The aqueous suspension type pharmaceutical preparation according to any one of items 1 to 47, which further contains a thickener.

[Item 49] The aqueous suspension type pharmaceutical preparation according to Item 48, which contains at least one selected from polysaccharides as a thickener.

[Item 50] The aqueous suspension type pharmaceutical preparation as described in Item 48, wherein the viscosity-increasing agent is Sanxian gum.

[Item 51] The aqueous suspension type pharmaceutical preparation according to any one of items 48 to 50, wherein the content of the thickener in the preparation is about 0.5 to about 20 mg/mL.

[Item 52] The aqueous suspension type pharmaceutical preparation according to any one of items 1 to 51, which further contains a preservative.

[Item 53] The aqueous suspension type pharmaceutical preparation according to Item 52, wherein the preservative is at least one selected from benzoic acid derivatives.

[Item 54] The aqueous suspension type pharmaceutical preparation as described in Item 52 or Item 53, wherein the content of the preservative in the preparation is about 0.1 to about 10 mg/mL.

[Item 55] The aqueous suspension type pharmaceutical preparation according to any one of items 1 to 54, which further contains a stabilizer.

[Item 56] The aqueous suspension type pharmaceutical preparation according to Item 55, wherein the stabilizer is at least one selected from polyhydric alcohols.

[Item 57] The aqueous suspension type pharmaceutical preparation as described in Item 55 or Item 56, wherein the content of the stabilizer in the preparation is about 1 to about 500 mg/mL.

[Item 58] The aqueous suspension type pharmaceutical preparation according to any one of items 1 to 57, wherein the content of compound 1, its pharmacologically acceptable acid addition salt or a mixture thereof in the preparation is converted into The hydrochloride of Compound 1 is about 5 to about 120 mg/mL.

[Item 59] The aqueous suspension type pharmaceutical preparation according to any one of items 1 to 57, wherein the content of compound 1, its pharmacologically acceptable acid addition salt or a mixture thereof in the preparation is converted into The hydrochloride of Compound 1 is about 10 to about 100 mg/mL.

[Item 60] The aqueous suspension type pharmaceutical preparation according to any one of items 1 to 57, wherein the content of compound 1, its pharmacologically acceptable acid addition salt or a mixture thereof in the preparation is converted into The hydrochloride of compound 1 is about 20 to about 80 mg/mL.

[Item 61] The aqueous suspension type pharmaceutical preparation according to any one of items 1 to 60, wherein compound 1, its pharmaceutically acceptable acid addition salt or a mixture thereof is the hydrochloride of compound 1 .

[Item 62] The aqueous suspension type pharmaceutical preparation according to any one of items 1 to 61, which is for oral administration.

[Item 63] An aqueous suspension type pharmaceutical preparation as described in any one of items 1 to 62, which is based on the dissolution test method (stirring paddle method) described in the 17th revised edition of the Japanese Pharmacopoeia under the following test conditions When the test is carried out, the dissolution rate of compound 1, its pharmacologically acceptable acid addition salt or the mixture of these compounds within 5 minutes of the start of the test is 30-90% or less: [Test conditions] Test solution: Japanese Pharmacopoeia 17th revised edition, dissolution test first solution Liquid volume of test solution: 900 mL Test solution temperature: 36.5～37.5℃ Rotation speed: 50 revolutions per minute Test preparation: a preparation containing 40 mg of compound 1, its pharmacologically acceptable acid addition salt or a mixture thereof when converted into the hydrochloride salt of compound 1.

[Item 64] The aqueous suspension type pharmaceutical preparation described in any one of Item 1 to Item 62, which is based on the dissolution test method (stirring paddle method) described in the 17th revised edition of the Japanese Pharmacopoeia under the following test conditions When the test is carried out, the dissolution rate of compound 1, its pharmacologically acceptable acid addition salt or a mixture of these within 10 minutes of the start of the test is 45-95% or less: [Test conditions] Test solution: Japanese Pharmacopoeia 17th revised edition, dissolution test first solution Liquid volume of test solution: 900 mL Test solution temperature: 36.5～37.5℃ Rotation speed: 50 revolutions per minute Test preparation: a preparation containing 40 mg of compound 1, its pharmacologically acceptable acid addition salt or a mixture thereof when converted into the hydrochloride salt of compound 1.

[Item 65] The aqueous suspension type pharmaceutical preparation according to any one of items 1 to 64, which shows that the AUC obtained when LATUDA (registered trademark) tablets (40 mg) is orally administered is within ± AUC within 10%.

[Item 66] An aqueous suspension type pharmaceutical preparation, characterized in that it contains (1)(3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2- Benzoisothiazol-3-yl)piperidin-1-ylmethyl)cyclohexylmethyl)hexahydro-4,7-methyl bridge-2H-isoindole-1,3-dione (compound 1), The acid addition salt or the mixture of these pharmacologically acceptable, and (2) one or more chlorides selected from inorganic chlorides or quaternary ammonium chlorides with 4-12 carbons, in the preparation The particle size distribution of the suspended particles is bimodal or more multimodal, D90 is 1-100 μm, and its mass ratio is 1:9-4:6 containing D50 with 75 μm～190 μm And 120 μm～420 μm D90 particles and 0.8 μm～3 μm D50 and 2 μm～9 μm D90 particles.

[Item 67] The aqueous suspension type pharmaceutical preparation as described in Item 66, wherein the mass ratio is 1:9 to 3:7.

[Item 68] An aqueous suspension type pharmaceutical preparation containing (3aR, 4S, 7R, 7aS)-2-{(1R, 2R)-2-[4-(1,2-benzisothiazole -3-yl)piperidin-1-ylmethyl)cyclohexylmethyl)hexahydro-4,7-methyl bridge-2H-isoindole-1,3-dione (compound 1), its pharmaceutical Allowable acid addition salts or mixtures of these particles have a D50 of 75 μm～190 μm and a D90 of 120 μm～420 μm, and a particle of a D50 of 0.8 μm～3 μm and a D90 of 2 μm～9 μm (1) Compound 1, its pharmacologically acceptable acid addition salt or a mixture of these, and (2) selected from inorganic chloride or carbon by mixing in a mass ratio of 1:9 to 4:6 One or more chlorides among 4-12 quaternary ammonium and chlorides.

[Item 69] A therapeutic and/or preventive agent for mental illness, which contains the aqueous suspension type pharmaceutical preparation according to any one of items 1 to 68.

[Item 70] The therapeutic and/or preventive agent according to Item 69, wherein the mental illness is schizophrenia, bipolar disorder, senile dementia, or depression.

[Item 71] A method for treating and/or preventing mental illness, which comprises administering the aqueous suspension type pharmaceutical preparation described in any one of items 1 to 68 to a patient in need of treatment.

[Item 72] The method as described in Item 71, wherein the mental illness is schizophrenia, bipolar disorder, senile dementia, or depression.

[Item 73] A use of the aqueous suspension type pharmaceutical preparation according to any one of items 1 to 68 for the manufacture of a therapeutic and/or preventive agent for mental illness.

[Item 74] The use as described in Item 73, wherein the mental illness is schizophrenia, bipolar disorder, dementia and depression.

[Item 75] The aqueous suspension type pharmaceutical preparation according to any one of items 1 to 68, which is used for the treatment and/or prevention of mental illness.

[Item 76] The aqueous suspension type pharmaceutical preparation as described in Item 75, wherein the mental illness is schizophrenia, bipolar disorder, and Alzheimer's depression.

[Item 77] A (3aR, 4S, 7R, 7aS)-2-{(1R, 2R)-2-[4-(1,2-benzisothiazol-3-yl)piper-1-ylmethyl Cyclohexylmethyl)hexahydro-4,7-methyl bridge-2H-isoindole-1,3-dione (compound 1), its pharmacologically acceptable acid addition salt or a mixture of these The bulk drug particles are used to prepare the aqueous suspension type pharmaceutical preparations described in any one of items 1 to 68, and have a D50 of 3 μm-9 μm and a D90 of 9 μm-27 μm.

Item 66 to item 68 can be combined with any or all of the features described in item 33 to item 65, and also includes aspects having such features as aspects of the present invention. [Effects of Invention]

According to the present invention, even in the case of oral administration of an aqueous suspension type pharmaceutical preparation containing Compound 1 or its salt as an active ingredient, the bioequivalence with existing tablets can be guaranteed. Thereby, it is possible to inhibit excessive dissolution and absorption, and to reduce the risk of unexpected side effects caused by a temporary increase in blood concentration. In addition, the ability to mask the bitter taste of Compound 1 or its salt can be improved, and the feeling of ingestion can be improved.

Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the following embodiments.

The present invention relates to compound 1 or its salt, and discloses an aqueous suspension type pharmaceutical preparation suitable for oral administration as a therapeutic drug for schizophrenia and the like.

In the present invention, the so-called "aqueous suspension type pharmaceutical preparation" containing compound 1 or its salt as an active ingredient refers to a compound 1 or its salt dispersed in the solvent in the form of suspended particles using water as the main solvent preparation. In the present invention, the so-called "suspended particles in the preparation" is preferably "suspended particles containing compound 1 or its salt" (or in this specification, it is also referred to as "suspended particles of compound 1 or its salt" with the same meaning. Turbid particles"). The term "suspended particles containing compound 1 or its salt" means that it is suspended in a solvent, or is in a state capable of being suspended, and can infiltrate or swell to the particles other than the solvent. Only compound 1 or its salt is used as the substance Suspended particles of its constituent components. The "aqueous suspension type pharmaceutical preparation" in the present invention may contain, in addition to water, a polar solvent in an amount that does not adversely affect the feeling of ingestion (bitterness, astringency, astringency, etc.).

In the present invention, the so-called "polar solvent" means a solvent that has polarity and can be uniformly mixed with water. Examples of the polar solvent include methanol, ethanol, butanol, propanol, tert-butanol, propylene glycol, and acetonitrile, preferably ethanol, tert-butanol, and propylene glycol, and more preferably propylene glycol.

(3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piper𠯤-1-ylmethyl] of the present invention Cyclohexylmethyl}hexahydro-4,7-methyl bridge-2H-isoindole-1,3-dione (compound 1) is a compound represented by the following formula. [化1]

Compound 1 or its salt has pharmacological effects as antipsychotics. More specifically, compound 1 or its salts, and pharmaceutical preparations containing them can be used as therapeutic drugs for mental illnesses such as schizophrenia, bipolar disorder, and depression, and are also useful for improving depressive symptoms in bipolar disorder.

