WO2023054668A1

WO2023054668A1 - Amorphous Tolvaptan-Containing Composition

Info

Publication number: WO2023054668A1
Application number: PCT/JP2022/036672
Authority: WO
Inventors: Kai Suzuki; Koichi Kiyota
Original assignee: Otsuka Pharmaceutical Co., Ltd.
Priority date: 2021-10-01
Filing date: 2022-09-30
Publication date: 2023-04-06

Abstract

Provided is an amorphous tolvaptan-containing composition, for preparing a suspension, that has good storage stability and that can be prepared at the time of use. More specifically, a composition for preparing a suspension, comprising (a) particles containing amorphous tolvaptan, (b) xanthan gum, and (c) benzoic acid or a salt thereof is provided.

Description

Amorphous Tolvaptan-Containing Composition

The present disclosure relates to a composition comprising amorphous tolvaptan, and the like. More preferably, the present disclosure relates to a pharmaceutical composition comprising amorphous tolvaptan. The contents of all of the documents mentioned in the present specification are incorporated herein by reference.

Tolvaptan, which is 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine, represented by formula (I), is a vasopressin antagonist with aquaretic activity (Patent Literature (PTL) 1). Tolvaptan is sold as a therapeutic agent for hyponatremia, body fluid retention in heart failure, and body fluid retention in liver cirrhosis.

When tolvaptan is formulated into a solid preparation by using a common preparation technique, it becomes crystalline, resulting in reduced solubility and absorbability from the gastrointestinal tract. As a means for solving this problem, PTL 2 reports that a composition comprising amorphous tolvaptan can be prepared by dissolving tolvaptan and hydroxypropyl cellulose in an organic solvent and spray-drying the mixture to obtain a powder, thereby improving solubility and absorbability from the gastrointestinal tract.

Examples of reports relating to the above preparation comprising amorphous tolvaptan include the following. For example, PTL 3 reports that a pharmaceutical solid preparation with superior disintegration properties can be obtained by mixing a composition containing amorphous tolvaptan with specific low-substituted hydroxypropyl cellulose.

PTL 4 reports that a matrix-type solid preparation with advanced release controllability can be obtained by mixing a composition containing amorphous tolvaptan with an enteric polymer and a specific sugar and/or sugar alcohol.

PTL 5 reports that a gradual disintegration-type, sustained-release pharmaceutical solid preparation whose pharmacologically active substance-release behavior is controlled can be obtained by mixing a composition containing amorphous tolvaptan with calcium polycarbophil and a sugar and/or sugar alcohol.

PTL 6 discloses a specific suspension for oral administration (e.g., a syrup), comprising a composition containing amorphous tolvaptan.

JPH04-154765A JPH11-021241A WO2008/156217 (JP2010-530355A) WO2009/051022 (JP2011-500511A) WO2010/026971 (JP2012-501960A) WO2014/133196 (JP2016-509990A)

The present inventors conducted extensive research to obtain an amorphous tolvaptan-containing composition, for preparing a suspension, that has good storage stability and that can be prepared at the time of use.

The present inventors found that when a suspension is prepared using a composition comprising amorphous tolvaptan, a specific suspending agent, and benzoic acid, the stability of tolvaptan and benzoic acid is excellent, and conducted further research.

The present disclosure includes, for example, the subjects described in the following Items.
Item 1.
A composition for preparing a suspension, comprising:
(a) particles containing amorphous tolvaptan;
(b) xanthan gum; and
(c) benzoic acid or a salt thereof.
Item 2.
The composition according to Item 1, further comprising (d) at least one organic acid selected from the group consisting of succinic acid, citric acid, malic acid, and mixtures of two or more thereof.
Item 3.
The composition according to Item 1 or 2, further comprising (e) carboxymethyl cellulose or a salt thereof.
Item 4.
The composition according to any one of Items 1 to 3, further comprising (f) starch glycolic acid or a salt thereof.
Item 5.
The composition according to any one of Items 1 to 4, which is in the form of granules.
Item 6.
The composition according to Item 4, which is in the form of granules comprising:
(a) particles containing amorphous tolvaptan;
(b) xanthan gum;
(c) sodium benzoate;
(d) at least one organic acid selected from the group consisting of succinic acid, citric acid, malic acid, and salts thereof, and mixtures of two or more thereof;
(e) sodium carboxymethyl cellulose; and
(f) sodium starch glycolate.
Item 7.
The granule kit for preparing a suspension, comprising:
(a) particles containing amorphous tolvaptan;
(b) xanthan gum;
(c) sodium benzoate;
(d) at least one organic acid selected from the group consisting of succinic acid, citric acid, malic acid, and salts thereof, and mixtures of two or more thereof;
(e) sodium carboxymethyl cellulose; and
(f) sodium starch glycolate,
wherein the kit comprises at least two granule packaging bags,
a first packaging bag comprises first granules containing components (a), (b), (c), and (e), and
a second packaging bag comprises second granules containing components (d) and (f).
Item 8.
The kit according to Item 7, wherein the composition according to Item 6 is prepared by combining the first granules and the second granules.
Item 9.
A suspension prepared from the composition according to any one of Items 1 to 6 or the kit according to Item 7 or 8.

The composition according to Item 6 is preferably, for example, a composition that satisfies at least one of the following conditions 6-1 to 6-6. In particular, the composition according to Item 6 is more preferably a composition that satisfies all of the conditions.
Condition 6-1: the content of component (a) is 1 to 20 mass%.
Condition 6-2: the content of component (b) is 1 to 25 mass%.
Condition 6-3: the content of component (c) is 1 to 25 mass%.
Condition 6-4: the content of component (d) is 0.5 to 30 mass%.
Condition 6-5: the content of component (e) is 0.5 to 15 mass%.
Condition 6-6: the content of component (f) is 10 to 50 mass%.

Moreover, the kit according to Item 7 is preferably, for example, a kit that satisfies at least one of the following conditions 7-1 to 7-6. In particular, the kit according to Item 7 is more preferably a kit that satisfies all of the conditions.
Condition 7-1: The content of component (a) is 10 to 15 mass% based on the total amount of the first granules.
Condition 7-2: The content of component (b) is 7 to 10 mass% based on the total amount of the first granules.
Condition 7-3: The content of component (c) is 30 to 40 mass% based on the total amount of the first granules.
Condition 7-4: The content of component (e) is 3 to 6 mass% based on the total amount of the first granules.
Condition 7-5: The content of component (d) is 1 to 10 mass% based on the total amount of the second granules.
Condition 7-6: The content of component (f) is 85 to 95 mass% based on the total amount of the second granules.

A composition (in particular, granular composition) comprising amorphous tolvaptan, xanthan gum, and benzoic acid is provided. A suspension prepared using the composition is advantageous because the stability of tolvaptan and benzoic acid is excellent, and the suspension time required for preparation of the suspension is relatively short.

A composition further comprising a specific organic acid is provided. By using the specific organic acid, the PH can be adjusted in an appropriate range during preparation of suspensions to better maintain the effect of benzoic acid as a preservative.

It is preferred that the composition further comprises carboxymethyl cellulose or a salt thereof. When the composition comprises carboxymethyl cellulose or a salt thereof, the adsorption of tolvaptan and benzoic acid in a suspension prepared from the composition to containers etc. can be prevented.

The composition does not comprise components that are considered to have a high risk to safety when administered to a subject (in particular, children), and discomfort during administration is reduced. The composition is also preferable from these points (in particular, when administered to children).

Fig. 1 shows the results of powder X-ray diffraction analysis of granules equivalent to 50 mg of tolvaptan (Example 10) stored in a constant temperature and humidity chamber.

Embodiments included in the present disclosure are described in more detail below. The present disclosure preferably includes a composition comprising (a) particles containing amorphous tolvaptan and specific components, and the like. However, the present disclosure is not limited thereto, and includes everything that is disclosed in the present specification and that can be recognized by a person skilled in the art.

The composition included in the present disclosure comprises (a) particles containing amorphous tolvaptan. The composition included in the present disclosure may be referred to as “the composition of the present disclosure.”

The composition of the present disclosure comprises (b) xanthan gum and (c) benzoic acid or a salt thereof in addition to component (a). The composition of the present disclosure preferably further comprises (d) an organic acid or a salt thereof. The composition of the present disclosure more preferably further comprises (e) carboxymethyl cellulose or a salt thereof. The composition of the present disclosure even more preferably further comprises (f) starch glycolic acid or a salt thereof. The composition of the present disclosure may also comprise other components, as described later.

Tolvaptan is a compound represented by formula (I) described above, and contains an asymmetric carbon atom (hydroxyl-bonded carbon atom). The term “tolvaptan” encompasses a racemic mixture, optically active substances (R-(+) form and S-(-) form), and a mixture of the optically active substances. Tolvaptan is preferably racemic tolvaptan. Tolvaptan can be produced by a known method. For example, tolvaptan can be produced according to the method disclosed in JPH04-154765A (PTL 1).

Tolvaptan encompasses anhydrides, solvates (e.g., hydrates, alcoholates, etc.), co-crystals, etc. of tolvaptan. Furthermore, tolvaptan encompasses those in which one or more atoms in the tolvaptan molecule are replaced by one or more isotopic atoms. Examples of isotopic atoms include deuterium (²H), tritium (³H), ¹³C, ¹⁴N, ¹⁸O, and the like.

The term “amorphous” in amorphous tolvaptan indicates that the content of crystalline tolvaptan is less than 5 wt%, preferably less than 3 wt%, and more preferably less than 1 wt%, based on the total tolvaptan content of the particles; and particularly preferably indicates that no crystalline tolvaptan is detected. The content of crystalline tolvaptan based on the total tolvaptan content of the particles can be determined by measuring X-ray diffraction of the particles.

The term “particles containing amorphous tolvaptan” encompasses particles consisting essentially of amorphous tolvaptan, and particles containing amorphous tolvaptan and a polymer component (particles of solid dispersion). Examples of polymer components include water-soluble polymers, enteric polymers, gastro-soluble polymers, water-insoluble polymers, biodegradable polymers, and the like. Specific examples include polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), povidone, crospovidone, copolyvidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers, methacrylic acid copolymer L, methacrylic acid copolymer S, ethyl cellulose, cellulose acetate, aminoalkyl copolymer RS (e.g., trade name: Eudragit RS or RL), ethyl acrylate/methyl methacrylate copolymers (e.g., Eudragit NE30D), and the like. These polymer components may be used singly or in a combination of two or more. Preferred examples of polymer components include HPC and HPMC, and HPC is more preferable.

The weight ratio of tolvaptan to polymer component (tolvaptan : polymer component) in the particles is generally 1:0 to 1:4, preferably 8:1 to 1:4, more preferably 4:1 to 1:2, even more preferably 2:1 to 2:3, and particularly preferably 2:1 to 1:1.

The particles containing amorphous tolvaptan can be prepared by various methods.

For example, the particles containing amorphous tolvaptan can be produced by a spray-drying method according to the disclosure of JPH11-021241A (PTL 2). Specifically, the particles containing amorphous tolvaptan can be produced by dissolving tolvaptan together with, if necessary, a polymer component in an organic solvent that can dissolve tolvaptan and the polymer component; evaporating the organic solvent; and making the residue into the form of a powder (particles). Examples of polymer components include water-soluble polymers, biodegradable polymers, and the like. Examples of organic solvents include methylene chloride, a mixture of methylene chloride and ethanol, a mixture of methylene chloride and methanol, and the like. By spray-drying the resulting solution, a powder (particles) with a preferable particle size distribution can be obtained. Furthermore, the resulting powder can be dried under reduced pressure or freeze-dried to remove the residual solvent, if necessary.

When a spray-drying method is used, the mean particle size of the particles containing amorphous tolvaptan can be controlled by adjusting the type of spray nozzle, the tolvaptan concentration and polymer concentration in an organic solvent, spray rate, etc.

The mean particle size of the particles is generally about 0.1 to 200 μm, preferably about 1 to 150 μm, and more preferably about 10 to 100 μm. The absorption rate of tolvaptan can be controlled by controlling the mean particle size of the particles. The mean particle size of the particles is a volume mean diameter, and can be determined using a laser diffraction particle size distribution meter.

The content of the particles containing amorphous tolvaptan in the composition of the present disclosure may be, for example, about 1 to 20 mass%, based on the total weight of the composition of the present disclosure. The upper or lower limit of this range may be, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 mass%. For example, this range may be 2 to 15 mass%. Moreover, it is preferred that, for example, 30 to 90 mass% of the particles containing amorphous tolvaptan is amorphous tolvaptan. The upper or lower limit of this range may be, for example, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, or 85 mass%. For example, this range may be 40 to 80 mass%.

The content of (b) xanthan gum in the composition of the present disclosure may be, for example, about 1 to 25 mass%, based on the total weight of the composition of the present disclosure. The upper or lower limit of this range may be, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 mass%. For example, this range may be 2 to 24 mass%.

Although there is no particular limitation, the xanthan gum preferably has a viscosity of 800 mPa・s or more, for example, more preferably about 800 to 1800 mPa・s, even more preferably about 1200 to 1800 mPa・s, and still even more preferably about 1200 to 1700 mPa・s. The viscosity of the xanthan gum is the value measured at 25±0.5℃ in a 1% aqueous solution containing 1% KCl with a Brookfield viscometer (based on Japanese Pharmaceutical Excipients).

Without wishing to be bound by theory, component (b) is expected to function as a suspending agent.

The content of (c) benzoic acid or a salt thereof in the composition of the present disclosure may be, for example, about 1 to 25 mass% based on the total weight of the composition of the present disclosure. The upper or lower limit of this range may be, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 mass%. For example, this range may be 2 to 24 mass%.

Preferred examples of benzoic acid salts include alkali metal salts of benzoic acid, and specific examples include sodium salt, potassium salt, and the like of benzoic acid. These salts may be used singly or in a combination of two or more.

Without wishing to be bound by theory, component (c) is expected to function as an antiseptic.

The content of (d) the organic acid or a salt thereof in the composition of the present disclosure may be, for example, about 0.5 to 30 mass% based on the total amount of the composition of the present disclosure. The upper or lower limit of this range may be, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29 mass%. For example, this range may be 1 to 28 mass%. The organic acid can act as a pH adjuster. As described later, the composition of the present disclosure can be preferably used for preparing suspensions. When a suspension is prepared using the composition, it is preferred that the pH of the suspension is, for example, about 3 to 6. The upper or lower limit of the range of the pH may be, for example, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, or 5.9. For example, this range may be 3.5 to 5.5. In particular, a pH range of 4.5 to 5.5 is particularly preferable because the sourness derived from the organic acid sensed when the suspension is taken is favorably reduced; thus, the discomfort when the suspension is taken is further reduced.

Examples of organic acid salts include, but are not limited to, alkali metal salts and alkaline earth metal salts of organic acids. Specific examples include sodium salts, potassium salts, calcium salts, and the like of organic acids. These salts may be used singly or in a combination of two or more.

Preferred examples of the organic acid used in the composition of the present disclosure include succinic acid, citric acid, malic acid, and mixtures of two or more thereof. Of these, citric acid is preferable. Citric acid can be used in the form of an anhydride or hydrate.

The organic acids and salts thereof may be used singly or in a combination of two or more.

Without wishing to be bound by theory, component (d) is expected to function as a pH adjuster.

The content of (e) carboxymethyl cellulose (also referred to as “carmellose”) or a salt thereof in the composition of the present disclosure may be, for example, about 0.5 to 15 mass% based on the total weight of the composition of the present disclosure. The upper or lower limit of this range may be, for example, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 mass%. For example, this range may be 0.7 to 14 mass%.

Preferred examples of carboxymethyl cellulose salts include alkali metal salts and alkaline earth metal salts of carboxymethyl cellulose, and specific examples include sodium salt, potassium salt, calcium salt, and the like of carboxymethyl cellulose. Sodium salt or calcium salt of carboxymethyl cellulose is preferable, and sodium salt of carboxymethyl cellulose is more preferable. These salts may be used singly or in a combination of two or more.

Without wishing to be bound by theory, component (e) is expected to function as a suspending agent.

The content of (f) starch glycolic acid or a salt thereof in the composition of the present disclosure may be, for example, about 10 to 50 mass% based on the total weight of the composition of the present disclosure. The upper or lower limit of this range may be, for example, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, or 49 mass%. For example, this range may be 12 to 45 mass%.

Preferred examples of starch glycolic acid salts include alkali metal salts of starch glycolic acid, and specific examples include sodium salt, potassium salt, and the like of starch glycolic acid. These salts may be used singly or in a combination of two or more.

Without wishing to be bound by theory, component (f) is expected to function as a disintegrant.

The composition of the present disclosure may also contain components other than the above components, if necessary. Examples of the other components include pharmaceutically acceptable components, such as suspending agents other than the above-mentioned carboxymethyl cellulose or a salt thereof and xanthan gum, excipients, disintegrants other than the above-mentioned starch glycolic acid or a salt thereof, pH adjusters other than the above-mentioned organic acid or a salt thereof, preservatives (antiseptics) other than the above-mentioned benzoic acid or a salt thereof, stabilizers, flavoring agents, sweetening agents, fluidizers, and lubricants. These components may be used singly or in a combination of two or more.

Examples of suspending agents include hypromellose (hydroxypropyl methylcellulose), methylcellulose, gellan gum, carrageenan, carboxyvinyl polymers, sodium carboxymethyl cellulose, and like thickeners. Preferably, the suspending agent may be selected from hypromellose (hydroxypropyl methylcellulose), methylcellulose, carboxyvinyl polymers, and carrageenan. These suspending agents have been confirmed for use in pediatric formulations.

Examples of excipients include starch sodium octenyl succinate, crystalline cellulose-carmellose sodium, starch, and the like.

Examples of disintegrants include low-substituted hydroxypropyl cellulose, croscarmellose sodium, and the like.

Examples of pH adjusters include inorganic acids, and specific examples include hydrochloric acid, phosphoric acid, and the like.

Examples of preservatives (antiseptics) include quaternary ammonium salts, such as benzalkonium chloride and benzethonium chloride; cationic compounds, such as chlorhexidine gluconate; p-hydroxybenzoic acid esters, such as methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, and propyl p-hydroxybenzoate; alcohol compounds such as chlorobutanol and benzyl alcohol; sodium dehydroacetate; thimerosal; and the like.

Examples of stabilizers include sodium edetate (EDTA-Na), and the like.

Examples of flavoring agents include cherry flavor, orange flavor, strawberry flavor, and the like

Examples of sweetening agents include sugars and sugar alcohols. Specific examples include mannitol, sorbitol, xylitol, maltitol, erythritol, sucrose, sucralose, aspartame, acesulfame potassium, saccharin sodium, thaumatin, stevia extracts, trehalose, lactose, maltose, glucose, glycerin, and the like. One or more of these can be used. Preferred examples include sucralose, saccharin sodium, and aspartame. Of these, sucralose is most preferable.

Examples of fluidizers include silicon dioxide, colloidal silicon dioxide, and the like.

Examples of lubricants include stearic acid salts (in particular, magnesium stearate), talc, and the like.

The content of each of the other components is not particularly limited, and is, for example, about 0 to 50 mass% based on the total weight of the composition of the present disclosure. The upper or lower limit of this range may be, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, or 49 mass%. For example, this range may be 1 to 40 mass%.

The composition of the present disclosure can be obtained, for example, by mixing the components and, if necessary, other components mentioned above.

The composition of the present disclosure is preferably used for preparing suspensions. The form of the composition is not particularly limited as long as it can be used for preparing suspensions. The composition of the present disclosure is preferably a solid composition; from the viewpoint of ease of preparation, the composition of the present disclosure is particularly preferably in the form of granules. For example, granules can be prepared by mixing the components and, if necessary, other components mentioned above with a kneader or the like, and subjecting the resulting mixture to dry granulation. When the composition of the present disclosure is in the form of granules, the granules may be particularly referred to as “the granules of the present disclosure.”

The granules of the present disclosure preferably have a particle size (mean particle size) of, for example, about 20 to 500 μm. The upper or lower limit of this range may be, for example, 50, 100, 150, 200, 250, 300, 350, 400, or 450 μm. For example, this range may be about 50 to 400 μm.

The particle size (mean particle size) here refers to the value at which the cumulative weight reaches 50% in a sieving particle size distribution. The particle size (mean particle size) is measured using a sieving particle size distribution analyzer. More specifically, eight different sieves with openings of 850 μm, 710 μm, 500 μm, 355 μm, 250 μm, 150 μm, 106 μm, and 75 μm are set vertically in a sieving particle size distribution analyzer such that sieves with larger openings are at higher positions, about 5 g of granules to be measured are passed through the sieves, the granule weight remaining on each sieve is measured, the percentage (%) of granule weight remaining on each sieve relative to the total granule weight is calculated, and the particle size corresponding to the 50% cumulative value is determined as the mean particle size. As the sieving particle size distribution analyzer, for example, an automated sieving particle size distribution analyzer (Robot Sifter RPS-205, produced by Seishin Enterprise Co., Ltd.) can be used.

When the composition of the present disclosure is in the form of granules, the present disclosure also includes an embodiment in which the formulation of the composition of the present disclosure is achieved by containing the above-mentioned components and other components in different kinds of granules, and combining the different kinds of granules. Specifically, for example, when the above-mentioned components and other components are contained in two or more different kinds of granules, which may be referred to as “first granules” and “second granules” (and “third granules,” “fourth granules,” and so on), the present disclosure also includes an embodiment in which granules obtained by combining these kinds of granules (which may be referred to as “mixed granules”) are the granules of the present disclosure.

More specifically, a preferred example is an embodiment in which first granules contain components (a), (b), and (c), and, if necessary, component (e), and second granules contain components (d) and (f). The composition (granules) of the present disclosure is preferably obtained by combining the first granules and the second granules; thus, the first granules and the second granules contain the components so that the formulation of the composition of the present disclosure is preferably achieved when these granules are combined. In this case, the mixed granules obtained by combining the first granules and the second granules correspond to the granules of the present disclosure.

In this embodiment, components that affect the pH when a suspension is prepared are preferably contained in the second granules. Thus, (d) the organic acid or a salt thereof and (f) the starch glycolic acid or a salt thereof are contained in the second granules. In addition, other components that significantly affect the pH when a suspension is prepared are preferably contained in the second granules.

More specifically, it is preferred that the first granules contains components (a), (b), (c), and (e), and further, if necessary, crystalline cellulose-carmellose sodium and croscarmellose sodium; and it is preferred that the second granules contain components (d) and (f), and further, if necessary, a sweetening agent (preferably sucralose). Moreover, either the first granules or the second granules, or both, may contain a fluidizer and a lubricant, and it is preferred that both the first granules and the second granules contain a fluidizer and a lubricant.

As described above, the first granules and the second granules contain the components so that the formulation of the composition of the present disclosure is achieved when the granules are combined. Within the range in which the formulation of the composition of the present disclosure is achieved, for example, in the first granules, it is preferred that the content of component (a) is about 10 to 15 mass%, the content of component (b) is about 7 to 10 mass%, and the content of component (c) is about 30 to 40 mass%, based on the total amount of the first granules. The upper or lower limit of the content range (10 to 15 mass%) of component (a) may be, for example, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, or 14.5 mass%, and the content range of component (a) may be, for example, 10.5 to 14.5 mass%. The upper or lower limit of the content range (7 to 10 mass%) of component (b) may be, for example, 7.5, 8, 8.5, 9, or 9.5 mass%, and the content range of component (b) may be, for example, 7.5 to 9.5 mass%. The upper or lower limit of the content range (30 to 40 mass%) of component (c) may be, for example, 31, 32, 33, 34, 35, 36, 37, 38, or 39 mass%, and the content range of component (c) may be, for example, 31 to 39 mass%.

It is also preferred that the first granules further contain component (e), and it is more preferred that the content of component (e) is, for example, about 3 to 6 mass% based on the total amount of the first granules. The upper or lower limit of the content range (3 to 6 mass%) of component (e) may be, for example, 3.5, 4, 4.5, 5, or 5.5 mass%, and the content range of component (e) may be, for example, 3.5 to 5.5 mass%.

Moreover, for example, in the second granules, it is preferred that the content of component (d) is about 1 to 10 mass%, and the content of component (f) is about 85 to 95 mass%, based on the total amount of the second granules. The upper or lower limit of the content range (1 to 10 mass%) of component (d) may be, for example, 2, 3, 4, 5, 6, 7, 8, or 9 mass%, and the content range of component (d) may be, for example, 2 to 9 mass%. The upper or lower limit of the content range (85 to 95 mass%) of component (f) may be, for example, 86, 87, 88, 89, 90, 91, 92, 93, or 94 mass%, and the content range of component (f) may be, for example, 86 to 94 mass%.

The different kinds of granules are preferably placed in separate packaging bags. The present disclosure also preferably includes a kit that comprises all of the packaging bags separately containing the different kinds of granules. The kit may be referred to as “the kit of the present disclosure.”