Pharmaceutically acceptable acid addition salts of Compound 1 include organic acid addition salts and inorganic acid addition salts. For example, as an addition salt of an organic acid, acetate, lactate, adipate, citrate, tartrate, methanesulfonate, fumarate, maleate, etc. can be cited. Examples of addition salts of inorganic acids include hydrochloride, sulfate, nitrate, and phosphate, but are not limited to these. Preferably it is hydrochloride. Furthermore, compound 1 and its pharmaceutically acceptable acid addition salt may be a solvate, or may be either a hydrate or a non-hydrate.

Compound 1 or a pharmaceutically acceptable acid addition salt thereof can be produced, for example, by the method described in Patent Document 1 and Patent Document 2, or a method based thereon. The manufactured compound 1 or its pharmacologically acceptable acid addition salt can be pulverized by a commonly used method if necessary.

In the present invention, the so-called "(3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piper𠯤-1- Methyl]cyclohexylmethyl)hexahydro-4,7-methyl bridge-2H-isoindole-1,3-dione, its pharmacologically acceptable acid addition salt or a mixture of these The "mixtures" include: (1) Compound 1 (free form) and the pharmaceutically acceptable acid addition salt of Compound 1 (the acid addition salt can be one or more than two) Mixture, (2) Two or more kinds of compound 1 pharmacologically acceptable acid addition salt mixture, etc.

In the present invention, "(3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperidin-1-yl Methyl)cyclohexylmethyl)hexahydro-4,7-methyl bridge-2H-isoindole-1,3-dione, its pharmacologically acceptable acid addition salt or a mixture of these (compound 1 The content of "or its salt)" is appropriately changed according to the amount of the drug solution, and is usually about 0.1 to about 400 mg/mL when converted to the hydrochloride of compound 1 in the preparation. The content of "compound 1 or its salt" is preferably about 1 to about 300 mg/mL when converted to the hydrochloride of compound 1, more preferably about 5 to about 120 mg/mL, and still more preferably about 10 to about 100 mg/mL, more preferably about 20 to about 80 mg/mL, particularly preferably about 25 to about 80 mg/mL, most preferably about 25 to about 50 mg/mL. Specific examples thereof include formulations of 25 mg/mL, 30 mg/mL, 35 mg/mL, 40 mg/mL, 45 mg/mL, 50 mg/mL, and the like. Here, the term "converted to the hydrochloride of compound 1" means that the acid addition salt or hydrate or solvate of compound 1, which is acceptable in pharmacology of compound 1, is replaced by a compound equivalent to that of compound 1. 1 based on the weight of the hydrochloride.

In the present invention, the so-called "chloride" refers to inorganic chloride or quaternary ammonium chloride with 4 to 12 carbon atoms. Examples of the inorganic chloride include sodium chloride, potassium chloride, ferrous chloride, calcium chloride, magnesium chloride, zinc chloride, ammonium chloride, etc., preferably sodium chloride and potassium chloride, and more preferably Sodium chloride. The quaternary ammonium chloride with 4 to 12 carbon atoms may be organic quaternary ammonium chloride with the total carbon number in the range of 4 to 12, and it is not particularly limited. It is preferably chain-like Or organic quaternary ammonium composed of cyclic alkyl, alkylene, etc. (the quaternary ammonium may also have functional groups such as hydroxyl, amino, and acyl groups), and choline chloride is particularly preferred.

The chloride ion concentration in the preparation is about 0.015 to about 1 mol/L, preferably about 0.05 to about 1 mol/L, more preferably about 0.10 to about 1 mol/L, but is not limited to these . Wherein, the chloride ion concentration in the preparation does not contain the chloride ion derived from the salt of compound 1.

The pH of the aqueous suspension type pharmaceutical preparation of the present invention is in the range of 2.5 to 5.5, preferably in the range of 3.0 to 5.5, and more preferably in the range of 3.0 to 5.0.

The dissolution rate of suspended particles of Compound 1 or its salt contained in the aqueous suspension type pharmaceutical preparation of the present invention can be measured. The dissolution rate of suspended particles of Compound 1 or its salt can be measured in accordance with the dissolution test method (stirring paddle method) described in the 17th revised edition of the Japanese Pharmacopoeia, for example. In this dissolution test method, put (inject) the compound containing the hydrochloride converted to compound 1 into the first solution (900 mL) of the dissolution test of the 17th revised edition of the Japanese Pharmacopoeia at 36.5～37.5℃. 1 or its salt preparation. For example, as a method of injecting (injecting) a preparation containing compound 1 or its salt, the following method can be cited: measuring the preparation containing compound 1 or its salt into a syringe, and installing a needle (needle) at the front end of the syringe containing the preparation The outer and inner diameters are not limited.) After that, the tip of the needle is immersed in the test solution, and the preparation is injected into the test solution at a speed at which the preparation is sufficiently dispersed in the test solution, but it is not limited Here. Then, the stirring blade was rotated at 50 rpm, and the test solution was sampled at 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, and 60 minutes from the start of the test, and the dissolved concentration of compound 1 or its salt was measured. The value obtained by expressing the measured dissolved concentration in the test solution as a percentage relative to the dissolved concentration (40 mg/900 mL) when completely dissolved is defined as the dissolution rate.

In the aqueous suspension type pharmaceutical preparation of the present invention, when the dissolution test method described in the 17th revised edition of the Japanese Pharmacopoeia (stirring paddle method) is implemented by the above method, the dissolution of compound 1 or its salt at 5 minutes after the start of the test When the rate is converted into the hydrochloride of Compound 1, it is, for example, 30 to 90%, preferably 35 to 86%, and more preferably 40 to 81%. In addition, when the elution rate of compound 1 or its salt at 10 minutes from the start of the test is converted into the hydrochloride of compound 1, it is, for example, 45-95%, preferably 50-95, more preferably 60-95%. When the dissolution rate of compound 1 or its salt at 60 minutes from the start of the test is converted into the hydrochloride of compound 1, for example, it is 60 to 110%, preferably 70 to 105%, more preferably 75 to 100%.

The area under the concentration curve (AUC) of the aqueous suspension type pharmaceutical preparation of the present invention is within ±10% of the AUC obtained when LATUDA (registered trademark) Tablet (40 mg) is orally administered. In the present invention, the subjects of administration of aqueous suspension type pharmaceutical preparations and existing lozenges (LATUDA (registered trademark) Tablet (40 mg)) can be animals such as dogs or humans.

In the present invention, the term "D50" means 50% particle diameter (median diameter). D50 can be calculated by "volume basis", "number basis", "area basis", "quality basis", etc., but is not limited to these. In the present invention, when there is no special description, it is calculated by "volume basis". The D50 of the suspended particles in the aqueous suspension type pharmaceutical preparation of the present invention is in the range of about 0.1 to about 15 μm, about 0.5 to about 15 μm, about 1 to about 15 μm, and about 2 to about 15 μm. The range is about 3 to about 15 μm, about 5 to about 15 μm, about 7 to about 15 μm, or about 9 to about 15 μm, but it is not limited to these. Regarding the D50 of the suspended particles in the aqueous suspension type pharmaceutical preparation of the present invention, when the particle size distribution is unimodal, it is preferably in the range of about 1 to about 15 μm, more preferably about 2 to about 11 μm The range is more preferably about 3 to about 11 μm, about 3 to about 8 μm, about 3 to about 7 μm, about 3 to about 6 μm, about 4 to about 6 μm, about 5 to about 11 μm, about 5 to about 8 μm, about 5 to about 7 μm, about 6 to about 11 μm, about 6 to about 8 μm, about 7 to about 11 μm, about 9 to about 11 μm, the particle size distribution is double In the case of peaking or more peaks, it is preferably in the range of about 1 to about 6 μm, more preferably in the range of about 2 to about 5 μm, and still more preferably in the range of about 2 to about 3.5 μm.

In the present invention, the term "D90" refers to 90% particle diameter. D90 can be calculated by "volume basis", "number basis", "area basis", "quality basis", etc., but is not limited to these. In the present invention, when there is no special description, it is calculated by "volume basis". The D90 of the suspended particles in the aqueous suspension type pharmaceutical preparation of the present invention is in the range of about 1 to about 100 μm, but is not limited to these. Regarding the D90 of the suspended particles in the aqueous suspension type pharmaceutical preparation of the present invention, when the particle size distribution is unimodal, it is preferably in the range of about 1 to about 50 μm, more preferably about 4 to about 35 μm The range is more preferably about 5 to about 20 μm, about 6 to about 29 μm, about 6 to about 25 μm, about 6 to about 24 μm, about 6 to about 18 μm, about 6 to about 12 μm, about 8 to about 17 μm, about 10 to about 15 μm, about 10 to about 12 μm, about 11 to about 29 μm, about 11 to about 24 μm, about 11 to about 18 μm, about 16 to about 18 μm, about 17 Any range of ~ about 29 μm, about 17 to about 24 μm, about 23 to about 29 μm, about 27 to about 29 μm, when the particle size distribution is bimodal or more multimodal, it is preferred It is in the range of about 1 to about 100 μm, more preferably in the range of about 5 to about 70 μm, and most preferably in the range of about 10 to about 55 μm.

Suspended particles of compound 1 or its salt having D50 in the range of about 1 to about 15 μm and D90 in the range of about 1 to about 50 μm, for example, can be used for compound 1 or the like by using a jet mill or a hammer mill. The salt is obtained by dry-grinding and dispersing it in a liquid, but it is not limited to these. Moreover, it can also be obtained by adding compound 1 or its salt to a solvent, and performing wet grinding using a homomixer, a high-speed rotating disperser, a high-pressure homogenizer, a bead mill, etc. Suspended particles of compound 1 or its salt having D50 in the range of about 1 to about 6 μm and D90 in the range of about 1 to about 100 μm can also be obtained by adding D50 and about D50 in the range of about 75 to about 190 μm. Compound 1 or its salt with D90 in the range of 120 to about 420 μm, and compound 1 or its salt with D50 in the range of about 0.8 to about 3 μm and D90 in the range of about 2 to about 9 μm at 1:9 to After adding the mass ratio of 4:6 to the solvent, it can be obtained by decoagulating or wet grinding using a homomixer, high-speed rotating disperser, high-pressure homogenizer, bead mill, etc., but it is not limited to these. Furthermore, the quality ratio is preferably 1:9 to 3:7, more preferably 2:8 to 3:7. Furthermore, as a method other than pulverizing Compound 1 or its salt, it can also be obtained by subjecting Compound 1 or its salt to a commonly used recrystallization operation.