For example, when the first granules and the second granules are placed in separate packaging bags, the packaging bag containing the first granules may be referred to as “first packaging bag,” and the packaging bag containing the second granules may be referred to as “second packaging bag.” In this case, the present disclosure particularly preferably include a kit comprising the first packaging bag and the second packaging bag.

The composition of the present disclosure (preferably, the granules of the present disclosure) and the kit of the present disclosure are preferably used for preparing suspensions. As described above, the granules of the present disclosure can be obtained by combining the granules placed in the packing bags in the kit of the present disclosure. Thus, when a suspension is prepared using the kit of the present disclosure, it is preferable to first combine the granules to prepare the granules of the present disclosure and use the granules of the present disclosure for preparing a suspension, although there is no particular limitation.

The composition of the present disclosure can be mixed with a solvent for suspension to prepare a suspension. The solvent is preferably water.

The amount of solvent (water) used is not limited as long as a suspension can be prepared. For example, a suspension can be prepared by adding preferably 90 to 99.9 parts by mass, more preferably 95 to 99.9 parts by mass of water to 1 part by mass of the composition of the present disclosure for suspension.

A suspension prepared from the composition of the present disclosure may be referred to as “the suspension of the present disclosure.”

The concentration (mass%) of each component in the suspension of the present disclosure is not limited. For example, the concentration of component (a) is preferably about 0.01 to 0.3 mass%. The upper or lower limit of this range may be, for example, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, or 0.29 mass%. For example, this range may be 0.05 to 0.25 mass%.

For example, the concentration of component (b) is preferably about 0.01 to 0.3 mass%. The upper or lower limit of this range may be, for example, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, or 0.29 mass%. For example, this range may be 0.05 to 0.25 mass%.

For example, the concentration of component (c) is preferably about 0.01 to 0.5 mass%. The upper or lower limit of this range may be, for example, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, or 0.45 mass%. For example, this range may be 0.05 to 0.45 mass%.

For example, the concentration of component (d) is preferably about 0 to 0.3 mass%. The upper or lower limit of this range may be, for example, 0.0005, 0.001, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, or 0.29 mass%. For example, this range may be 0.0005 to 0.25 mass%.

For example, the concentration of component (e) is preferably about 0 to 0.3 mass%. The upper or lower limit of this range may be, for example, 0.0005, 0.001, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, or 0.29 mass%. For example, this range may be 0.0005 to 0.25 mass%.

For example, the concentration of component (f) is preferably about 0 to 1.5 mass%. The upper or lower limit of this range may be, for example, 0.0005, 0.001, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.1, 1.2, 1.3, or 1.4 mass%. For example, this range may be 0.0005 to 1.4 mass%.

The dosage form of the suspension of the present disclosure is not particularly limited, and is preferably such that the suspension of the present disclosure is administered orally or transvascularly (in particular, intravenously), and more preferably administered orally.

Since the suspension of the present disclosure preferably has a pleasant taste and a minimally required antiseptic concentration, the suspension of the present disclosure is suitable for oral administration. The suspension of the present disclosure is also suitable for oral administration to children (in particular, newborns). For oral administration to children (in particular, newborns) and people having mastication and swallowing difficulties, a tube such as a nasogastric tube can also be used. The suspension of the present disclosure is preferred because its uniformity can be favorably maintained even when the suspension is passed through such a tube, and the suspension is less likely to cause tube blockage etc.

In the present specification, the term “comprising” includes “consisting essentially of” and “consisting of.” Further, the present disclosure includes all of any combinations of the constituent requirements described in the present specification.

Various characteristics (properties, structures, functions, etc.) described in the above embodiments of the present disclosure may be combined in any manner to specify the subject matter included in the present disclosure. That is, this disclosure includes all of the subject matter comprising any combination of the combinable characteristics described herein.

Examples

The embodiments of the present disclosure are described in more detail below with reference to Examples. However, the embodiments of the present disclosure are not limited to the following Examples.

In the following study, particles containing amorphous tolvaptan (spray-dried product; tolvaptan SD (spray-dried) powder) in which tolvaptan and hydroxypropyl cellulose (HPC; HPC-SL, produced by Nippon Soda Co., Ltd., the same applies hereinafter) are present in a weight ratio of 2:1 were used as an amorphous tolvaptan powder (tolvaptan concentration: 66.7%). The crystalline cellulose-carmellose sodium (trade name: Ceolus RC-A591NF, produced by Asahi Kasei Corp.) as used here contains 89 parts by mass of crystalline cellulose and 11 parts by mass of carmellose sodium.

Specific methods conducted in each study are described below.

Preparation method for suspension and measurement of preparation time
Water (50 mL) measured in a graduated cylinder was poured into a 100-mL PET bottle with an opening of 28 mm. Separately, granules equivalent to 50 mg of tolvaptan were weighed and placed in the purified water-containing bottle, and the bottle was tightly closed with a cap. While the bottle was kept tilted at about 30 degrees, the bottle was shaken back and forth in the vertical direction. The shaking was performed at a rate of about three back-and-forth movements per second. The shaking process was stopped every 10 seconds to observe the inside of the bottle from the outside. When the presence of large grains (visually 0.3 mm or larger) was observed, the shaking process was continued for another 10 seconds. When the grains disappeared and were thus suspended completely, the shaking process was terminated, and the time required for shaking was recorded.
In all of the studies, suspensions were prepared using granules according to the above procedure, unless otherwise noted.

Measurement of pH of suspension
The pH of the suspension was measured at about 25℃ with a pH meter (D-52, produced by Horiba Ltd.).

Evaluation of suspension durability and component stability (quantitative method)
A PET bottle containing a suspension prepared on the previous day and left to stand was shaken back and forth in the vertical direction while the bottle was kept tilted at about 30 degrees. The shaking was performed for 15 seconds at a rate of about three back-and-forth movements per second. Immediately after shaking, the cap was removed from the bottle, and 3 mL of the suspension was accurately collected with a volumetric pipette from the center at the middle height of the suspension.
The suspension durability was evaluated according to the following procedure. Specifically, the suspension was collected 1) immediately after shaking (immediately after the shaking was performed for the first time after being left to stand), 2) 5 minutes after being left to stand (after being left to stand for 5 minutes after the first shaking), 3) 15 minutes after being left to stand (after being left to stand for 15 minutes after the first shaking), and 4) after shaking again (immediately after the shaking was performed again). Using these four collected samples, tolvaptan and sodium benzoate in the suspension were quantified by liquid chromatography.

Dissolution test of suspension
A dissolution test of a suspension was performed according to the paddle method (method 2) for the dissolution test of the Japanese Pharmacopoeia. Using a dissolution tester (NTR-6200, produced by Toyama Sangyo Co., Ltd.), 885 mL of a buffer solution with a pH of 1.2 of the United States Pharmacopeia (USP), heated to about 37℃, was injected into each vessel, and the paddle speed was set at 50 rpm. Then, 15 mL of a suspension that had been sufficiently shaken in advance was accurately collected with a volumetric pipette and fed into the test liquid with the paddle rotating, to start the dissolution test. Then, 10 mL of a sample solution was collected from each

vessel

10, 20, 30, 45, and 60 minutes after the start of the test. Each of the sample solutions was filtered through a membrane filter with a pore diameter of about 5 μm to remove insoluble matter, and 6 mL of the resulting liquid was accurately collected, to which methanol was added to adjust the volume to 25 mL. This liquid was filtered through a membrane filter with a pore diameter of 0.45 μm, and 1 mL of the resulting product obtained immediately after the start of filtration was discarded to use the next liquid as a sample for analysis and measurement. Tolvaptan in the sample for analysis and measurement was measured by HPLC, and its quantitative value was used to calculate the dissolution profile.

Powder X-ray diffraction analysis
Powder X-ray diffraction analysis of granules was performed with an X-ray diffractometer (X’Pert Pro MPD).

Particle size measurement
The particle size of granules was measured with an automated sieving particle size distribution analyzer (Robot Sifter RPS-205, produced by Seishin Enterprise Co., Ltd.).

Eight different sieves with openings of 850 μm, 710 μm, 500 μm, 355 μm, 250 μm, 150 μm, 106 μm, and 75 μm were stacked vertically and set in a fine powder catcher such that sieves with larger openings were at higher positions. Weighed granules (about 5 g) were placed on the sieve; and the granule weight placed on the sieve, as well as the granule weight remaining on each sieve after the process, were measured accurately to calculate the percentage (%) of granule weight remaining on each sieve relative to the total granule weight. Furthermore, the particle size corresponding to the 50% cumulative value was determined as the mean particle size.

The classification process was performed automatically. Specifically, the assembled sieve set was subjected to sound waves and vibration to perform classification under the conditions of a vibration intensity level of 5, a sound wave intensity of 51, a sound wave frequency of 51 Hz, a vibration time (classification time) of 3 minutes, and a pulse interval of 1 second.

Preparation of each granule
Example A
37.5 g of an amorphous tolvaptan powder obtained by amorphization of tolvaptan with hydroxypropyl cellulose by a spray-drying method (tolvaptan concentration: 66.7%), 25.0 g of xanthan gum (trade name: Keltrol CG-T, produced by CP Kelco), 25.0 g of crystalline cellulose-carmellose sodium (trade name: Ceolus RC-A591NF, produced by Asahi Kasei Corp.), 50.0 g of sodium starch glycolate (trade name: Primojel, produced by DFE Pharma), 25.0 g of croscarmellose sodium (trade name: Kiccolate ND-2HS, produced by Nichirin Chemical Industries, Ltd.), 75.0 g of succinic acid (produced by Merck Millipore), 5 g of colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.), 50.0 g of sucralose (produced by San-Ei Gen F.F.I., Inc.), 25.0 g of sodium benzoate (produced by FUJIFILM Wako Pure Chemical Corporation), and 3.0 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed and placed in a polyethylene bag, and mixed inside the bag. After the mixture was passed through a No. 22 sieve (710 μm) with a diameter of 30 cm, the total amount of the resulting product was placed in an NSK-150 mini kneader (produced by Okada Seiko Co., Ltd.) and mixed at 300 rpm for 5 minutes. The resulting mixture was fed into the feeder of a TF-Mini roller compactor (produced by Freund Corporation) to perform dry granulation under the conditions of a roll pressure of 7 MPa, a roll speed of 6 rpm, and a feeder screw speed of 15 rpm. The resulting ribbon-like flakes were directly fed into a crusher equipped with an 850-μm mesh screen to obtain granules. The obtained granules were forcibly passed through a No. 30 sieve (500 μm) with a diameter of 30 cm to adjust the particle size, and colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.) equivalent to 1.453% by weight of the granules was added and mixed, thereby obtaining granules (weight: 651.0 mg) containing 50 mg of tolvaptan. The mean particle size of the resulting product was about 116 μm.

Example B
37.5 g of an amorphous tolvaptan powder obtained by amorphization of tolvaptan with hydroxypropyl cellulose by a spray-drying method (tolvaptan concentration: 66.7%), 25.0 g of starch sodium octenyl succinate (trade name: Cleargum CO 01, produced by Roquette), 25.0 g of xanthan gum (trade name: San Ace PH, produced by San-Ei Gen F.F.I., Inc.), 25.0 g of crystalline cellulose-carmellose sodium (trade name: Ceolus RC-A591NF, produced by Asahi Kasei Corp.), 50.0 g of sodium starch glycolate (trade name: Primojel, produced by DFE Pharma), 25.0 g of croscarmellose sodium (trade name: Kiccolate ND-2HS, produced by Nichirin Chemical Industries, Ltd.), 75.0 g of succinic acid (produced by Merck Millipore), 2.5 g of colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.), 5.0 g of sucralose (produced by San-Ei Gen F.F.I., Inc.), 25.0 g of sodium benzoate (produced by FUJIFILM Wako Pure Chemical Corporation), 0.5 g of sodium edetate (produced by FUJIFILM Wako Pure Chemical Corporation), and 1.0 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed and placed in a polyethylene bag, and mixed inside the bag. After the mixture was passed through a No. 22 sieve (710 μm) with a diameter of 30 cm, the total amount of the resulting product was placed in an NSK-150 mini kneader (produced by Okada Seiko Co., Ltd.) and mixed at 300 rpm for 5 minutes. The resulting mixture was fed into the feeder of a TF-Mini roller compactor (produced by Freund Corporation) to perform dry granulation under the conditions of a roll pressure of 7 MPa, a roll speed of 6 rpm, and a feeder screw speed of 15 rpm. The resulting ribbon-like flakes were directly fed into a crusher equipped with an 850-μm mesh screen to perform crushing and adjust the particle size, thereby obtaining granules (weight: 593.0 mg) containing 50 mg of tolvaptan. The mean particle size of the resulting product was about 196 μm.

Example C
37.5 g of an amorphous tolvaptan powder obtained by amorphization of tolvaptan with hydroxypropyl cellulose by a spray-drying method (tolvaptan concentration: 66.7%), 25.0 g of starch sodium octenyl succinate (trade name: Cleargum CO 01, produced by Roquette), 50.0 g of xanthan gum (trade name: San Ace PH, produced by San-Ei Gen F.F.I., Inc.), 25.0 g of crystalline cellulose-carmellose sodium (trade name: Ceolus RC-A591NF, produced by Asahi Kasei Corp.), 50.0 g of sodium starch glycolate (trade name: Primojel, produced by DFE Pharma), 25.0 g of croscarmellose sodium (trade name: Kiccolate ND-2HS, produced by Nichirin Chemical Industries, Ltd.), 75.0 g of succinic acid (produced by Merck Millipore), 2.5 g of colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.), 5.0 g of sucralose (produced by San-Ei Gen F.F.I., Inc.), 25.0 g of sodium benzoate (produced by FUJIFILM Wako Pure Chemical Corporation), 0.5 g of sodium edetate (produced by FUJIFILM Wako Pure Chemical Corporation), and 1.0 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed and placed in a polyethylene bag, and mixed inside the bag. After the mixture was passed through a No. 18 sieve (850 μm) with a diameter of 30 cm, the total amount of the resulting product was placed in an NSK-150 mini kneader (produced by Okada Seiko Co., Ltd.) and mixed at 300 rpm for 5 minutes. The resulting mixture was fed into the feeder of a TF-Mini roller compactor (produced by Freund Corporation) to perform dry granulation under the conditions of a roll pressure of 7 MPa, a roll speed of 6 rpm, and a feeder screw speed of 15 rpm. The resulting ribbon-like flakes were directly fed into a crusher equipped with an 850-μm mesh screen, thereby obtaining granules (weight: 643.0 mg) containing 50 mg of tolvaptan. The mean particle size of the resulting product was about 307 μm.

Example D
37.5 g of an amorphous tolvaptan powder obtained by amorphization of tolvaptan with hydroxypropyl cellulose by a spray-drying method (tolvaptan concentration: 66.7%), 25.0 g of starch sodium octenyl succinate (trade name: Cleargum CO 03, produced by Roquette), 37.5 g of xanthan gum (trade name: San Ace PH, produced by San-Ei Gen F.F.I., Inc.), 25.0 g of crystalline cellulose-carmellose sodium (trade name: Ceolus RC-A591NF, produced by Asahi Kasei Corp.), 50.0 g of sodium starch glycolate (trade name: Primojel, produced by DFE Pharma), 25.0 g of croscarmellose sodium (trade name: Kiccolate ND-2HS, produced by Nichirin Chemical Industries, Ltd.), 75.0 g of succinic acid (produced by Merck Millipore), 2.5 g of colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.), 5.0 g of sucralose (produced by San-Ei Gen F.F.I., Inc.), 25.0 g of sodium benzoate (produced by FUJIFILM Wako Pure Chemical Corporation), 0.5 g of sodium edetate (produced by FUJIFILM Wako Pure Chemical Corporation), and 1.0 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed and placed in a polyethylene bag, and mixed inside the bag. After the mixture was passed through a No. 18 sieve (850 μm) with a diameter of 30 cm, the total amount of the resulting product was placed in an NSK-150 mini kneader (produced by Okada Seiko Co., Ltd.) and mixed at 300 rpm for 5 minutes. The resulting mixture was fed into the feeder of a TF-Mini roller compactor (produced by Freund Corporation) to perform dry granulation under the conditions of a roll pressure of 7 MPa, a roll speed of 6 rpm, and a feeder screw speed of 15 rpm. The resulting ribbon-like flakes were directly fed into a crusher equipped with an 850-μm mesh screen, thereby obtaining granules (weight: 618.0 mg) containing 50 mg of tolvaptan. The mean particle size of the resulting product was about 322 μm.

Example E
37.5 g of an amorphous tolvaptan powder obtained by amorphization of tolvaptan with hydroxypropyl cellulose by a spray-drying method (tolvaptan concentration: 66.7%), 25.0 g of starch sodium octenyl succinate (trade name: Cleargum CO 01, produced by Roquette), 50.0 g of xanthan gum (trade name: San Ace PH, produced by San-Ei Gen F.F.I., Inc.), 25.0 g of crystalline cellulose-carmellose sodium (trade name: Ceolus RC-A591NF, produced by Asahi Kasei Corp.), 50.0 g of sodium starch glycolate (trade name: Primojel, produced by DFE Pharma), 75.0 g of succinic acid (produced by Merck Millipore), 2.5 g of colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.), 5.0 g of sucralose (produced by San-Ei Gen F.F.I., Inc.), 25.0 g of sodium benzoate (produced by FUJIFILM Wako Pure Chemical Corporation), 0.5 g of sodium edetate (produced by FUJIFILM Wako Pure Chemical Corporation), and 1.0 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed and placed in a polyethylene bag, and mixed inside the bag. After the mixture was passed through a No. 22 sieve (710 μm) with a diameter of 30 cm, the total amount of the resulting product was placed in an NSK-150 mini kneader (produced by Okada Seiko Co., Ltd.) and mixed at 300 rpm for 5 minutes. The resulting mixture was fed into the feeder of a TF-Mini roller compactor (produced by Freund Corporation) to perform dry granulation under the conditions of a roll pressure of 7 MPa, a roll speed of 6 rpm, and a feeder screw speed of 15 rpm. The resulting ribbon-like flakes were directly fed into a crusher equipped with an 850-μm mesh screen to perform crushing and adjust the particle size, thereby obtaining granules (weight: 593.0 mg) containing 50 mg of tolvaptan. The mean particle size of the resulting product was about 282 μm.

Example F
37.5 g of an amorphous tolvaptan powder obtained by amorphization of tolvaptan with hydroxypropyl cellulose by a spray-drying method (tolvaptan concentration: 66.7%), 25.0 g of starch sodium octenyl succinate (trade name: Cleargum CO 01, produced by Roquette), 50.0 g of xanthan gum (trade name: San Ace PH, produced by San-Ei Gen F.F.I., Inc.), 50.0 g of sodium starch glycolate (trade name: Primojel, produced by DFE Pharma), 75.0 g of succinic acid (produced by Merck Millipore), 2.5 g of colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.), 5.0 g of sucralose (produced by San-Ei Gen F.F.I., Inc.), 25.0 g of sodium benzoate (produced by FUJIFILM Wako Pure Chemical Corporation), 0.5 g of sodium edetate (produced by FUJIFILM Wako Pure Chemical Corporation), and 1.0 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed and placed in a polyethylene bag, and mixed inside the bag. After the mixture was passed through a No. 22 sieve (710 μm) with a diameter of 30 cm, the total amount of the resulting product was placed in an NSK-150 mini kneader (produced by Okada Seiko Co., Ltd.) and mixed at 300 rpm for 5 minutes. The resulting mixture was fed into the feeder of a TF-Mini roller compactor (produced by Freund Corporation) to perform dry granulation under the conditions of a roll pressure of 7 MPa, a roll speed of 6 rpm, and a feeder screw speed of 15 rpm. The resulting ribbon-like flakes were directly fed into a crusher equipped with an 850-μm mesh screen to perform crushing and adjust the particle size, thereby obtaining granules (weight: 493.0 mg) containing 50 mg of tolvaptan. The mean particle size of the resulting product was about 313 μm.

Example 1
37.5 g of an amorphous tolvaptan powder obtained by amorphization of tolvaptan with hydroxypropyl cellulose by a spray-drying method (tolvaptan concentration: 66.7%), 25.0 g of xanthan gum (trade name: San Ace PH, produced by San-Ei Gen F.F.I., Inc.), 12.5 g of carmellose sodium (PR-S Nikkyoku, produced by DKS Co., Ltd.), 25.0 g of crystalline cellulose-carmellose sodium (trade name: Ceolus RC-A591NF, produced by Asahi Kasei Corp.), 50.0 g of sodium starch glycolate (trade name: Primojel, produced by DFE Pharma), 25.0 g of croscarmellose sodium (trade name: Kiccolate ND-2HS, produced by Nichirin Chemical Industries, Ltd.), 75.0 g of succinic acid (produced by Merck Millipore), 10.0 g of colloidal silicon dioxide (trade name: Aerosil 200 Pharma, produced by Evonik Industries AG), 5.0 g of sucralose (produced by San-Ei Gen F.F.I., Inc.), 25.0 g of sodium benzoate (produced by FUJIFILM Wako Pure Chemical Corporation), 0.5 g of sodium edetate (produced by FUJIFILM Wako Pure Chemical Corporation), and 1.0 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed and placed in a polyethylene bag, and mixed inside the bag. After the mixture was passed through a No. 18 sieve (850 μm) with a diameter of 30 cm, the total amount of the resulting product was placed in an NSK-150 mini kneader (produced by Okada Seiko Co., Ltd.) and mixed at 300 rpm for 5 minutes. The resulting mixture was fed into the feeder of a TF-Mini roller compactor (produced by Freund Corporation) to perform dry granulation under the conditions of a roll pressure of 7 MPa, a roll speed of 6 rpm, and a feeder screw speed of 15 rpm. The resulting ribbon-like flakes were directly fed into a crusher equipped with an 850-μm mesh screen, thereby obtaining granules (weight: 583.0 mg) containing 50 mg of tolvaptan. The mean particle size of the resulting product was about 174 μm.

Example 2
37.9 g of an amorphous tolvaptan powder obtained by amorphization of tolvaptan with hydroxypropyl cellulose by a spray-drying method (tolvaptan concentration: 66.7%), 25.0 g of xanthan gum (trade name: Keltrol CG-T, produced by CP Kelco), 12.5 g of carmellose sodium (trade name: Aqualon CMC 7L2P, produced by Ashland), 25.0 g of crystalline cellulose-carmellose sodium (trade name: Ceolus RC-A591NF, produced by Asahi Kasei Corp.), 50.0 g of sodium starch glycolate (trade name: Primojel, produced by DFE Pharma), 25.0 g of croscarmellose sodium (trade name: Kiccolate ND-2HS, produced by Nichirin Chemical Industries, Ltd.), 75.0 g of succinic acid (produced by Merck Millipore), 5.0 g of colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.), 5.0 g of sucralose (produced by San-Ei Gen F.F.I., Inc.), 25.0 g of sodium benzoate (produced by FUJIFILM Wako Pure Chemical Corporation), and 1.5 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed and placed in a polyethylene bag, and mixed inside the bag. After the mixture was passed through a No. 22 sieve (710 μm) with a diameter of 30 cm, the total amount of the resulting product was placed in an NSK-150 mini kneader (produced by Okada Seiko Co., Ltd.) and mixed at 300 rpm for 5 minutes. The resulting mixture was fed into the feeder of a TF-Mini roller compactor (produced by Freund Corporation) to perform dry granulation under the conditions of a roll pressure of 7 MPa, a roll speed of 6 rpm, and a feeder screw speed of 15 rpm. The resulting ribbon-like flakes were directly fed into a crusher equipped with an 850-μm mesh screen to perform crushing and adjust the particle size. To further adjust the particle size, the resulting product was forcibly passed through a No. 30 sieve (500 μm) with a diameter of 30 cm. The resulting granules and colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.) weighed to be equivalent to 1.48% of the granule weight were mixed in a bag and forcibly passed through a No. 30 sieve (500 μm) with a diameter of 30 cm again, thereby obtaining granules as a product. The granules (weight: 583.9 mg) contained 50 mg of tolvaptan. The mean particle size of the obtained granules was about 82 μm.