As the compound 1 or its salt used in the production of the aqueous suspension type pharmaceutical preparation of the present invention, for example, the compound 1 or its salt obtained by dry pulverization, wet pulverization, recrystallization operations, etc., having a diameter of about 0.1 to about 15 μm can be used. Compound 1 or its salt with D50 in the range and D90 in the range of about 1 to about 100 μm, but not limited to these. On the other hand, even when the compound 1 or its salt having no D50 in the range of about 0.1 to about 15 μm and D90 in the range of about 1 to about 100 μm is used in the production of the aqueous suspension type pharmaceutical preparation of the present invention In this case, it is also possible to prepare suspended particles of compound 1 or its salt having D50 in the range of about 0.1 to about 15 μm and D90 in the range of about 1 to about 100 μm by performing wet pulverization in the production step. In addition, as the compound 1 or its salt used in the production of the aqueous suspension type pharmaceutical preparation of the present invention, the unpulverized compound 1 or its salt and the pulverized compound 1 or its salt can be mixed and used. At the time of manufacture, the D50 of Compound 1 or its salt obtained by dry pulverization, wet pulverization, recrystallization operations, etc., may be in the range of about 0.1 to about 15 μm, preferably about 1 to about 10 μm. The range is more preferably in the range of about 3 to about 9 μm, and still more preferably in the range of about 3 to about 5 μm or about 7 to about 9 μm. During manufacture, the D90 of Compound 1 or its salt obtained by dry pulverization, wet pulverization, recrystallization operations, etc., should be in the range of about 1 to about 100 μm, preferably about 5 to about 30 μm. Or about 9 to about 27 μm, more preferably about 5 to about 20 μm or about 22 to about 29 μm, still more preferably about 5 to about 17 μm, about 12 to about 18 μm, or about 23 ～Any one in the range of 28 μm.

Generally, the particle diameter system is measured and calculated using a laser diffraction type particle size measuring device, a dynamic light scattering type particle size distribution measuring device, an image processing type particle size distribution measuring device, or the like. The values of D50 and D90 used in the present invention can be calculated from the particle size distribution measured by a laser diffraction particle size distribution measuring device: HELOS BR-MULTI (Sympatec). When the obtained particle size distribution becomes a mountain with a specific particle diameter as the apex, it is called "unimodality", and when there is a valley between the mountains of the particle size distribution, it is called "bimodality". The situation where there are more than two valleys between the mountains is called "multimodality".

The aqueous suspension type pharmaceutical preparation of the present invention may also contain "(3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl )Piper-1-ylmethyl)cyclohexylmethyl)hexahydro-4,7-methyl bridge-2H-isoindole-1,3-dione, its pharmacologically acceptable acid addition salt or These mixtures (compound 1 or its salt)" suspended particles (ie, "compound 1 or its salt-containing suspended particles") other than a trace or arbitrary amount of suspended particles (hereinafter also referred to as "Suspended particles other than compound 1 or its salt" or "suspended particles other than suspended particle containing compound 1 or its salt") are referred to as "suspended particles". As the aqueous suspension type pharmaceutical preparation, it is preferable that the content of "suspended particles of compound 1 or its salt" is such that it does not affect the absorbability of the preparation (including preparations with zero content). ), more preferably a preparation that does not contain suspended particles other than compound 1 or its salt. Alternatively, in the aqueous suspension type pharmaceutical preparation of the present invention, "suspended particles other than the suspended particles containing compound 1 or its salt" may be used for ordinary suspensions as long as it does not interfere with the effects of the present invention. The content of particles etc. prepared as additives for formulations or oral formulations is not limited to a trace amount as long as it does not interfere with the effects of the present invention, and may be any amount. In addition, the particle size distribution, D50, and D90 of "suspended particles other than suspended particles containing compound 1 or its salt" are arbitrary as long as they do not interfere with the effects of the present invention, and are not limited to those containing compound 1 or its salt Particle size distribution, D50, and D90 of suspended particles.

The aqueous suspension type pharmaceutical preparation of the present invention may also contain additives that can be used in ordinary suspension preparations as long as the effects of the present invention are not hindered. Examples of the additives include dispersants, thickeners, preservatives, stabilizers, buffers, sweeteners, colorants, fragrances, etc., but are not limited to these.

In the present invention, the "dispersant" is not particularly limited, as long as it is used as an additive in ordinary suspension formulations. Examples of dispersants include cellulose, hypromellose (hydroxypropyl methyl cellulose), hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, carboxyl Cellulose derivatives such as sodium methylcellulose; alkanols such as polyvinyl alcohol; sucrose fatty acid esters such as sucrose myristate, sucrose laurate, and sucrose stearate; polyglyceryl myristate, polyglyceryl laurel Polyglycerol fatty acid esters such as polyglyceryl stearate and polyglyceryl stearate; pyrrolidone derivatives such as polyvinylpyrrolidone; Poloxamer 188, HCO-60, polysorbate 80, polyoxyl stearate (40) Nonionic surfactants such as esters; Sodium lauryl sulfate ionic surfactants. As the dispersant, preferably, cellulose derivatives, sucrose fatty acid esters, and alkanols are cited, more preferably, cellulose derivatives, sucrose fatty acid esters, and polyvinyl alcohol are cited, and more preferably, cellulose derivatives are cited. As specific examples of the dispersant, preferably, hypromellose, hydroxypropyl cellulose, and hydroxyethyl cellulose are used, and more preferably, hypromellose is used. In addition, one type of dispersant may be used, or two or more types may be mixed and used.

The content of the dispersant is not particularly limited, but it is preferably about 0.01 to about 40 mg/mL relative to the total amount of the preparation. More specifically, when using cellulose derivatives such as hypromellose, hydroxypropyl cellulose, and hydroxyethyl cellulose or sucrose fatty acid esters such as sucrose laurate as a dispersing agent, the added concentration is relatively The total amount of the preparation is preferably about 0.1 to about 30 mg/mL, more preferably about 0.2 to about 20 mg/mL, and still more preferably about 0.1 to about 10 mg/mL, but is not limited to these. In addition, the concentration of addition in the case of using an alkanol such as polyvinyl alcohol as a dispersant is preferably about 0.1 to about 10 mg/mL, more preferably about 0.5 to about 5 mg/mL, relative to the total amount of the preparation. But it is not limited to these. When using polyglycerol fatty acid esters, pyrrolidone derivatives, nonionic surfactants, ionic surfactants, etc. as dispersants, the concentration of addition is preferably about 0.01 to about about 0.5 mg/mL, more preferably about 0.01 to about 0.1 mg/mL, but it is not limited to these.

The thickener is not particularly limited, as long as it is used as an additive in a usual suspension formulation. As the thickener, for example, polysaccharides such as trixian gum, ancient gum, tamarind gum, gellan gum, carrageenan, sodium carboxymethyl cellulose, sodium alginate, pectin, and agar; casein , Gelatin and other proteins; carboxyvinyl polymers and other acrylic polymers. As the thickener, preferably, polysaccharides and acrylic polymers are cited, and more preferably, polysaccharides are cited. As specific examples of the tackifier, it is preferable to cite three gums, ancient gums, carrageenans, sodium alginate and pectin, more preferably to cite three gums, ancient gums and sodium alginate, and more preferably To enumerate Sanxian gum and sodium alginate. In addition, one type of thickener may be used, or two or more types may be mixed and used. The content of the thickener is not particularly limited. It is preferably from about 0.5 to about 20 mg/mL, more preferably from about 1 to about 15 mg/mL, and still more preferably from about 2 to about 10 mg/mL.

The preservative is not particularly limited, as long as it is used as an additive in a usual suspension formulation. Examples of preservatives include: methylparaben, ethylparaben, propylparaben, butylparaben, paraben, paraben, benzoic acid, sodium benzoate and other benzoic acid derivatives. Compounds; sorbic acid, potassium sorbate, sodium ethylenediaminetetraacetate, citric acid, etc. have 1 to 4 carboxyl groups in a skeleton containing more than 3 carbon atoms; glycerol, ethanol, 2-propanol, propylene glycol and other alcohols . As the preservative, benzoic acid derivatives are preferred. As specific examples of the preservative, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, and sodium benzoate are preferably cited, more preferably paraben Methyl ester, propyl p-hydroxybenzoate, and sodium benzoate, more preferably methyl p-hydroxybenzoate and sodium benzoate, most preferably methyl p-hydroxybenzoate. In addition, one kind of preservative may be used, or two or more kinds may be mixed and used. The content of the preservative is not particularly limited. It is preferably about 0.1 to about 10 mg/mL, more preferably about 0.2 to about 5 mg/mL, and still more preferably about 0.25 to about 3 relative to the total amount of the preparation. mg/mL, more preferably about 0.5 to about 2.5 mg/mL.

The stabilizer is not particularly limited, as long as it is used as an additive in a usual suspension formulation. As a stabilizer, alcohol etc. are mentioned, for example. Examples of the alcohol include monohydric alcohols such as ethanol; polyhydric alcohols such as glycerol, propylene glycol, and polyethylene glycol; and sugar alcohols such as sorbitol, erythritol, and mannitol. As the stabilizer, polyhydric alcohols are preferably cited. As specific examples of the stabilizer, glycerin, sorbitol, erythritol, and propylene glycol are preferably cited, and propylene glycol is more preferably cited. In addition, one type of stabilizer may be used, or two or more types may be mixed and used. The content of the stabilizer is not particularly limited. It is preferably about 1 to about 500 mg/mL, more preferably about 10 to about 400 mg/mL, and still more preferably about 30 to about 350 relative to the total amount of the preparation. mg/mL, more preferably about 50 to about 300 mg/mL, particularly preferably about 50 to about 150 mg/mL.

The buffer is not particularly limited, as long as it is used as an additive in a usual suspension formulation. As a buffering agent, sodium salt, potassium salt, and these hydrates etc. are mentioned, for example. Examples of the sodium salt include disodium phosphate, monosodium phosphate, sodium bicarbonate, sodium carbonate, sodium citrate, and hydrates of these. Examples of potassium salts include dipotassium phosphate, monopotassium phosphate, potassium hydrogen carbonate, potassium carbonate, potassium citrate, and hydrates of these. As the buffer, sodium salt and potassium salt are preferred. Specific examples of the buffering agent include dipotassium phosphate, monopotassium phosphate, disodium phosphate, monosodium phosphate, and hydrates of these, more preferably dipotassium phosphate, monopotassium phosphate, disodium phosphate, phosphoric acid Monosodium and these hydrates, more preferably dipotassium phosphate, monosodium phosphate and these hydrates. In addition, one type of buffer may be used, or two or more types may be mixed and used.

Dipotassium phosphate and dipotassium hydrogen phosphate are the same substance, and monopotassium phosphate and potassium dihydrogen phosphate are the same substance.