Example 3
37.9 g of an amorphous tolvaptan powder obtained by amorphization of tolvaptan with hydroxypropyl cellulose by a spray-drying method (tolvaptan concentration: 66.7%), 25.0 g of xanthan gum (trade name: Keltrol CG-SFT, produced by CP Kelco), 12.5 g of carmellose sodium (trade name: Aqualon CMC 7L2P, produced by Ashland), 25.0 g of crystalline cellulose-carmellose sodium (trade name: Ceolus RC-A591NF, produced by Asahi Kasei Corp.), 50.0 g of sodium starch glycolate (trade name: Primojel, produced by DFE Pharma), 25.0 g of croscarmellose sodium (trade name: Kiccolate ND-2HS, produced by Nichirin Chemical Industries, Ltd.), 75.0 g of succinic acid (produced by Merck Millipore), 5.0 g of colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.), 5.0 g of sucralose (produced by San-Ei Gen F.F.I., Inc.), 25.0 g of sodium benzoate (produced by FUJIFILM Wako Pure Chemical Corporation), and 1.5 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed and placed in a polyethylene bag, and mixed inside the bag. After the mixture was passed through a No. 22 sieve (710 μm) with a diameter of 30 cm, the total amount of the resulting product was placed in an NSK-150 mini kneader (produced by Okada Seiko Co., Ltd.) and mixed at 300 rpm for 5 minutes. The resulting mixture was fed into the feeder of a TF-Mini roller compactor (produced by Freund Corporation) to perform dry granulation under the conditions of a roll pressure of 7 MPa, a roll speed of 6 rpm, and a feeder screw speed of 15 rpm. The resulting ribbon-like flakes were directly fed into a crusher equipped with an 850-μm mesh screen to perform crushing and adjust the particle size. To further adjust the particle size, the resulting product was forcibly passed through a No. 30 sieve (500 μm) with a diameter of 30 cm. The resulting granules and colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.) weighed to be equivalent to 1.48% of the granule weight were mixed in a bag and forcibly passed through a No. 30 sieve (500 μm) with a diameter of 30 cm again, thereby obtaining granules as a product. The granules (weight: 583.9 mg) contained 50.5 mg of tolvaptan. The mean particle size of the obtained granules was about 91 μm.

Example 4
37.9 g of an amorphous tolvaptan powder obtained by amorphization of tolvaptan with hydroxypropyl cellulose by a spray-drying method (tolvaptan concentration: 66.7%), 25.0 g of xanthan gum (trade name: Keltrol CG, produced by CP Kelco), 12.5 g of carmellose sodium (trade name: Aqualon CMC 7L2P, produced by Ashland), 25.0 g of crystalline cellulose-carmellose sodium (trade name: Ceolus RC-A591NF, produced by Asahi Kasei Corp.), 50.0 g of sodium starch glycolate (trade name: Primojel, produced by DFE Pharma), 25.0 g of croscarmellose sodium (trade name: Kiccolate ND-2HS, produced by Nichirin Chemical Industries, Ltd.), 75.0 g of succinic acid (produced by Merck Millipore), 5.0 g of colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.), 5.0 g of sucralose (produced by San-Ei Gen F.F.I., Inc.), 25.0 g of sodium benzoate (produced by FUJIFILM Wako Pure Chemical Corporation), and 1.5 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed and placed in a polyethylene bag, and mixed inside the bag. After the mixture was passed through a No. 22 sieve (710 μm) with a diameter of 30 cm, the total amount of the resulting product was placed in an NSK-150 mini kneader (produced by Okada Seiko Co., Ltd.) and mixed at 300 rpm for 5 minutes. The resulting mixture was fed into the feeder of a TF-Mini roller compactor (produced by Freund Corporation) to perform dry granulation under the conditions of a roll pressure of 7 MPa, a roll speed of 6 rpm, and a feeder screw speed of 15 rpm. The resulting ribbon-like flakes were directly fed into a crusher equipped with an 850-μm mesh screen to perform crushing and adjust the particle size. To further adjust the particle size, the resulting product was forcibly passed through a No. 30 sieve (500 μm) with a diameter of 30 cm. The resulting granules and colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.) weighed to be equivalent to 1.48% of the granule weight were mixed in a bag and forcibly passed through a No. 30 sieve (500 μm) with a diameter of 30 cm again, thereby obtaining granules as a product. The granules (weight: 583.9 mg) contained 50.5 mg of tolvaptan. The mean particle size of the obtained granules was about 86 μm.

Example 5
38.0 g of an amorphous tolvaptan powder obtained by amorphization of tolvaptan with hydroxypropyl cellulose by a spray-drying method (tolvaptan concentration: 66.7%), 31.25 g of xanthan gum (trade name: Keltrol CG-SFT, produced by CP Kelco), 12.5 g of carmellose sodium (trade name: Aqualon CMC 7L2P, produced by Ashland), 25.0 g of crystalline cellulose-carmellose sodium (trade name: Ceolus RC-A591NF, produced by Asahi Kasei Corp.), 50.0 g of sodium starch glycolate (trade name: Primojel, produced by DFE Pharma), 25.0 g of croscarmellose sodium (trade name: Kiccolate ND-2HS, produced by Nichirin Chemical Industries, Ltd.), 75.0 g of succinic acid (produced by Merck Millipore), 5.0 g of colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.), 50.0 g of sucralose (produced by San-Ei Gen F.F.I., Inc.), 25.0 g of sodium benzoate (produced by FUJIFILM Wako Pure Chemical Corporation), and 3.0 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed and placed in a polyethylene bag, and mixed inside the bag. After the mixture was passed through a No. 22 sieve (710 μm) with a diameter of 30 cm, the total amount of the resulting product was placed in an NSK-150 mini kneader (produced by Okada Seiko Co., Ltd.) and mixed at 300 rpm for 5 minutes. The resulting mixture was fed into the feeder of a TF-Mini roller compactor (produced by Freund Corporation) to perform dry granulation under the conditions of a roll pressure of 7 MPa, a roll speed of 6 rpm, and a feeder screw speed of 15 rpm. The resulting ribbon-like flakes were directly fed into a crusher equipped with an 850-μm mesh screen to perform crushing and adjust the particle size. To further adjust the particle size, the resulting product was forcibly passed through a No. 30 sieve (500 μm) with a diameter of 30 cm. The resulting granules and colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.) weighed to be equivalent to 1.50% of the granule weight were mixed in a bag and forcibly passed through a No. 30 sieve (500 μm) with a diameter of 30 cm again, thereby obtaining granules as a product. The granules (weight: 688.5 mg) contained 50.7 mg of tolvaptan. The mean particle size of the obtained granules was about 102 μm.

Example 6
38.0 g of an amorphous tolvaptan powder obtained by amorphization of tolvaptan with hydroxypropyl cellulose by a spray-drying method (tolvaptan concentration: 66.7%), 37.5 g of xanthan gum (trade name: Keltrol CG-SFT, produced by CP Kelco), 12.5 g of carmellose sodium (trade name: Aqualon CMC 7L2P, produced by Ashland), 25.0 g of crystalline cellulose-carmellose sodium (trade name: Ceolus RC-A591NF, produced by Asahi Kasei Corp.), 50.0 g of sodium starch glycolate (trade name: Primojel, produced by DFE Pharma), 25.0 g of croscarmellose sodium (trade name: Kiccolate ND-2HS, produced by Nichirin Chemical Industries, Ltd.), 75.0 g of succinic acid (produced by Merck Millipore), 5.0 g of colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.), 50.0 g of sucralose (produced by San-Ei Gen F.F.I., Inc.), 25.0 g of sodium benzoate (produced by FUJIFILM Wako Pure Chemical Corporation), and 3.0 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed and placed in a polyethylene bag, and mixed inside the bag. After the mixture was passed through a No. 22 sieve (710 μm) with a diameter of 30 cm, the total amount of the resulting product was placed in an NSK-150 mini kneader (produced by Okada Seiko Co., Ltd.) and mixed at 300 rpm for 5 minutes. The resulting mixture was fed into the feeder of a TF-Mini roller compactor (produced by Freund Corporation) to perform dry granulation under the conditions of a roll pressure of 7 MPa, a roll speed of 6 rpm, and a feeder screw speed of 15 rpm. The resulting ribbon-like flakes were directly fed into a crusher equipped with an 850-μm mesh screen to perform crushing and adjust the particle size. To further adjust the particle size, the resulting product was forcibly passed through a No. 30 sieve (500 μm) with a diameter of 30 cm. The resulting granules and colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.) weighed to be equivalent to 1.50% of the granule weight were mixed in a bag and forcibly passed through a No. 30 sieve (500 μm) with a diameter of 30 cm again, thereby obtaining granules as a product. The granules (weight: 701.0 mg) contained 50.7 mg of tolvaptan. The mean particle size of the obtained granules was about 97 μm.

Example 7
38.0 g of an amorphous tolvaptan powder obtained by amorphization of tolvaptan with hydroxypropyl cellulose by a spray-drying method (tolvaptan concentration: 66.7%), 43.75 g of xanthan gum (trade name: Keltrol CG-SFT, produced by CP Kelco), 12.5 g of carmellose sodium (trade name: Aqualon CMC 7L2P, produced by Ashland), 25.0 g of crystalline cellulose-carmellose sodium (trade name: Ceolus RC-A591NF, produced by Asahi Kasei Corp.), 50.0 g of sodium starch glycolate (trade name: Primojel, produced by DFE Pharma), 25.0 g of croscarmellose sodium (trade name: Kiccolate ND-2HS, produced by Nichirin Chemical Industries, Ltd.), 75.0 g of succinic acid (produced by Merck Millipore), 5.0 g of colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.), 50.0 g of sucralose (produced by San-Ei Gen F.F.I., Inc.), 25.0 g of sodium benzoate (produced by FUJIFILM Wako Pure Chemical Corporation), and 3.0 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed and placed in a polyethylene bag, and mixed inside the bag. After the mixture was passed through a No. 22 sieve (710 μm) with a diameter of 30 cm, the total amount of the resulting product was placed in an NSK-150 mini kneader (produced by Okada Seiko Co., Ltd.) and mixed at 300 rpm for 5 minutes. The resulting mixture was fed into the feeder of a TF-Mini roller compactor (produced by Freund Corporation) to perform dry granulation under the conditions of a roll pressure of 7 MPa, a roll speed of 6 rpm, and a feeder screw speed of 15 rpm. The resulting ribbon-like flakes were directly fed into a crusher equipped with an 850-μm mesh screen to perform crushing and adjust the particle size. To further adjust the particle size, the resulting product was forcibly passed through a No. 30 sieve (500 μm) with a diameter of 30 cm. The resulting granules and colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.) weighed to be equivalent to 1.40% of the granule weight were mixed in a bag and forcibly passed through a No. 30 sieve (500 μm) with a diameter of 30 cm again, thereby obtaining granules as a product. The granules (weight: 713.5 mg) contained 50.7 mg of tolvaptan.

Example 8
38.0 g of an amorphous tolvaptan powder obtained by amorphization of tolvaptan with hydroxypropyl cellulose by a spray-drying method (tolvaptan concentration: 66.7%), 50.0 g of xanthan gum (trade name: Keltrol CG-SFT, produced by CP Kelco), 12.5 g of carmellose sodium (trade name: Aqualon CMC 7L2P, produced by Ashland), 25.0 g of crystalline cellulose-carmellose sodium (trade name: Ceolus RC-A591NF, produced by Asahi Kasei Corp.), 50.0 g of sodium starch glycolate (trade name: Primojel, produced by DFE Pharma), 25.0 g of croscarmellose sodium (trade name: Kiccolate ND-2HS, produced by Nichirin Chemical Industries, Ltd.), 75.0 g of succinic acid (produced by Merck Millipore), 5.0 g of colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.), 50.0 g of sucralose (produced by San-Ei Gen F.F.I., Inc.), 25.0 g of sodium benzoate (produced by FUJIFILM Wako Pure Chemical Corporation), and 3.0 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed and placed in a polyethylene bag, and mixed inside the bag. After the mixture was passed through a No. 22 sieve (710 μm) with a diameter of 30 cm, the total amount of the resulting product was placed in an NSK-150 mini kneader (produced by Okada Seiko Co., Ltd.) and mixed at 300 rpm for 5 minutes. The resulting mixture was fed into the feeder of a TF-Mini roller compactor (produced by Freund Corporation) to perform dry granulation under the conditions of a roll pressure of 7 MPa, a roll speed of 6 rpm, and a feeder screw speed of 15 rpm. The resulting ribbon-like flakes were directly fed into a crusher equipped with an 850-μm mesh screen to perform crushing and adjust the particle size. To further adjust the particle size, the resulting product was forcibly passed through a No. 30 sieve (500 μm) with a diameter of 30 cm. The resulting granules and colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.) weighed to be equivalent to 1.395% of the granule weight were mixed in a bag and forcibly passed through a No. 30 sieve (500 μm) with a diameter of 30 cm again, thereby obtaining granules as a product. The granules (weight: 727.0 mg) contained 50.7 mg of tolvaptan.

Example 9
37.5 g of an amorphous tolvaptan powder obtained by amorphization of tolvaptan with hydroxypropyl cellulose by a spray-drying method (tolvaptan concentration: 66.7%), 12.5 g of xanthan gum (trade name: San Ace PH, produced by San-Ei Gen F.F.I., Inc.), 25.0 g of carmellose sodium (PR-S Nikkyoku, produced by DKS Co., Ltd.), 25.0 g of crystalline cellulose-carmellose sodium (trade name: Ceolus RC-A591NF, produced by Asahi Kasei Corp.), 50.0 g of sodium starch glycolate (trade name: Primojel, produced by DFE Pharma), 25.0 g of croscarmellose sodium (trade name: Kiccolate ND-2HS, produced by Nichirin Chemical Industries, Ltd.), 75.0 g of succinic acid (produced by Merck Millipore), 10.0 g of colloidal silicon dioxide (trade name: Aerosil 200 Pharma, produced by Evonik Industries AG), 5.0 g of sucralose (produced by San-Ei Gen F.F.I., Inc.), 25.0 g of sodium benzoate (produced by FUJIFILM Wako Pure Chemical Corporation), 0.5 g of sodium edetate (produced by FUJIFILM Wako Pure Chemical Corporation), and 1.0 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed and placed in a polyethylene bag, and mixed inside the bag. After the mixture was passed through a No. 18 sieve (850 μm) with a diameter of 30 cm, the total amount of the resulting product was placed in an NSK-150 mini kneader (produced by Okada Seiko Co., Ltd.) and mixed at 300 rpm for 5 minutes. The resulting mixture was fed into the feeder of a TF-Mini roller compactor (produced by Freund Corporation) to perform dry granulation under the conditions of a roll pressure of 7 MPa, a roll speed of 6 rpm, and a feeder screw speed of 15 rpm. The resulting ribbon-like flakes were directly fed into a crusher equipped with an 850-μm mesh screen, thereby obtaining granules (weight: 583.0 mg) containing 50 mg of tolvaptan. The mean particle size of the resulting product was about 211 μm.

Example 10
38.0 g of an amorphous tolvaptan powder obtained by amorphization of tolvaptan with hydroxypropyl cellulose by a spray-drying method (tolvaptan concentration: 66.7%), 25.0 g of xanthan gum (trade name: Keltrol CG-SFT, produced by CP Kelco), 12.5 g of carmellose sodium (trade name: Aqualon CMC 7L2P, produced by Ashland), 25.0 g of crystalline cellulose-carmellose sodium (trade name: Ceolus RC-A591NF, produced by Asahi Kasei Corp.), 50.0 g of sodium starch glycolate (trade name: Primojel, produced by DFE Pharma), 25.0 g of croscarmellose sodium (trade name: Kiccolate ND-2HS, produced by Nichirin Chemical Industries, Ltd.), 75.0 g of succinic acid (produced by Merck Millipore), 5.0 g of colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.), 50.0 g of sucralose (produced by San-Ei Gen F.F.I., Inc.), 25.0 g of sodium benzoate (produced by FUJIFILM Wako Pure Chemical Corporation), and 2.0 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed and placed in a polyethylene bag, and mixed inside the bag. After the mixture was passed through a No. 22 sieve (710 μm) with a diameter of 30 cm, the total amount of the resulting product was placed in an NSK-150 mini kneader (produced by Okada Seiko Co., Ltd.) and mixed at 300 rpm for 5 minutes. The resulting mixture was fed into the feeder of a TF-Mini roller compactor (produced by Freund Corporation) to perform dry granulation under the conditions of a roll pressure of 7 MPa, a roll speed of 6 rpm, and a feeder screw speed of 15 rpm. The resulting ribbon-like flakes were directly fed into a crusher equipped with an 850-μm mesh screen to perform crushing and adjust the particle size. To further adjust the particle size, the resulting product was forcibly passed through a No. 30 sieve (500 μm) with a diameter of 30 cm. The resulting granules and colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.) weighed to be equivalent to 1.50% of the granule weight were mixed in a bag and forcibly passed through a No. 30 sieve (500 μm) with a diameter of 30 cm again, thereby obtaining granules as a product. The granules (weight: 674.0 mg) contained 50.7 mg of tolvaptan. The mean particle size of the obtained granules was about 95 μm.

Example 11
37.5 g of an amorphous tolvaptan powder obtained by amorphization of tolvaptan with hydroxypropyl cellulose by a spray-drying method (tolvaptan concentration: 66.7%), 25.0 g of xanthan gum (trade name: Keltrol CG-T, produced by CP Kelco), 12.5 g of carmellose sodium (trade name: Blanose CMC 7LP EP, produced by Ashland), 50.0 g of crystalline cellulose-carmellose sodium (trade name: Ceolus RC-A591NF, produced by Asahi Kasei Corp.), 125.0 g of sodium starch glycolate (trade name: Primojel, produced by DFE Pharma), 50.0 g of croscarmellose sodium (trade name: Kiccolate ND-2HS, produced by Nichirin Chemical Industries, Ltd.), 7.5 g of succinic acid (produced by Merck Millipore), 5.0 g of colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.), 5.0 g of sucralose (produced by San-Ei Gen F.F.I., Inc.), 75.0 g of sodium benzoate (produced by FUJIFILM Wako Pure Chemical Corporation), and 1.5 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed and placed in a polyethylene bag, and mixed inside the bag. After the mixture was passed through a No. 22 sieve (710 μm) with a diameter of 30 cm, the total amount of the resulting product was placed in an NSK-150 mini kneader (produced by Okada Seiko Co., Ltd.) and mixed at 300 rpm for 5 minutes. The resulting mixture was fed into the feeder of a TF-Mini roller compactor (produced by Freund Corporation) to perform dry granulation under the conditions of a roll pressure of 7 MPa, a roll speed of 6 rpm, and a feeder screw speed of 15 rpm. The resulting ribbon-like granules were collected and crushed with an ND-2S mini mill (produced by Okada Seiko Co., Ltd.) equipped with a 2-mm herringbone screen. To further adjust the particle size, the resulting product was forcibly passed through a No. 30 sieve (500 μm) with a diameter of 30 cm. The resulting granules and colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.) weighed to be equivalent to 1.27% of the granule weight were mixed in a bag and forcibly passed through a No. 30 sieve (500 μm) with a diameter of 30 cm again, thereby obtaining granules as a product. The granules (weight: 798.0 mg) contained 50 mg of tolvaptan.

Example 12
37.5 g of an amorphous tolvaptan powder obtained by amorphization of tolvaptan with hydroxypropyl cellulose by a spray-drying method (tolvaptan concentration: 66.7%), 25.0 g of xanthan gum (trade name: Keltrol CG-T, produced by CP Kelco), 12.5 g of carmellose sodium (trade name: Blanose CMC 7LP EP, produced by Ashland), 50.0 g of crystalline cellulose-carmellose sodium (trade name: Ceolus RC-A591NF, produced by Asahi Kasei Corp.), 125.0 g of sodium starch glycolate (trade name: Primojel, produced by DFE Pharma), 50.0 g of croscarmellose sodium (trade name: Kiccolate ND-2HS, produced by Nichirin Chemical Industries, Ltd.), 7.5 g of anhydrous citric acid (produced by FUJIFILM Wako Pure Chemical Corporation), 5.0 g of colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.), 5.0 g of sucralose (produced by San-Ei Gen F.F.I., Inc.), 75.0 g of sodium benzoate (produced by FUJIFILM Wako Pure Chemical Corporation), and 1.5 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed and placed in a polyethylene bag, and mixed inside the bag. After the mixture was passed through a No. 22 sieve (710 μm) with a diameter of 30 cm, the total amount of the resulting product was placed in an NSK-150 mini kneader (produced by Okada Seiko Co., Ltd.) and mixed at 300 rpm for 5 minutes. The resulting mixture was fed into the feeder of a TF-Mini roller compactor (produced by Freund Corporation) to perform dry granulation under the conditions of a roll pressure of 7 MPa, a roll speed of 6 rpm, and a feeder screw speed of 15 rpm. The resulting ribbon-like granules were collected and crushed with an ND-2S mini mill (produced by Okada Seiko Co., Ltd.) equipped with a 2-mm herringbone screen. To further adjust the particle size, the resulting product was forcibly passed through a No. 30 sieve (500 μm) with a diameter of 30 cm. The resulting granules and colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.) weighed to be equivalent to 1.27% of the granule weight were mixed in a bag and forcibly passed through a No. 30 sieve (500 μm) with a diameter of 30 cm again, thereby obtaining granules as a product. The granules (weight: 798.0 mg) contained 50 mg of tolvaptan.

Example 13
37.5 g of an amorphous tolvaptan powder obtained by amorphization of tolvaptan with hydroxypropyl cellulose by a spray-drying method (tolvaptan concentration: 66.7%), 25.0 g of xanthan gum (trade name: Keltrol CG-T, produced by CP Kelco), 12.5 g of carmellose sodium (trade name: Blanose CMC 7LP EP, produced by Ashland), 50.0 g of crystalline cellulose-carmellose sodium (trade name: Ceolus RC-A591NF, produced by Asahi Kasei Corp.), 125.0 g of sodium starch glycolate (trade name: Primojel, produced by DFE Pharma), 50.0 g of croscarmellose sodium (trade name: Kiccolate ND-2HS, produced by Nichirin Chemical Industries, Ltd.), 7.5 g of dl-malic acid (produced by FUJIFILM Wako Pure Chemical Corporation), 5.0 g of colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.), 5.0 g of sucralose (produced by San-Ei Gen F.F.I., Inc.), 75.0 g of sodium benzoate (produced by FUJIFILM Wako Pure Chemical Corporation), and 1.5 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed and placed in a polyethylene bag, and mixed inside the bag. After the mixture was passed through a No. 22 sieve (710 μm) with a diameter of 30 cm, the total amount of the resulting product was placed in an NSK-150 mini kneader (produced by Okada Seiko Co., Ltd.) and mixed at 300 rpm for 5 minutes. The resulting mixture was fed into the feeder of a TF-Mini roller compactor (produced by Freund Corporation) to perform dry granulation under the conditions of a roll pressure of 7 MPa, a roll speed of 6 rpm, and a feeder screw speed of 15 rpm. The resulting ribbon-like granules were collected and crushed with an ND-2S mini mill (produced by Okada Seiko Co., Ltd.) equipped with a 2-mm herringbone screen. To further adjust the particle size, the resulting product was forcibly passed through a No. 30 sieve (500 μm) with a diameter of 30 cm. The resulting granules and colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.) weighed to be equivalent to 1.27% of the granule weight were mixed in a bag and forcibly passed through a No. 30 sieve (500 μm) with a diameter of 30 cm again, thereby obtaining granules as a product. The granules (weight: 798.0 mg) contained 50 mg of tolvaptan.

Example 14
7.5 g of an amorphous tolvaptan powder obtained by amorphization of tolvaptan with hydroxypropyl cellulose by a spray-drying method (tolvaptan concentration: 66.7%), 5.0 g of xanthan gum (trade name: Keltrol CG-T, produced by CP Kelco), 2.5 g of carmellose sodium (trade name: Blanose CMC 7LP EP, produced by Ashland), 5.0 g of crystalline cellulose-carmellose sodium (trade name: Ceolus RC-A591NF, produced by Asahi Kasei Corp.), 10.0 g of sodium starch glycolate (trade name: Primojel, produced by DFE Pharma), 5.0 g of croscarmellose sodium (trade name: Kiccolate ND-2HS, produced by Nichirin Chemical Industries, Ltd.), 15.0 g of succinic acid (produced by Merck Millipore), 2.0 g of colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.), 10.0 g of sucralose (produced by San-Ei Gen F.F.I., Inc.), 5.0 g of sodium benzoate (produced by FUJIFILM Wako Pure Chemical Corporation), and 0.4 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed, placed in a polyethylene bag, mixed inside the bag, and passed through a No. 22 sieve (710 μm) with a diameter of 30 cm, thereby obtaining a mixed powder. The mixed powder (weight: 674.0 mg) contained 50 mg of tolvaptan.

Example 15
7.5 g of an amorphous tolvaptan powder obtained by amorphization of tolvaptan with hydroxypropyl cellulose by a spray-drying method (tolvaptan concentration: 66.7%), 5.0 g of xanthan gum (trade name: Keltrol CG-T, produced by CP Kelco), 2.5 g of carmellose sodium (trade name: Blanose CMC 7LP EP, produced by Ashland), 5.0 g of crystalline cellulose-carmellose sodium (trade name: Ceolus RC-A591NF, produced by Asahi Kasei Corp.), 10.0 g of sodium starch glycolate (trade name: Primojel, produced by DFE Pharma), 5.0 g of croscarmellose sodium (trade name: Kiccolate ND-2HS, produced by Nichirin Chemical Industries, Ltd.), 10.0 g of succinic acid (produced by Merck Millipore), 2.0 g of colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.), 10.0 g of sucralose (produced by San-Ei Gen F.F.I., Inc.), 5.0 g of sodium benzoate (produced by FUJIFILM Wako Pure Chemical Corporation), and 0.4 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed, placed in a polyethylene bag, mixed inside the bag, and passed through a No. 22 sieve (710 μm) with a diameter of 30 cm, thereby obtaining a mixed powder. The mixed powder (weight: 624.0 mg) contained 50 mg of tolvaptan.