The content of the buffer in the aqueous suspension type pharmaceutical preparation of the present invention is preferably about 0 to about 15 relative to 1 mg of compound 1 or its salt contained in the preparation (calculated as the weight of the hydrochloride salt of compound 1). mg is more preferably about 0 to about 5 mg, more preferably about 0 to about 0.85 mg, particularly preferably about 0 to about 0.5 mg, but is not limited to these. If the content of the buffer exceeds 15 mg relative to 1 mg of compound 1 or its salt contained in the formulation (converted to the weight of the hydrochloride of compound 1), it is considered that there are other additives such as dispersants that precipitate due to the salting-out effect , It is difficult to maintain the possibility of suspension.

The sweetener is not particularly limited, as long as it is used as an additive in a usual suspension formulation. Examples of sweeteners include sucralose, stevia, white sugar, liquid sugar, fructose, sorbitol, xylitol, erythritol, trehalose, maltitol, potassium acetosulfamate, and the like. As the sweetener, sucralose, stevia, sorbitol, and erythritol are preferably used, sucralose, stevia, and erythritol are more preferably used, and sucralose and stevia are more preferably used. In addition, one kind of sweetener may be used, or two or more kinds may be mixed and used.

The coloring agent is not particularly limited, as long as it is used as an additive in a usual suspension formulation. As a coloring agent, a tar color, yellow No. 5, caramel, etc. are mentioned, for example. Moreover, a coloring agent can be used 1 type or in mixture of 2 or more types.

The fragrance is not particularly limited, as long as it is used as an additive in a usual suspension formulation. Examples of flavors include apple flavor, medical flavor, lemon oil, orange oil, and peach oil. In addition, one kind of fragrance may be used, or two or more kinds may be mixed and used.

As a method for producing the aqueous suspension type pharmaceutical preparation of the present invention, a usual method for producing oral liquid preparations can be used. The aqueous suspension type pharmaceutical preparation of the present invention can be produced by, for example, the steps including the following (1) to (5), but it is not limited to these. (1) The dispersant and other additives are added to the solvent for dissolution. (2) To the solution prepared in (1) above, dry-pulverized compound 1 or its salt is added and mixed to prepare a liquid A. (3) If necessary, use a homomixer, agitator, a high-speed rotating disperser, etc., to disperse the agglomerates of compound 1 or its salt added in (2) above, or perform stirring, dispersion, etc., thereby making compound 1 or its salt Suspend evenly. (4) On the other hand, in another container, additives other than "Compound 1 or its salt and dispersant" are added to the solvent to dissolve to prepare liquid B. (5) The above-prepared liquid A and liquid B are each mixed in appropriate amounts, whereby the aqueous suspension type pharmaceutical preparation of the present invention can be manufactured. Here, in the steps including the above (1) to (5), the compound 1 or its salt, and the dispersant are preferably contained in the A liquid, and additives other than them may be contained in the A liquid, or It may be contained in liquid B, or in both liquid A and liquid B.

In addition, the aqueous suspension preparation of the present invention can also be produced by including the following steps (1) to (4). (1) The dispersant and other additives are added to the solvent for dissolution. (2) Add compound 1 or its salt to the solution prepared in (1) above, use a homomixer, agitator, high-speed rotating disperser, etc. to wet pulverize compound 1 or its salt, and then stir, disperse, etc. This suspends compound 1 or its salt uniformly, and prepares A liquid. (3) On the other hand, in another container, additives other than the dispersant are added to the solvent for dissolution to prepare liquid B. (4) The above-prepared liquid A and liquid B are each mixed in an appropriate amount to produce the aqueous suspension type pharmaceutical preparation of the present invention.

Furthermore, the aqueous suspension type preparation of this invention can also be manufactured by the process including the following (1)-(4). (1) The dispersant and other additives are added to the solvent for dissolution. (2) To the solution prepared in (1) above, respectively add an appropriate amount of unpulverized compound 1 or its salt and pulverized compound 1 or its salt, and use a homomixer, agitator, high-speed rotating disperser, etc. to mix compound 1 or The agglomerates of the salt are disassembled, and further stirred, dispersed, etc., to thereby uniformly suspend the compound 1 or its salt, and prepare a liquid A. (3) On the other hand, in another container, additives other than the dispersant are added to the solvent for dissolution to prepare liquid B. (4) The above-prepared liquid A and liquid B are each mixed in an appropriate amount to produce the aqueous suspension type pharmaceutical preparation of the present invention.

In the production of the aqueous suspension type pharmaceutical preparation of the present invention, when additives are added to a solvent for dissolution, a heated solvent can also be used for dissolution. In addition, the additives may be dissolved or suspended in propylene glycol, ethanol, glycerin, etc. in advance, and the solution may be mixed in the solvent. These steps are useful when dissolving additives that have low solubility in the solvent or take time to dissolve in the solvent. Examples of additives that have low solubility in the solvent or take time to dissolve include, but are not limited to, preservatives and thickeners.

The aqueous suspension type pharmaceutical preparation of the present invention has no particular problem even if bubbles exist in the preparation, and the production method can be studied in a manner that prevents the existence of bubbles. Specifically, for example, by appropriately adjusting the processing time, the intensity of the processing, the liquid temperature of the processed material, the pressure in the chamber, and other manufacturing conditions in the wet pulverization, stirring or dispersing step, it can be manufactured without air bubbles visually mixed. The aqueous suspension type pharmaceutical preparation of the present invention is not limited to these. On the other hand, even if bubbles are mixed in the preparation in the manufacturing step, the mixed bubbles can be removed from the aqueous suspension type pharmaceutical preparation of the present invention by providing a pressure reduction step, a stirring step, etc.

The storage container for the aqueous suspension type pharmaceutical preparation of the present invention is not particularly limited as long as it is used in ordinary oral liquid or injection medicines. Examples include vials, ampoules, glass bottles, and poly Ethylene bottles, sub-package containers using aluminum multilayer film, etc.

The aqueous suspension type pharmaceutical preparation of the present invention is manufactured at an appropriate concentration according to the main factors such as the dosage, and the dosage can be adjusted as needed for administration.

Even when the aqueous suspension type pharmaceutical preparation of the present invention is administered orally, it has less influence on the exercise state of the digestive tract or the environment in the digestive tract. Therefore, the aqueous suspension type pharmaceutical preparation of the present invention can also be used for emergency administration.

The aqueous suspension type pharmaceutical preparation of the present invention can be used as a therapeutic drug for schizophrenia, bipolar disorder, depression and other mental diseases, and is also useful for improving depressive symptoms in bipolar disorder. [Example]

Hereinafter, examples, comparative examples, test examples, etc. are given to further describe the present invention in detail, but the present invention is not limited to these.

In the following examples and comparative examples, hypromellose, sodium chloride, propylene glycol, sodium benzoate, dipotassium phosphate, sanxian gum, sucralose, and methyl paraben are the following ones, but The present invention is not limited to these. ・Hypromellose: TC-5R (Shin-Etsu Chemical Industry Co., Ltd.) ・Sodium chloride: Sodium chloride suitable for the biopharmaceutical production (Merck Co., Ltd.) ・Propylene Glycol: Japanese Pharmacopoeia Propylene Glycol (ADEKA) ・Sodium benzoate: Japanese Pharmacopoeia Sodium benzoate (Fushimi Pharmaceutical Co., Ltd.) ・Dipotassium phosphate: Dipotassium hydrogen phosphate (Taiping Chemical Industry Co., Ltd.) ・Sanxian Gum: Echo Gum T/KELTROL T (DSP GOKYO FOOD & CHEMICAL Co., Ltd.) ・Sucralose: Sucralose P (Saneigen FFI Co., Ltd.) ・Methyl parahydroxybenzoate: Methyl parahydroxybenzoate (Ueno Pharmaceutical Co., Ltd.)

Examples 1 to 7 used the hydrochloride salt, additives and solvents of compound 1 in the amounts shown in the following table to prepare the preparations of Examples 1 to 7 by the following methods. (1) Preparation of the hydrochloride salt of compound 1 Prepare the hydrochloride salt of compound 1 with D90 particle diameter of 120-420 μm as A particles. Next, the hydrochloride salt of compound 1 with a particle diameter of D90 of 3-9 μm was prepared as B particles. The particle size distribution of the particles is measured by the dry measurement method of the laser diffraction particle size distribution measuring device: HELOS BR-MULTI (Sympatec). In addition, the A particle uses R3 as the measurement range, and the B particle uses R5 as the measurement range. The results of the particle size distribution are converted on a volume basis.

(2) Preparation of Example 1 Dissolve hypromellose, sodium benzoate and sodium chloride in purified water. Then, the A particles and the B particles were added so that the mass ratio became 3:7, and a precision dispersing emulsifier: CLEARMIX CLM-0.8S (M-TECHNIQUE) was used to disperse at 12000 rpm for 30 minutes to prepare liquid A. In addition, the purified water was weighed and placed in another container, and sodium benzoate, propylene glycol, and sanxian gum were added to dissolve them to prepare liquid B. The above-mentioned liquid A and liquid B were mixed so that the mass ratio became 1:1, thereby preparing the formulation of Example 1.

(3) Preparation of Example 2 Dissolve hypromellose, sodium benzoate and sodium chloride in purified water. Then, A particles and B particles were added so that the mass ratio became 2:8, and a precision dispersing emulsifier: CLEARMIX CLM-0.8S (M-TECHNIQUE) was used to disperse at 12000 rpm for 30 minutes to prepare A liquid. In addition, the purified water was weighed and placed in another container, and sodium benzoate, propylene glycol, and sanxian gum were added to dissolve them to prepare liquid B. The above-mentioned liquid A and liquid B were mixed so that the mass ratio became 1:1, thereby preparing the formulation of Example 2.

(4) Preparation of Example 3 Dissolve hypromellose, sodium benzoate and sodium chloride in purified water. Then, A particles and B particles were added so that the mass ratio became 1:9, and a precision dispersing emulsifier: CLEARMIX CLM-0.8S (M-TECHNIQUE) was used to disperse at 12000 rpm for 30 minutes to prepare A liquid. In addition, the purified water was weighed and placed in another container, and sodium benzoate, propylene glycol, and sanxian gum were added to dissolve them to prepare liquid B. The above-mentioned liquid A and liquid B were mixed so that the mass ratio became 1:1, thereby preparing the formulation of Example 3.

(5) Preparation of Example 4 Dissolve hypromellose, sodium benzoate and sodium chloride in purified water. Then, A particles and B particles were added so that the mass ratio became 4:6, and a precision dispersing emulsifier: CLEARMIX CLM-0.8S (M-TECHNIQUE) was used to disperse at 6000 rpm for 5 minutes to prepare A liquid. In addition, the purified water was weighed and placed in another container, and sodium benzoate, propylene glycol, and sanxian gum were added to dissolve them to prepare liquid B. The above-mentioned liquid A and liquid B were mixed so that the mass ratio became 1:1, thereby preparing the formulation of Example 4.

(6) Preparation of Example 5 Dissolve hypromellose, sodium benzoate and sodium chloride in purified water. Then, the A particles and the B particles were added so that the mass ratio became 3:7, and a precision dispersing emulsifier: CLEARMIX CLM-0.8S (M-TECHNIQUE) was used to disperse at 6000 rpm for 5 minutes to prepare A liquid. In addition, the purified water was weighed and placed in another container, and sodium benzoate, propylene glycol, and sanxian gum were added to dissolve them to prepare liquid B. The above-mentioned liquid A and liquid B were mixed so that the mass ratio became 1:1, thereby preparing the formulation of Example 5.

(7) Preparation of Example 6 Dissolve hypromellose, sodium benzoate and sodium chloride in purified water. Then, A particles and B particles were added so that the mass ratio became 2:8, and a precision dispersing emulsifier: CLEARMIX CLM-0.8S (M-TECHNIQUE) was used to disperse at 6000 rpm for 5 minutes to prepare A liquid. In addition, the purified water was weighed and placed in another container, and sodium benzoate, propylene glycol, and sanxian gum were added to dissolve them to prepare liquid B. The above-mentioned liquid A and liquid B were mixed so that the mass ratio became 1:1, thereby preparing the formulation of Example 6.

(8) Preparation of Example 7 Dissolve hypromellose, sodium benzoate and sodium chloride in purified water. Then, the A particles and the B particles were added so that the mass ratio became 1:9, and a precision dispersing emulsifier: CLEARMIX CLM-0.8S (M-TECHNIQUE company) was used to disperse at 6000 rpm for 5 minutes to prepare A liquid. In addition, the purified water was weighed and placed in another container, and sodium benzoate, propylene glycol, and sanxian gum were added to dissolve them to prepare liquid B. The above-mentioned liquid A and liquid B were mixed so that the mass ratio became 1:1, thereby preparing the formulation of Example 7.

[Table 1] Formula amount (content) Example 1 Example 2 A particle 12 mg/mL 8 mg/mL B particle 28 mg/mL 32 mg/mL Hypromellose 10 mg/mL 2 mg/mL Propylene Glycol 50 mg/mL 50 mg/mL sodium benzoate 2 mg/mL 2 mg/mL Sanxian Gum 5 mg/mL 5 mg/mL Sodium chloride 10 mg/mL 20 mg/mL purified water 400 mL total 400 mL total Speed of precision dispersing and emulsifying machine 12000 rpm 12000 rpm Processing time of precision dispersion emulsifier 30 minutes 30 minutes [Table 2] Formula amount (content) Example 3 Example 4 A particle 4 mg/mL 16 mg/mL B particle 36 mg/mL 24 mg/mL Hypromellose 10 mg/mL 2 mg/mL Propylene Glycol 50 mg/mL 50 mg/mL sodium benzoate 2 mg/mL 2 mg/mL Sanxian Gum 5 mg/mL 5 mg/mL Sodium chloride 10 mg/mL 20 mg/mL purified water 400 mL total 400 mL total Speed of precision dispersing and emulsifying machine 12000 rpm 6000 rpm Processing time of precision dispersion emulsifier 30 minutes 5 minutes [table 3] Formula amount (content) Example 5 Example 6 A particle 12 mg/mL 8 mg/mL B particle 28 mg/mL 32 mg/mL Hypromellose 10 mg/mL 2 mg/mL Propylene Glycol 50 mg/mL 50 mg/mL sodium benzoate 2 mg/mL 2 mg/mL Sanxian Gum 5 mg/mL 5 mg/mL Sodium chloride 10 mg/mL 20 mg/mL purified water 400 mL total 400 mL total Speed of precision dispersing and emulsifying machine 6000 rpm 6000 rpm Processing time of precision dispersion emulsifier 5 minutes 5 minutes [Table 4] Formula amount (content) Example 7 A particle 4 mg/mL B particle 36 mg/mL Hypromellose 10 mg/mL Propylene Glycol 50 mg/mL sodium benzoate 2 mg/mL Sanxian Gum 5 mg/mL Sodium chloride 10 mg/mL purified water 400 mL total Speed of precision dispersing and emulsifying machine 6000 rpm Processing time of precision dispersion emulsifier 5 minutes

Under Examples 8 to 12 shown in Table amount of a hydrochloride of the compound, and a solvent of an additive, the formulation of Examples 8 to 12 was prepared by the following embodiment of the method. (1) Preparation of the hydrochloride salt of compound 1 Prepare the hydrochloride salt of compound 1 with D90 particle diameter of 3-4 μm as C particles, and prepare the hydrochloride salt of compound 1 with D90 particle diameter of 8-9 μm as D particles, prepare the hydrochloride salt of compound 1 with D90 particle diameter of 14-15 μm as E particles, prepare the hydrochloride salt of compound 1 with D90 particle diameter of 19-20 μm as F particles, and prepare the particle diameter of D90 The hydrochloride salt of compound 1 with a size of 25 to 26 μm is used as G particles. The particle size distribution of the particles is measured by the dry measurement method of the laser diffraction particle size distribution measuring device: HELOS BR-MULTI (Sympatec). In addition, R3 is used as the measurement range. The results of the particle size distribution are converted on a volume basis.

(2) Preparation of Example 8 Dissolve hypromellose, sodium benzoate and sodium chloride in purified water. Then, C particles were added, and a precision dispersing emulsifier: CLEARMIX CLM-0.8S (M-TECHNIQUE) was used to disperse at 6000 rpm for 5 minutes to prepare liquid A. In addition, the purified water was weighed and placed in another container, and sodium benzoate, propylene glycol, and sanxian gum were added to dissolve them to prepare liquid B. The above-mentioned liquid A and liquid B were mixed so that the mass ratio became 1:1, thereby preparing the formulation of Example 8.

(3) Preparation of Example 9 Dissolve hypromellose, sodium benzoate and sodium chloride in purified water. Then, D particles were added, and a precision dispersing emulsifier: CLEARMIX CLM-0.8S (M-TECHNIQUE) was used to disperse at 6000 rpm for 5 minutes to prepare A liquid. In addition, the purified water was weighed and placed in another container, and sodium benzoate, propylene glycol, and sanxian gum were added to dissolve them to prepare liquid B. The above-mentioned liquid A and liquid B were mixed so that the mass ratio became 1:1, thereby preparing the formulation of Example 9.

(4) Preparation of Example 10 Dissolve hypromellose, sodium benzoate and sodium chloride in purified water. Then, E particles were added, and a precision dispersing emulsifier: CLEARMIX CLM-0.8S (M-TECHNIQUE) was used to disperse at 6000 rpm for 5 minutes to prepare A liquid. In addition, the purified water was weighed and placed in another container, and sodium benzoate, propylene glycol, and sanxian gum were added to dissolve them to prepare liquid B. The above-mentioned liquid A and liquid B were mixed so that the mass ratio became 1:1, thereby preparing the formulation of Example 10.

(5) Preparation of Example 11 Dissolve hypromellose, sodium benzoate and sodium chloride in purified water. Then, F particles were added, and a precision dispersion emulsifier: CLEARMIX CLM-0.8S (M-TECHNIQUE) was used to disperse at 6000 rpm for 5 minutes to prepare A liquid. In addition, the purified water was weighed and placed in another container, and sodium benzoate, propylene glycol, and sanxian gum were added to dissolve them to prepare liquid B. The above-mentioned liquid A and liquid B were mixed so that the mass ratio became 1:1, thereby preparing the formulation of Example 11.

(6) Preparation of Example 12 Dissolve hypromellose, sodium benzoate and sodium chloride in purified water. Then, G particles were added, and a precision dispersion emulsifier: CLEARMIX CLM-0.8S (M-TECHNIQUE) was used to disperse at 6000 rpm for 5 minutes to prepare liquid A. In addition, the purified water was weighed and placed in another container, and sodium benzoate, propylene glycol, and sanxian gum were added to dissolve them to prepare liquid B. The above-mentioned liquid A and liquid B were mixed so that the mass ratio became 1:1, thereby preparing the formulation of Example 12.

[table 5] Formula amount (content) Example 8 Example 9 C particle 40 mg/mL ― D particle ― 40 mg/mL Hypromellose 2 mg/mL 2 mg/mL Propylene Glycol 50 mg/mL 50 mg/mL sodium benzoate 2 mg/mL 2 mg/mL Sanxian Gum 5 mg/mL 5 mg/mL Sodium chloride 20 mg/mL 20 mg/mL purified water 400 mL total 400 mL total Speed of precision dispersing and emulsifying machine 6000 rpm 6000 rpm Processing time of precision dispersion emulsifier 5 minutes 5 minutes [Table 6] Formula amount (content) Example 10 Example 11 E particle 40 mg/mL ― F particle ― 40 mg/mL Hypromellose 2 mg/mL 2 mg/mL Propylene Glycol 50 mg/mL 50 mg/mL sodium benzoate 2 mg/mL 2 mg/mL Sanxian Gum 5 mg/mL 5 mg/mL Sodium chloride 20 mg/mL 20 mg/mL purified water 400 mL total 400 mL total Speed of precision dispersing and emulsifying machine 6000 rpm 6000 rpm Processing time of precision dispersion emulsifier 5 minutes 5 minutes [Table 7] Formula amount (content) Example 12 G particle 40 mg/mL Hypromellose 2 mg/mL Propylene Glycol 50 mg/mL sodium benzoate 2 mg/mL Sanxian Gum 5 mg/mL Sodium chloride 20 mg/mL purified water 400 mL total Speed of precision dispersing and emulsifying machine 6000 rpm Processing time of precision dispersion emulsifier 5 minutes

Examples 13 and 14 used the hydrochloride salt, additives, and solvent of Compound 1 in the amounts shown in the following table, and the preparations of Examples 13 and 14 were prepared by the following methods. (1) Preparation of the hydrochloride salt of compound 1 Prepare the hydrochloride salt of compound 1 with D90 particle diameter of 17-18 μm as H particles, and prepare the hydrochloride salt of compound 1 with D90 particle diameter of 19-20 μm as I particles. The particle size distribution of the particles is measured by the dry measurement method of the laser diffraction particle size distribution measuring device: HELOS BR-MULTI (Sympatec). In addition, R3 is used as the measurement range. The results of the particle size distribution are converted on a volume basis.