Example 16
7.5 g of an amorphous tolvaptan powder obtained by amorphization of tolvaptan with hydroxypropyl cellulose by a spray-drying method (tolvaptan concentration: 66.7%), 5.0 g of xanthan gum (trade name: Keltrol CG-T, produced by CP Kelco), 2.5 g of carmellose sodium (trade name: Blanose CMC 7LP EP, produced by Ashland), 5.0 g of crystalline cellulose-carmellose sodium (trade name: Ceolus RC-A591NF, produced by Asahi Kasei Corp.), 10.0 g of sodium starch glycolate (trade name: Primojel, produced by DFE Pharma), 5.0 g of croscarmellose sodium (trade name: Kiccolate ND-2HS, produced by Nichirin Chemical Industries, Ltd.), 5.0 g of succinic acid (produced by Merck Millipore), 2.0 g of colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.), 10.0 g of sucralose (produced by San-Ei Gen F.F.I., Inc.), 5.0 g of sodium benzoate (produced by FUJIFILM Wako Pure Chemical Corporation), and 0.4 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed, placed in a polyethylene bag, mixed inside the bag, and passed through a No. 22 sieve (710 μm) with a diameter of 30 cm, thereby obtaining a mixed powder. The mixed powder (weight: 574.0 mg) contained 50 mg of tolvaptan.

Example 17
15.0 g of an amorphous tolvaptan powder obtained by amorphization of tolvaptan with hydroxypropyl cellulose by a spray-drying method (tolvaptan concentration: 66.7%), 10.0 g of xanthan gum (trade name: Keltrol CG-T, produced by CP Kelco), 5.0 g of carmellose sodium (trade name: Blanose CMC 7LP EP, produced by Ashland), 20.0 g of crystalline cellulose-carmellose sodium (trade name: Ceolus RC-A591NF, produced by Asahi Kasei Corp.), 50.0 g of sodium starch glycolate (trade name: Primojel, produced by DFE Pharma), 20.0 g of croscarmellose sodium (trade name: Kiccolate ND-2HS, produced by Nichirin Chemical Industries, Ltd.), 3.0 g of succinic acid (produced by Merck Millipore), 4.0 g of colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.), 2.0 g of sucralose (produced by San-Ei Gen F.F.I., Inc.), 15.0 g of sodium benzoate (produced by FUJIFILM Wako Pure Chemical Corporation), and 0.6 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed, placed in a polyethylene bag, and mixed inside the bag, thereby obtaining a mixed powder. The mixed powder (weight: 723.0 mg) contained 50 mg of tolvaptan and 75 mg of sodium benzoate.

Example 18
15.0 g of an amorphous tolvaptan powder obtained by amorphization of tolvaptan with hydroxypropyl cellulose by a spray-drying method (tolvaptan concentration: 66.7%), 15.0 g of xanthan gum (trade name: Keltrol CG-T, produced by CP Kelco), 5.0 g of carmellose sodium (trade name: Blanose CMC 7LP EP, produced by Ashland), 20.0 g of crystalline cellulose-carmellose sodium (trade name: Ceolus RC-A591NF, produced by Asahi Kasei Corp.), 50.0 g of sodium starch glycolate (trade name: Primojel, produced by DFE Pharma), 20.0 g of croscarmellose sodium (trade name: Kiccolate ND-2HS, produced by Nichirin Chemical Industries, Ltd.), 3.0 g of succinic acid (produced by Merck Millipore), 4.0 g of colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.), 2.0 g of sucralose (produced by San-Ei Gen F.F.I., Inc.), and 0.6 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed and placed in a polyethylene bag, and mixed inside the bag. Sodium benzoate (produced by FUJIFILM Wako Pure Chemical Corporation) weighed to be equivalent to 14.9% of the weight of the resulting mixed powder was added to the mixed powder, thereby obtaining a mixed powder. The mixed powder (weight: 773.0 mg) contained 50 mg of tolvaptan and 100 mg of sodium benzoate.

Example 19
7.5 g of an amorphous tolvaptan powder obtained by amorphization of tolvaptan with hydroxypropyl cellulose by a spray-drying method (tolvaptan concentration: 66.7%), 5.0 g of xanthan gum (trade name: Keltrol CG-T, produced by CP Kelco), 2.5 g of carmellose sodium (trade name: Blanose CMC 7LP EP, produced by Ashland), 5.0 g of crystalline cellulose-carmellose sodium (trade name: Ceolus RC-A591NF, produced by Asahi Kasei Corp.), 10.0 g of sodium starch glycolate (trade name: Primojel, produced by DFE Pharma), 5.0 g of croscarmellose sodium (trade name: Kiccolate ND-2HS, produced by Nichirin Chemical Industries, Ltd.), 1.5 g of succinic acid (produced by Merck Millipore), 2.0 g of colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.), 0.5 g of sucralose (produced by San-Ei Gen F.F.I., Inc.), 5.0 g of sodium benzoate (produced by FUJIFILM Wako Pure Chemical Corporation), and 0.4 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed, placed in a polyethylene bag, mixed inside the bag, and passed through a No. 22 sieve (710 μm) with a diameter of 30 cm, thereby obtaining a mixed powder. The mixed powder (weight: 444.0 mg) contained 50 mg of tolvaptan.

Example 20
15.0 g of an amorphous tolvaptan powder obtained by amorphization of tolvaptan with hydroxypropyl cellulose by a spray-drying method (tolvaptan concentration: 66.7%), 10.0 g of xanthan gum (trade name: Keltrol CG-T, produced by CP Kelco), 5.0 g of carmellose sodium (trade name: Blanose CMC 7LP EP, produced by Ashland), 20.0 g of crystalline cellulose-carmellose sodium (trade name: Ceolus RC-A591NF, produced by Asahi Kasei Corp.), 50.0 g of sodium starch glycolate (trade name: Primojel, produced by DFE Pharma), 20.0 g of croscarmellose sodium (trade name: Kiccolate ND-2HS, produced by Nichirin Chemical Industries, Ltd.), 3.0 g of succinic acid (produced by Merck Millipore), 4.0 g of colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.), 2.0 g of sucralose (produced by San-Ei Gen F.F.I., Inc.), and 0.6 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed and placed in a polyethylene bag, and mixed inside the bag. Sodium benzoate (produced by FUJIFILM Wako Pure Chemical Corporation) weighed to be equivalent to 6.92% of the weight of the resulting mixed powder was added to the mixed powder, thereby obtaining a mixed powder. The mixed powder (weight: 773.0 mg) contained 50 mg of tolvaptan and 125 mg of sodium benzoate.

Example 21
15.0 g of an amorphous tolvaptan powder obtained by amorphization of tolvaptan with hydroxypropyl cellulose by a spray-drying method (tolvaptan concentration: 66.7%), 10.0 g of xanthan gum (trade name: Keltrol CG-T, produced by CP Kelco), 5.0 g of carmellose sodium (trade name: Blanose CMC 7LP EP, produced by Ashland), 20.0 g of crystalline cellulose-carmellose sodium (trade name: Ceolus RC-A591NF, produced by Asahi Kasei Corp.), 50.0 g of sodium starch glycolate (trade name: Primojel, produced by DFE Pharma), 20.0 g of croscarmellose sodium (trade name: Kiccolate ND-2HS, produced by Nichirin Chemical Industries, Ltd.), 3.0 g of succinic acid (produced by Merck Millipore), 4.0 g of colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.), 2.0 g of sucralose (produced by San-Ei Gen F.F.I., Inc.), and 0.6 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed and placed in a polyethylene bag, and mixed inside the bag. Sodium benzoate (produced by FUJIFILM Wako Pure Chemical Corporation) weighed to be equivalent to 10.4% of the weight of the resulting mixed powder was added to the mixed powder, thereby obtaining a mixed powder. The mixed powder (weight: 798.0 mg) contained 50 mg of tolvaptan and 150 mg of sodium benzoate.

Example 22
15.0 g of an amorphous tolvaptan powder obtained by amorphization of tolvaptan with hydroxypropyl cellulose by a spray-drying method (tolvaptan concentration: 66.7%), 10.0 g of xanthan gum (trade name: Keltrol CG-T, produced by CP Kelco), 5.0 g of carmellose sodium (trade name: Blanose CMC 7LP EP, produced by Ashland), 20.0 g of crystalline cellulose-carmellose sodium (trade name: Ceolus RC-A591NF, produced by Asahi Kasei Corp.), 50.0 g of sodium starch glycolate (trade name: Primojel, produced by DFE Pharma), 20.0 g of croscarmellose sodium (trade name: Kiccolate ND-2HS, produced by Nichirin Chemical Industries, Ltd.), 3.0 g of succinic acid (produced by Merck Millipore), 4.0 g of colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.), 2.0 g of sucralose (produced by San-Ei Gen F.F.I., Inc.), and 0.6 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed and placed in a polyethylene bag, and mixed inside the bag. Sodium benzoate (produced by FUJIFILM Wako Pure Chemical Corporation) weighed to be equivalent to 17.3% of the weight of the resulting mixed powder was added to the mixed powder, thereby obtaining a mixed powder. The mixed powder (weight: 848.0 mg) contained 50 mg of tolvaptan and 200 mg of sodium benzoate.

Example 23
75 g of an amorphous tolvaptan powder obtained by amorphization of tolvaptan with hydroxypropyl cellulose by a spray-drying method (tolvaptan concentration: 66.7%), 50 g of xanthan gum (trade name: Keltrol CG-T, produced by CP Kelco), 25 g of carmellose sodium (trade name: Blanose CMC 7LP EP, produced by Ashland), 50 g of crystalline cellulose-carmellose sodium (trade name: Ceolus RC-A591NF, produced by Asahi Kasei Corp.), 150 g of croscarmellose sodium (trade name: Kiccolate ND-2HS, produced by Nichirin Chemical Industries, Ltd.), 5 g of colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.), 200 g of sodium benzoate (produced by FUJIFILM Wako Pure Chemical Corporation), and 2 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed and placed in a polyethylene bag, and mixed inside the bag. After the mixture was passed through a No. 22 sieve (710 μm) with a diameter of 30 cm, the total amount of the resulting product was fed into a high-speed stirring granulator (vertical granulator, VG-05, produced by Powrex Corporation) and mixed by stirring for 5 minutes at a blade rotational speed of 150 rpm and a chopper rotational speed of 500 rpm. The total amount of the resulting mixture was collected and fed into the feeder of a TF-Mini roller compactor (produced by Freund Corporation) to perform dry granulation under the conditions of a roll pressure of 7 MPa, a roll speed of 6 rpm, and a feeder screw speed of 15 rpm. The resulting ribbon-like granules were collected and crushed with an ND-2S mini mill (produced by Okada Seiko Co., Ltd.) equipped with a herringbone screen (1.0 × 10 mm). The particle size of the granules were further adjusted with an ND-2S equipped with a No. 30 mesh screen (500 μm). The resulting granules and colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.) weighed to be equivalent to 0.898% of the granule weight were mixed in a bag and forcibly passed through a No. 22 sieve (710 μm) with a diameter of 30 cm again, thereby obtaining granules as a product. The obtained granules A (weight: 562.0 mg) contained 50 mg of tolvaptan. The mean particle size of the obtained granules was about 130 μm.
Next, 400 g of sodium starch glycolate (trade name: Primojel, produced by DFE Pharma), 15 g of anhydrous citric acid (produced by Merck Millipore), 5 g of colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.), and 2 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed and placed in a polyethylene bag, and mixed inside the bag. After the mixture was passed through a No. 22 sieve (710 μm) with a diameter of 30 cm, the total amount of the resulting product was fed into a high-speed stirring granulator (vertical granulator, VG-05, produced by Powrex Corporation) and mixed by stirring for 5 minutes at a blade rotational speed of 150 rpm and a chopper rotational speed of 500 rpm. The total amount of the resulting mixture was collected and fed into the feeder of a TF-Mini roller compactor (produced by Freund Corporation) to perform dry granulation under the conditions of a roll pressure of 7 MPa, a roll speed of 6 rpm, and a feeder screw speed of 15 rpm. The resulting ribbon-like granules were collected and crushed with an ND-2S mini mill (produced by Okada Seiko Co., Ltd.) equipped with a herringbone screen (1.0 × 10 mm). The particle size of the granules were further adjusted with an ND-2S equipped with a No. 30 mesh screen (500 μm). The resulting granules and colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.) weighed to be equivalent to 1.185% of the granule weight were mixed in a bag and forcibly passed through a No. 22 sieve (710 μm) with a diameter of 30 cm again, thereby obtaining granules as a product. The obtained granules B were placebo granules (427.0 mg) without tolvaptan. The mean particle size of the obtained granules B was about 54 μm.
In order to prepare 50 mL of a suspension containing 50 mg of tolvaptan, 562.0 mg of granules A and 427.0 mg of granules B are separately weighed and added to 50 mL of purified water.