(2) Preparation of Example 13 Dissolve hypromellose, sodium benzoate and sodium chloride in purified water. Then, H particles were added, and a precision dispersing emulsifier: CLEARMIX CLM-0.8S (M-TECHNIQUE company) was used to disperse at 6000 rpm for 5 minutes to prepare liquid A. In addition, the purified water was weighed and placed in another container, and sodium benzoate, propylene glycol, and sanxian gum were added to dissolve them to prepare liquid B. The above-mentioned liquid A and liquid B were mixed so that the mass ratio became 1:1, thereby preparing the formulation of Example 13.

(3) Preparation of Example 14 Dissolve hypromellose, sodium benzoate and sodium chloride in purified water. Then, I particles were added, and a precision dispersing emulsifier: CLEARMIX CLM-0.8S (M-TECHNIQUE) was used to disperse at 6000 rpm for 5 minutes to prepare A liquid. In addition, the purified water was weighed and placed in another container, and sodium benzoate, propylene glycol, and sanxian gum were added to dissolve them to prepare liquid B. The above-mentioned liquid A and liquid B were mixed so that the mass ratio became 1:1, thereby preparing the formulation of Example 14.

[Table 8] Formula amount (content) Example 13 Example 14 H particle 40 mg/mL ― I particle ― 40 mg/mL Hypromellose 10 mg/mL 10 mg/mL Propylene Glycol 50 mg/mL 50 mg/mL sodium benzoate 2 mg/mL 2 mg/mL Sanxian Gum 5 mg/mL 5 mg/mL Sodium chloride 10 mg/mL 10 mg/mL purified water 200 mL total 200 mL total Speed of precision dispersing and emulsifying machine 6000 rpm 6000 rpm Processing time of precision dispersion emulsifier 5 minutes 5 minutes

Example 15 Using the hydrochloride salt, additives and solvent of Compound 1 in the amounts shown in the table below, the preparation of Example 15 was prepared by the following method. Dissolve hypromellose, methyl paraben, sucralose, propylene glycol and dipotassium phosphate in purified water. Then, B particles were added, and a precision dispersing emulsifier: CLEARMIX CLM-0.8S (M-TECHNIQUE) was used to disperse at 10,000 rpm for 10 minutes to prepare A liquid. In addition, the purified water was weighed and placed in another container, and methylparaben, propylene glycol, dipotassium phosphate, and sanxian gum were added and dissolved to prepare liquid B. The above-mentioned A liquid and B liquid were mixed so that the mass ratio became 1:1, thereby preparing the formulation of Example 15.

[Table 9] Formula amount (content) Example 15 B particle 40 mg/mL Sucralose 0.06 mg/mL Hypromellose 10 mg/mL Propylene Glycol 50 mg/mL Methyl p-hydroxybenzoate 2.5 mg/mL Sanxian Gum 4 mg/mL Dipotassium Phosphate 15.6 mg/mL purified water 300 mL total Speed of precision dispersing and emulsifying machine 10000 rpm Processing time of precision dispersion emulsifier 10 minutes

Example 16 Using the hydrochloride, additives and solvent of Compound 1 in the amounts shown in the table below, the preparation of Example 16 was prepared by the following method. Dissolve hypromellose, sodium benzoate, sodium chloride, sucralose, stevia extract and spices in purified water. Then, J particles were added, and a precision dispersing emulsifier: CLEARMIX CLM-3.7S (M-TECHNIQUE company) was used to disperse at 4000 rpm for 30 minutes to prepare A liquid. In addition, the purified water was weighed and placed in another container, and sodium benzoate, propylene glycol, trixian gum and sodium chloride were added to dissolve it to prepare liquid B. The above-mentioned liquid A and liquid B were mixed so that the mass ratio became 1:1, thereby preparing the formulation of Example 16.

[Table 10] Formula amount (content) Example 16 J particle 40 mg/mL Hypromellose 2 mg/mL Propylene Glycol 50 mg/mL sodium benzoate 2 mg/mL Sanxian Gum 5 mg/mL Sodium chloride 20 mg/mL Sucralose 1 mg/mL Stevia extract 1 mg/mL spices 0.2 mg/mL purified water Total amount 20 L Speed of precision dispersing and emulsifying machine 4000 rpm Processing time of precision dispersion emulsifier 30 minutes

Example 17 Using the hydrochloride, additives and solvent of Compound 1 in the amounts shown in the table below, the preparation of Example 17 was prepared by the following method. Dissolve hypromellose, sodium benzoate, sodium chloride, sucralose, stevia extract and spices in purified water. Then, K particles were added, and a precision dispersing emulsifier: CLEARMIX CLM-3.7S (M-TECHNIQUE) was used to disperse at 4000 rpm for 30 minutes to prepare liquid A. In addition, the purified water was weighed and placed in another container, and sodium benzoate, propylene glycol, trixian gum and sodium chloride were added to dissolve it to prepare liquid B. The above-mentioned liquid A and liquid B were mixed so that the mass ratio became 1:1, thereby preparing the formulation of Example 17.

[Table 11] Formula amount (content) Example 17 K particle 40 mg/mL Hypromellose 2 mg/mL Propylene Glycol 50 mg/mL sodium benzoate 2 mg/mL Sanxian Gum 5 mg/mL Sodium chloride 20 mg/mL Sucralose 1 mg/mL Stevia extract 1 mg/mL spices 0.2 mg/mL purified water Total amount 20 L Speed of precision dispersing and emulsifying machine 4000 rpm Processing time of precision dispersion emulsifier 30 minutes

Example 18 Using the hydrochloride salt, additives and solvent of Compound 1 in the amounts shown in the table below, the preparation of Example 18 was prepared by the following method. Dissolve hypromellose, sodium benzoate, sodium chloride, sucralose, stevia extract and spices in purified water. Then, L particles were added, and a precision dispersion emulsifier: CLEARMIX CLM-3.7S (M-TECHNIQUE) was used to disperse at 4000 rpm for 30 minutes to prepare liquid A. In addition, the purified water was weighed and placed in another container, and sodium benzoate, propylene glycol, trixian gum and sodium chloride were added to dissolve it to prepare liquid B. The above-mentioned liquid A and liquid B were mixed so that the mass ratio became 1:1, thereby preparing the preparation of Example 18.

[Table 12] Formula amount (content) Example 18 L particle 40 mg/mL Hypromellose 2 mg/mL Propylene Glycol 50 mg/mL sodium benzoate 2 mg/mL Sanxian Gum 5 mg/mL Sodium chloride 20 mg/mL Sucralose 1 mg/mL Stevia extract 1 mg/mL spices 0.2 mg/mL purified water Total amount 20 L Speed of precision dispersing and emulsifying machine 4000 rpm Processing time of precision dispersion emulsifier 30 minutes

Comparative Example 1 used the hydrochloride salt, additives and solvent of Compound 1 in the amounts shown in the following table to prepare the preparation of Comparative Example 1 by the following method. (1) Preparation of the hydrochloride salt of compound 1 Prepare the hydrochloride salt of compound 1 with D90 particle diameter of 120-420 μm as A particles. The particle size distribution of the particles is measured by the dry measurement method of the laser diffraction particle size distribution measuring device: HELOS BR-MULTI (Sympatec). Use R3 as the measurement range. The results of the particle size distribution are converted on a volume basis.

(2) Preparation of Comparative Example 1 Dissolve hypromellose, sodium benzoate and sodium chloride in purified water. Then, A particles were added, and a precision dispersion emulsifier: CLEARMIX CLM-0.8S (M-TECHNIQUE) was used to disperse at 12000 rpm for 30 minutes to prepare A liquid. In addition, the purified water was weighed and placed in another container, and sodium benzoate, propylene glycol, and sanxian gum were added to dissolve them to prepare liquid B. The above-mentioned A liquid and B liquid were mixed so that the mass ratio became 1:1, thereby preparing the preparation of Comparative Example 1.

[Table 13] Formula amount (content) Comparative example 1 A particle 40 mg/mL Hypromellose 10 mg/mL Propylene Glycol 50 mg/mL sodium benzoate 2 mg/mL Sanxian Gum 5 mg/mL Sodium chloride 10 mg/mL purified water 400 mL total Speed of precision dispersing and emulsifying machine 12000 rpm Processing time of precision dispersion emulsifier 30 minutes

Test Example 1 (Compound 1, or a salt of the particle size distribution) of particles A, B particles, C particles, D particle, E particles, F particles, G particles, J particles, particle size distribution system K and L of the particles by laser Diffraction particle size distribution measuring device: dry measuring method of HELOS BR-MULTI (Sympatec). When measuring A particles, use R5 as the measurement range, and use R3 for other particles. The results of the particle size distribution are converted on a volume basis. [Table 14] Particle size distribution (μm) D10 D50 D90 A particle 19.9 131.4 237.2 B particle 0.7 1.5 3.6 C particle 0.7 1.5 3.3 D particle 0.8 2.4 8.4 E particle 0.8 4.8 16.1 F particle 0.9 4.9 20.0 G particle 0.9 5.8 25.1 H particle 0.9 4.8 17.8 I particle 1.0 6.1 20.2 J particle 0.8 3.4 9.5 K particle 0.9 4.7 15.0 L particles 1.1 8.3 26.5

Test Example 2 ( particle size distribution of suspended compound 1 or its salt ) The particle size distribution was measured by a laser diffraction particle size distribution measuring device: HELOS BR-MULTI (Sympatec) wet measurement method. A solution obtained by adding 40 mL of a solvent (purified water or neutral buffer) that does not dissolve compound 1 or its salt to about 0.01 mL of an aqueous suspension preparation was used as the measurement solution. Furthermore, it is preferable to adjust the dilution rate of the measurement solution so that the "sample: measurement concentration" indicated during the measurement becomes 5-10%. Use R3 as the measurement range. The results of the particle size distribution are converted on a volume basis. [Table 15] Particle size distribution (μm) D10 D50 D90 Example 1 0.8 2.9 54.0 Example 2 0.8 2.3 12.7 Example 3 0.8 2.1 5.7 Example 4 1.1 3.5 65.8 Example 5 1.1 3.1 57.9 Example 6 1.2 3.4 64.7 Example 7 1.0 2.8 6.2 Example 8 0.9 2.2 4.9 Example 9 0.9 3.4 9.9 Example 10 1.1 6.0 16.9 Example 11 1.2 8.1 23.9 Example 12 1.4 10.7 31.8 Example 13 1.2 6.5 23.4 Example 14 1.6 9.2 25.8 Example 15 1.4 3.1 6.0 Example 16 1.2 5.4 11.6 Example 17 1.4 7.7 17.1 Example 18 1.5 10.8 28.6 Comparative example 1 1.7 17.4 69.0

Test Example 3 ( Dissolution rate of compound 1 or its salt ) According to the dissolution test method (stirring paddle method) described in the 17th revised edition of the Japanese Pharmacopoeia, the test was carried out under the following [test conditions]. Liquid chromatography was used to quantify the dissolved amount of compound 1 or its salt in the test solution. [Test conditions] Test solution: Japanese Pharmacopoeia 17th Revised Edition Dissolution Test No. 1 Test solution volume: 900 mL Test solution temperature: 36.5～37.5℃ Rotation speed: 50 revolutions per minute Test preparation: Contains salt converted to compound 1 The preparation test solution of "Compound 1 or its salt" equivalent to 40 mg in the acid salt time: 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, and 60 minutes from the start of the test Needle installed in the syringe: About In Examples 1-15 and Comparative Example 1, Terumo Non-Bevel Needle 18G (manufactured by Terumo) was used. For Examples 16 to 18, Terumo Non-Bevel Needle 18G was used. Non-Bevel Needle) 22G (manufactured by Terumo) The time required to inject the total amount of the preparation in the syringe into the test solution (the speed of injecting the preparation into the test solution): About Examples 1-15 and comparison Example 1, about 1 second, about Examples 16-18, about 3 to 5 seconds

[Table 16] Time after the start of the test (minutes) Dissolution rate of the first solution of dissolution test (%) 5 10 15 30 45 60 Example 1 75.2 80.7 82.1 84.1 85.1 86.0 Example 2 61.5 90.4 92.2 93.5 94.6 95.4 Example 3 88.3 93.4 94.6 95.6 96.0 96.3 Example 4 65.0 69.8 71.5 73.7 75.3 76.2 Example 5 70.4 74.5 75.2 76.0 76.3 76.7 Example 6 37.4 84.8 85.7 86.9 87.5 88.0 Example 7 85.4 90.3 90.8 91.4 91.5 91.7 Example 8 95.6 101.0 102.5 102.3 102.2 102.7 Example 9 80.8 92.0 96.4 101.4 102.0 102.5 Example 11 56.3 70.0 77.1 85.4 89.6 92.2 Example 12 50.6 64.4 70.4 80.0 85.5 88.4 Example 16 49.8 78.8 89.5 99.8 102.7 103.3 Example 17 41.0 67.5 78.7 92.2 97.8 100.7 Example 18 29.3 51.8 62.3 77.5 84.8 89.5 Comparative example 1 29.3 40.3 45.2 52.3 55.2 56.9

Test Example 4 ( Compound 1 or its salt drug dynamics 1) 30 minutes after feeding the dog, the standard formulation (LATUDA (Lurasidone HCl) Tablet 40 mg (Sunovion)) was administered orally with 50 mL of water at room temperature, conversion When it is the hydrochloride of compound 1, it becomes Example 1 or Example 13 in an amount of 40 mg. After oral administration, blood was collected from the vein at 0.25, 0.5, 1, 2, 4, 6, and 8 hours, and the plasma concentration of compound 1 was determined. The AUC (area under the concentration curve) was calculated for a graph drawn with time as the horizontal axis and plasma concentration as the vertical axis. When the AUC was calculated, dogs that vomited after oral administration were excluded from the analysis. Furthermore, AUC is used as an index of the absorption of compound 1 in the organism. In addition, the geometric mean ratio of the AUC of Example 1 and Example 13 to the AUC of the standard formulation was also calculated. [Experimental conditions] Dogs: 9 Beagles. Trial design: 3 groups and 3 phases of crossover test (crossover) [Table 17] AUC(ng・h/mL) Relative to the geometric mean ratio of the standard formulation Standard preparation 288±79 - Example 1 267±73 0.92 Example 13 267±56 0.94

It is clear from this result that Example 1 and Example 13 show the same level of absorption as the LATUDA (Lurasidone HCl) Tablet 40 mg (Sunovion) sold in the United States in 2018.

Test Example 5 ( Compound 1 or its salt drug dynamics 2) 30 minutes after feeding the dog, the standard formulation (LATUDA (Lurasidone HCl) Tablet 40 mg (Sunovion)) was orally administered with 50 mL of water at room temperature or converted When it is the hydrochloride salt of compound 1, Example 15 becomes 40 mg. After oral administration, blood was collected from the vein at 0.25, 0.5, 1, 2, 4, 6, and 8 hours, and the plasma concentration of compound 1 was determined. The AUC (area under the concentration curve) was calculated for a graph drawn with time as the horizontal axis and plasma concentration as the vertical axis. When the AUC was calculated, dogs that vomited after oral administration were excluded from the analysis. Furthermore, AUC is used as an index of the absorption of compound 1 in the organism. In addition, the geometric mean ratio of the AUC of Example 15 to the AUC of the standard formulation was also calculated. [Experimental conditions] Dogs: 10 beagle dogs. Trial design: 2 groups and 2 phases crossover test method [Table 18] AUC(ng・h/mL) Relative to the geometric mean ratio of the standard formulation Standard preparation 315±126 - Example 15 318±115 1.03

It is clear from this result that Example 15 shows the same level of absorption as the LATUDA (Lurasidone HCl) Tablet 40 mg (Sunovion) sold in the United States in 2018.

From the above results, it is suggested that the aqueous suspension type pharmaceutical preparations of the examples guarantee the bioequivalence with the existing lozenges. Therefore, an aqueous suspension type pharmaceutical preparation having a particle diameter that controls D50 and D90 within the range of the embodiment can guarantee bioequivalence with existing tablets. [Industrial availability]

According to the present invention, even when an aqueous suspension type pharmaceutical preparation containing Compound 1 or its salt as an active ingredient is orally administered, the bioequivalence with existing tablets can be guaranteed. Thereby, it is possible to inhibit excessive dissolution and absorption, and to reduce the risk of unexpected side effects caused by a temporary increase in blood concentration. In addition, the ability to mask the bitter taste of Compound 1 or its salt can be improved, and the feeling of ingestion can be improved.

Claims (77)

An aqueous suspension type pharmaceutical preparation containing (1)(3aR,4S,7R,7aS)-2-{(1R,2R)- 2-[4-(1,2-benzisothiazole-3- Yl)piperidin-1-ylmethyl)cyclohexylmethyl)hexahydro-4,7-methyl bridge-2H-isoindole-1,3-dione (compound 1), which is permitted in pharmacy Acid addition salts or mixtures of these, and (2) one or more chlorides selected from inorganic chlorides or quaternary ammonium chlorides with 4 to 12 carbon atoms, and having the following (I) or ( II) Features: (I) When the particle size distribution of the suspended particles in the formulation is unimodal, the D90 of the suspended particles is 1-50 μm; (II) When the particle size distribution of the suspended particles in the formulation is bimodal or more multimodal, the D90 of the suspended particles is 1-100 μm. The aqueous suspension type pharmaceutical preparation of claim 1, wherein the suspended particles in the preparation contain suspended particles containing compound 1, its pharmaceutically acceptable acid addition salt or a mixture thereof, and the compound 1 , Suspended particles of acid addition salts or mixtures of these pharmacologically permitted have the characteristics of (I) or (II) above. The aqueous suspension type pharmaceutical preparation of claim 2, wherein the suspended particles in the preparation are suspended particles containing compound 1, its pharmaceutically acceptable acid addition salt, or a mixture thereof. The aqueous suspension type pharmaceutical preparation of claim 2 or 3, wherein the preparation does not contain suspended particles other than suspended particles containing compound 1, its pharmaceutically acceptable acid addition salt, or a mixture of these . The aqueous suspension type pharmaceutical preparation according to any one of claims 1 to 4, wherein the suspended particles in the preparation have the characteristics of (I). The aqueous suspension type pharmaceutical preparation of claim 5, wherein the D50 of the suspended particles in the preparation is 3-15 μm. Such as the aqueous suspension type pharmaceutical preparation of claim 5, wherein the D50 of the suspended particles in the preparation is 3-11 μm. The aqueous suspension type pharmaceutical preparation of claim 5, wherein the D50 of the suspended particles in the preparation is 3-8 μm. The aqueous suspension type pharmaceutical preparation of claim 5, wherein the D50 of the suspended particles in the preparation is 3-6 μm. Such as the aqueous suspension type pharmaceutical preparation of claim 5, wherein the D50 of the suspended particles in the preparation is 4-6 μm. Such as the aqueous suspension type pharmaceutical preparation of claim 5, wherein the D50 of the suspended particles in the preparation is 5-11 μm. Such as the aqueous suspension type pharmaceutical preparation of claim 5, wherein the D50 of the suspended particles in the preparation is 5-8 μm. Such as the aqueous suspension type pharmaceutical preparation of claim 5, wherein the D50 of the suspended particles in the preparation is 5-7 μm. Such as the aqueous suspension type pharmaceutical preparation of claim 5, wherein the D50 of the suspended particles in the preparation is 6-11 μm. Such as the aqueous suspension type pharmaceutical preparation of claim 5, wherein the D50 of the suspended particles in the preparation is 6-8 μm. The aqueous suspension type pharmaceutical preparation according to claim 5, wherein the D50 of the suspended particles in the preparation is 7-11 μm. An aqueous suspension type pharmaceutical preparation according to claim 5, wherein the D50 of the suspended particles in the preparation is 9-11 μm. An aqueous suspension type pharmaceutical preparation according to claim 5, wherein the D90 of the suspended particles in the preparation is 6-29 μm. The aqueous suspension type pharmaceutical preparation according to claim 5, wherein the D90 of the suspended particles in the preparation is 6-18 μm. The aqueous suspension type pharmaceutical preparation of claim 5, wherein the D90 of the suspended particles in the preparation is 6-12 μm. The aqueous suspension type pharmaceutical preparation of claim 5, wherein the D90 of the suspended particles in the preparation is 10-12 μm. The aqueous suspension type pharmaceutical preparation of claim 5, wherein the D90 of the suspended particles in the preparation is 11-29 μm. An aqueous suspension type pharmaceutical preparation according to claim 5, wherein the D90 of the suspended particles in the preparation is 11-24 μm. The aqueous suspension type pharmaceutical preparation according to claim 5, wherein the D90 of the suspended particles in the preparation is 11-18 μm. Such as the aqueous suspension type pharmaceutical preparation of claim 5, wherein the D90 of the suspended particles in the preparation is 16-18 μm. The aqueous suspension type pharmaceutical preparation of claim 5, wherein the D90 of the suspended particles in the preparation is 17-29 μm. An aqueous suspension type pharmaceutical preparation according to claim 5, wherein the D90 of the suspended particles in the preparation is 17-24 μm. An aqueous suspension type pharmaceutical preparation according to claim 5, wherein the D90 of the suspended particles in the preparation is 23-29 μm. The aqueous suspension type pharmaceutical preparation of claim 5, wherein the D90 of the suspended particles in the preparation is 27-29 μm. The aqueous suspension type pharmaceutical preparation according to any one of claims 1 to 4, wherein the suspended particles in the preparation have the feature (II). Such as the aqueous suspension type pharmaceutical preparation of claim 30, wherein the D50 of the suspended particles in the preparation is 1 to 6 μm. The aqueous suspension type pharmaceutical preparation of claim 30 or 31, wherein the suspended particles in the preparation include particles having a D50 of 75-190 μm and a D90 of 120-420 μm, and a D50 of 0.8-3 μm and 2-9 The particles of D90 in μm have a mass ratio of 1:9 to 4:6. The aqueous suspension type pharmaceutical preparation according to any one of claims 1 to 32 has a pH in the range of 2.5 to 5.5. For example, the aqueous suspension type pharmaceutical preparation of claim 33 has a pH in the range of 3.0 to 5.5. For example, the aqueous suspension type pharmaceutical preparation of claim 33 has a pH in the range of 3.0 to 5.0. The aqueous suspension type pharmaceutical preparation according to any one of claims 1 to 35, wherein the chloride is selected from the group consisting of sodium chloride, potassium chloride, ferrous chloride, calcium chloride, magnesium chloride and choline chloride At least one species in the group. The aqueous suspension type pharmaceutical preparation of claim 36, wherein the chloride is at least one selected from the group consisting of sodium chloride, potassium chloride and choline chloride. The aqueous suspension type pharmaceutical preparation of claim 36, wherein the chloride is at least one selected from the group consisting of sodium chloride and choline chloride. The aqueous suspension type pharmaceutical preparation of claim 36, wherein the chloride is sodium chloride. The aqueous suspension type pharmaceutical preparation of any one of claims 1 to 39, wherein the chloride ion concentration in the preparation is about 0.015 to about 1 mol/L (wherein, the chloride ion derived from the salt of compound 1 is not included) . The aqueous suspension type pharmaceutical preparation of claim 40, wherein the chloride ion concentration is about 0.05 to about 1 mol/L. The aqueous suspension type pharmaceutical preparation of claim 40, wherein the chloride ion concentration is about 0.10 to about 1 mol/L. The aqueous suspension type pharmaceutical preparation according to any one of claims 1 to 42, which further contains a dispersant. The aqueous suspension type pharmaceutical preparation of claim 43, wherein the dispersant is at least one selected from the group consisting of cellulose derivatives, sucrose fatty acid esters, and polyvinyl alcohol. The aqueous suspension type pharmaceutical preparation according to claim 44, wherein the dispersant is a cellulose derivative. The aqueous suspension type pharmaceutical preparation of claim 43, wherein the dispersant is hypromellose. The aqueous suspension type pharmaceutical preparation according to any one of claims 43 to 46, wherein the content of the dispersant in the preparation is about 0.1 to about 20 mg/mL. The aqueous suspension type pharmaceutical preparation according to any one of claims 1 to 47, which further contains a viscosity increasing agent. The aqueous suspension type pharmaceutical preparation of claim 48, which contains at least one selected from polysaccharides as a viscosity-increasing agent. Such as the aqueous suspension type pharmaceutical preparation of claim 48, wherein the viscosity-increasing agent is Sanxian gum. The aqueous suspension type pharmaceutical preparation according to any one of claims 48 to 50, wherein the content of the thickener in the preparation is about 0.5 to about 20 mg/mL. The aqueous suspension type pharmaceutical preparation according to any one of claims 1 to 51, which further contains a preservative. The aqueous suspension type pharmaceutical preparation of claim 52, wherein the preservative is at least one selected from benzoic acid derivatives. The aqueous suspension type pharmaceutical preparation of Claim 52 or 53, wherein the content of the preservative in the preparation is about 0.1 to about 10 mg/mL. The aqueous suspension type pharmaceutical preparation according to any one of claims 1 to 54, which further contains a stabilizer. The aqueous suspension type pharmaceutical preparation of claim 55, wherein the stabilizer is at least one selected from polyhydric alcohols. Such as the aqueous suspension type pharmaceutical preparation of claim 55 or 56, wherein the content of the stabilizer in the preparation is about 1 to about 500 mg/mL. Such as the aqueous suspension type pharmaceutical preparation of any one of claims 1 to 57, wherein the content of compound 1, its pharmacologically acceptable acid addition salt or a mixture thereof in the preparation is converted into the hydrochloric acid of compound 1 The salt is about 5 to about 120 mg/mL. Such as the aqueous suspension type pharmaceutical preparation of any one of claims 1 to 57, wherein the content of compound 1, its pharmacologically acceptable acid addition salt or a mixture thereof in the preparation is converted into the hydrochloric acid of compound 1 It is about 10 to about 100 mg/mL in salt. Such as the aqueous suspension type pharmaceutical preparation of any one of claims 1 to 57, wherein the content of compound 1, its pharmacologically acceptable acid addition salt or a mixture thereof in the preparation is converted into the hydrochloric acid of compound 1 The salt is about 20 to about 80 mg/mL. An aqueous suspension type pharmaceutical preparation according to any one of claims 1 to 60, wherein compound 1, its pharmaceutically acceptable acid addition salt or a mixture thereof is the hydrochloride salt of compound 1. Such as the aqueous suspension type pharmaceutical preparation of any one of claims 1 to 61, which is administered orally. Such as the aqueous suspension type pharmaceutical preparation of any one of claims 1 to 62, in which the test is carried out under the following test conditions according to the dissolution test method (stirring paddle method) described in the 17th revised edition of the Japanese Pharmacopoeia The dissolution rate of compound 1, its pharmacologically acceptable acid addition salt or mixture of these in the first 5 minutes is 30-90% or less: [Test conditions] Test solution: Japanese Pharmacopoeia 17th revised edition, dissolution test first solution Liquid volume of test solution: 900 mL Test solution temperature: 36.5～37.5℃ Rotation speed: 50 revolutions per minute Test preparation: a preparation containing 40 mg of compound 1, its pharmacologically acceptable acid addition salt or a mixture thereof when converted into the hydrochloride salt of compound 1. Such as the aqueous suspension type pharmaceutical preparation of any one of claims 1 to 62, in which the test is carried out under the following test conditions according to the dissolution test method (stirring paddle method) described in the 17th revised edition of the Japanese Pharmacopoeia The dissolution rate of compound 1, its pharmacologically acceptable acid addition salt or mixture of these at the first 10 minutes is 45-95%: [Test conditions] Test solution: Japanese Pharmacopoeia 17th revised edition, dissolution test first solution Liquid volume of test solution: 900 mL Test solution temperature: 36.5～37.5℃ Rotation speed: 50 revolutions per minute Test preparation: a preparation containing 40 mg of compound 1, its pharmacologically acceptable acid addition salt or a mixture thereof when converted into the hydrochloride salt of compound 1. Such as the aqueous suspension type pharmaceutical preparation of any one of claims 1 to 64, which shows that it is within ±10% of the AUC obtained when LATUDA (registered trademark) tablets (40 mg) are orally administered The AUC. An aqueous suspension type pharmaceutical preparation, characterized in that it contains (1)(3aR,4S,7R,7aS)- 2-{(1R,2R)-2-[4-(1,2-benzisothiazole -3-yl)piperidin-1-ylmethyl)cyclohexylmethyl)hexahydro-4,7-methyl bridge-2H-isoindole-1,3-dione (compound 1), its pharmaceutical Allowable acid addition salts or mixtures of these, and (2) chlorides of more than one selected from inorganic chlorides or quaternary ammonium chlorides with 4 to 12 carbon atoms, suspended particles in the preparation The particle size distribution is bimodal or more multimodal, D90 is 1-100 μm, and its mass ratio is 1:9-4:6 containing D50 with 75 μm～190 μm and 120 μm～ 420 μm D90 particles and particles with 0.8 μm～3 μm D50 and 2 μm～9 μm D90. Such as the aqueous suspension type pharmaceutical preparation of claim 66, wherein the mass ratio is 1:9 to 3:7. An aqueous suspension type pharmaceutical preparation, which contains (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl )Piper-1-ylmethyl)cyclohexylmethyl)hexahydro-4,7-methyl bridge-2H-isoindole-1,3-dione (compound 1), its pharmaceutically acceptable acid Addition salt or a mixture of these particles with a D50 of 75 μm～190 μm and a D90 of 120 μm～420 μm and a particle with a D50 of 0.8 μm～3 μm and a D90 of 2 μm～9 μm are 1:9 ～4:6 mass ratio to produce (1) compound 1, its pharmacologically acceptable acid addition salt or a mixture of these, and (2) selected from inorganic chloride or carbon number 4-12 One or more of the four grade ammonium chlorides. A therapeutic and/or preventive agent for mental illness, which contains the aqueous suspension type pharmaceutical preparation according to any one of claims 1 to 68. The therapeutic and/or preventive agent according to claim 69, wherein the mental illness is schizophrenia, bipolar disorder, senile dementia or depression. A method for treating and/or preventing mental illness, which comprises administering an aqueous suspension type pharmaceutical preparation according to any one of claims 1 to 68 to a patient in need of treatment. The method according to claim 71, wherein the mental illness is schizophrenia, bipolar disorder, senile dementia or depression. A use of the aqueous suspension type pharmaceutical preparation according to any one of claims 1 to 68, which is used to manufacture a therapeutic and/or preventive agent for mental illness. Such as the use of claim 73, wherein the mental illness is schizophrenia, bipolar disorder, and Alzheimer's depression. The aqueous suspension type pharmaceutical preparation according to any one of claims 1 to 68, which is used for the treatment and/or prevention of mental illness. Such as the aqueous suspension type pharmaceutical preparation of claim 75, wherein the mental illness is schizophrenia, bipolar disorder, dementia and depression. One (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperidin-1-ylmethyl)cyclohexyl Methyl) hexahydro-4,7-methyl bridge-2H-isoindole-1,3-dione (compound 1), its pharmacologically acceptable acid addition salt or the raw material particles of a mixture of these , Which is used to prepare an aqueous suspension type pharmaceutical preparation as claimed in any one of claims 1 to 68, and has a D50 of 3 μm-9 μm and a D90 of 9 μm-27 μm.