Example 24
75 g of an amorphous tolvaptan powder obtained by amorphization of tolvaptan with hydroxypropyl cellulose by a spray-drying method (tolvaptan concentration: 66.7%), 50 g of xanthan gum (trade name: Keltrol CG-T, produced by CP Kelco), 25 g of carmellose sodium (trade name: Blanose CMC 7LP EP, produced by Ashland), 50 g of crystalline cellulose-carmellose sodium (trade name: Ceolus RC-A591NF, produced by Asahi Kasei Corp.), 150 g of croscarmellose sodium (trade name: Kiccolate ND-2HS, produced by Nichirin Chemical Industries, Ltd.), 5 g of colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.), 200 g of sodium benzoate (produced by FUJIFILM Wako Pure Chemical Corporation), and 2 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed and placed in a polyethylene bag, and mixed inside the bag. After the mixture was passed through a No. 22 sieve (710 μm) with a diameter of 30 cm, the total amount of the resulting product was fed into a high-speed stirring granulator (vertical granulator, VG-05, produced by Powrex Corporation) and mixed by stirring for 5 minutes at a blade rotational speed of 150 rpm and a chopper rotational speed of 500 rpm. The total amount of the resulting mixture was collected and fed into the feeder of a TF-Mini roller compactor (produced by Freund Corporation) to perform dry granulation under the conditions of a roll pressure of 7 MPa, a roll speed of 6 rpm, and a feeder screw speed of 15 rpm. The resulting ribbon-like granules were collected and crushed with an ND-2S mini mill (produced by Okada Seiko Co., Ltd.) equipped with a herringbone screen (1.0 × 10 mm). The particle size of the granules were further adjusted with an ND-2S equipped with a No. 30 mesh screen (500 μm). The resulting granules and colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.) weighed to be equivalent to 0.898% of the granule weight were mixed in a bag and forcibly passed through a No. 22 sieve (710 μm) with a diameter of 30 cm again, thereby obtaining granules as a product. The obtained granules A (weight: 562.0 mg) contained 50 mg of tolvaptan. The mean particle size of the obtained granules was about 130 μm.
Next, 400 g of sodium starch glycolate (trade name: Primojel, produced by DFE Pharma), 30 g of anhydrous citric acid (produced by Merck Millipore), 5 g of colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.), and 2 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed and placed in a polyethylene bag, and mixed inside the bag. After the mixture was passed through a No. 22 sieve (710 μm) with a diameter of 30 cm, the total amount of the resulting product was fed into a high-speed stirring granulator (vertical granulator, VG-05, produced by Powrex Corporation) and mixed by stirring for 5 minutes at a blade rotational speed of 150 rpm and a chopper rotational speed of 500 rpm. The total amount of the resulting mixture was collected and fed into the feeder of a TF-Mini roller compactor (produced by Freund Corporation) to perform dry granulation under the conditions of a roll pressure of 7 MPa, a roll speed of 6 rpm, and a feeder screw speed of 15 rpm. The resulting ribbon-like granules were collected and crushed with an ND-2S mini mill (produced by Okada Seiko Co., Ltd.) equipped with a herringbone screen (1.0 × 10 mm). The particle size of the granules were further adjusted with an ND-2S equipped with a No. 30 mesh screen (500 μm). The resulting granules and colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.) weighed to be equivalent to 1.03% of the granule weight were mixed in a bag and forcibly passed through a No. 22 sieve (710 μm) with a diameter of 30 cm again, thereby obtaining granules as a product. The obtained granules B were placebo granules (442.0 mg) without tolvaptan. The mean particle size of the obtained granules B was about 52 μm.
In order to prepare 50 mL of a suspension containing 50 mg of tolvaptan, 562.0 mg of granules A and 442.0 mg of granules B are separately weighed and added to 50 mL of purified water.

Example 25
75 g of an amorphous tolvaptan powder obtained by amorphization of tolvaptan with hydroxypropyl cellulose by a spray-drying method (tolvaptan concentration: 66.7%), 50 g of xanthan gum (trade name: Keltrol CG-T, produced by CP Kelco), 25 g of carmellose sodium (trade name: Blanose CMC 7LP EP, produced by Ashland), 50 g of crystalline cellulose-carmellose sodium (trade name: Ceolus RC-A591NF, produced by Asahi Kasei Corp.), 150 g of croscarmellose sodium (trade name: Kiccolate ND-2HS, produced by Nichirin Chemical Industries, Ltd.), 5 g of colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.), 200 g of sodium benzoate (produced by FUJIFILM Wako Pure Chemical Corporation), and 2 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed and placed in a polyethylene bag, and mixed inside the bag. After the mixture was passed through a No. 22 sieve (710 μm) with a diameter of 30 cm, the total amount of the resulting product was fed into a high-speed stirring granulator (vertical granulator, VG-05, produced by Powrex Corporation) and mixed by stirring for 5 minutes at a blade rotational speed of 150 rpm and a chopper rotational speed of 500 rpm. The total amount of the resulting mixture was collected and fed into the feeder of a TF-Mini roller compactor (produced by Freund Corporation) to perform dry granulation under the conditions of a roll pressure of 7 MPa, a roll speed of 6 rpm, and a feeder screw speed of 15 rpm. The resulting ribbon-like granules were collected and crushed with an ND-2S mini mill (produced by Okada Seiko Co., Ltd.) equipped with a herringbone screen (1.0 × 10 mm). The particle size of the granules were further adjusted with an ND-2S equipped with a No. 30 mesh screen (500 μm). The resulting granules and colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.) weighed to be equivalent to 0.898% of the granule weight were mixed in a bag and forcibly passed through a No. 22 sieve (710 μm) with a diameter of 30 cm again, thereby obtaining granules as a product. The obtained granules A (weight: 562.0 mg) contained 50 mg of tolvaptan. The mean particle size of the obtained granules was about 130 μm.
Next, 400 g of sodium starch glycolate (trade name: Primojel, produced by DFE Pharma), 15 g of anhydrous citric acid (produced by Merck Millipore), 10 g of sucralose (produced by San-Ei Gen F.F.I., Inc.), 5 g of colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.), and 2 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed and placed in a polyethylene bag, and mixed inside the bag. After the mixture was passed through a No. 22 sieve (710 μm) with a diameter of 30 cm, the total amount of the resulting product was fed into a high-speed stirring granulator (vertical granulator, VG-05, produced by Powrex Corporation) and mixed by stirring for 5 minutes at a blade rotational speed of 150 rpm and a chopper rotational speed of 500 rpm. The total amount of the resulting mixture was collected and fed into the feeder of a TF-Mini roller compactor (produced by Freund Corporation) to perform dry granulation under the conditions of a roll pressure of 7 MPa, a roll speed of 6 rpm, and a feeder screw speed of 15 rpm. The resulting ribbon-like granules were collected and crushed with an ND-2S mini mill (produced by Okada Seiko Co., Ltd.) equipped with a herringbone screen (1.0 × 10 mm). The particle size of the granules were further adjusted with an ND-2S equipped with a No. 30 mesh screen (500 μm). The resulting granules and colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.) weighed to be equivalent to 1.185% of the granule weight were mixed in a bag and forcibly passed through a No. 22 sieve (710 μm) with a diameter of 30 cm again, thereby obtaining granules as a product. The obtained granules B were placebo granules (437.0 mg) without tolvaptan. The mean particle size of the obtained granules B was about 54 μm.
In order to prepare 50 mL of a suspension containing 50 mg of tolvaptan, 562.0 mg of granules A and 437.0 mg of granules B are separately weighed and added to 50 mL of purified water.

Example 26
187.5 g of an amorphous tolvaptan powder obtained by amorphization of tolvaptan with hydroxypropyl cellulose by a spray-drying method (tolvaptan concentration: 66.7%), 125 g of xanthan gum (trade name: Keltrol CG-T, produced by CP Kelco), 62.5 g of carmellose sodium (trade name: Blanose CMC 7LP EP, produced by Ashland), 125 g of crystalline cellulose-carmellose sodium (trade name: Ceolus RC-A591NF, produced by Asahi Kasei Corp.), 375 g of croscarmellose sodium (trade name: Kiccolate ND-2HS, produced by Nichirin Chemical Industries, Ltd.), 12.5 g of colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.), 500 g of sodium benzoate (produced by FUJIFILM Wako Pure Chemical Corporation), and 5 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed and placed in a polyethylene bag, and mixed inside the bag. After the mixture was passed through a No. 22 sieve (710 μm) with a diameter of 30 cm, the total amount of the resulting product was fed into a high-speed stirring granulator (vertical granulator, VG-25, produced by Powrex Corporation) and mixed by stirring for 5 minutes at a blade rotational speed of 150 rpm and a chopper rotational speed of 500 rpm. The total amount of the resulting mixture was collected and fed into the feeder of a TF-Mini roller compactor (produced by Freund Corporation) to perform dry granulation under the conditions of a roll pressure of 7 MPa, a roll speed of 6 rpm, and a feeder screw speed of 15 rpm. The resulting ribbon-like granules were collected and crushed with an ND-2S mini mill (produced by Okada Seiko Co., Ltd.) equipped with a herringbone screen (1.0 × 10 mm). The particle size of the granules were further adjusted with an ND-2S equipped with a No. 30 mesh screen (500 μm). Colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.) weighed to be equivalent to 0.898% of the granule weight was premixed in a bag with a small amount of the granules. Thereafter, the mixture was fed into a 3-L drum container while being forcibly passed through a No. 22 sieve (710 μm) with a diameter of 30 cm. The remaining granules were also fed into the drum container and mixed at 12 rpm for 30 minutes, thereby obtaining 1,322.7 g of granules A. The obtained granules A (weight: 562.0 mg) contained 50 mg of tolvaptan. The mean particle size of the obtained granules was about 138 μm.
Next, 4000 g of sodium starch glycolate (trade name: Primojel, produced by DFE Pharma), 300 g of anhydrous citric acid (produced by Merck Millipore), 100 g of sucralose (produced by San-Ei Gen F.F.I., Inc.), 50 g of colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.), and 20 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed and placed in a polyethylene bag, and mixed inside the bag. After the mixture was passed through a No. 22 sieve (710 μm) with a diameter of 30 cm, the total amount of the resulting product was fed into a high-speed stirring granulator (vertical granulator, VG-25, produced by Powrex Corporation) and mixed by stirring for 5 minutes at a blade rotational speed of 150 rpm and a chopper rotational speed of 500 rpm. The total amount of the resulting mixture was collected and fed into the feeder of a TF-Mini roller compactor (produced by Freund Corporation) to perform dry granulation under the conditions of a roll pressure of 7 MPa, a roll speed of 6 rpm, and a feeder screw speed of 15 rpm. The resulting ribbon-like granules were collected and crushed with an ND-2S mini mill (produced by Okada Seiko Co., Ltd.) equipped with a herringbone screen (1.0 × 10 mm). The particle size of the granules were further adjusted with an ND-2S equipped with a No. 30 mesh screen (500 μm). Colloidal silicon dioxide (trade name: Aerosil 200, produced by Nippon Aerosil Co., Ltd.) weighed to be equivalent to 1.03% of the granule weight was premixed in a bag with a small amount of the granules. Thereafter, the mixture was fed into an 18-L drum container while being forcibly passed through a No. 22 sieve (710 μm) with a diameter of 30 cm. The remaining granules were also fed into the drum container and mixed at 12 rpm for 15 minutes, thereby obtaining 4380.7 g of granules B. The obtained granules B were placebo granules (452.0 mg) without tolvaptan. The mean particle size of the obtained granules B was about 54 μm.
In order to prepare 50 mL of a suspension containing 50 mg of tolvaptan, 562.0 mg of granules A and 452.0 mg of granules B are separately weighed and added to 50 mL of purified water.

Comparative Example 1
37.5 g of an amorphous tolvaptan powder obtained by amorphization of tolvaptan with hydroxypropyl cellulose by a spray-drying method (tolvaptan concentration: 66.7%), 37.5 g of carmellose sodium (PR-S Nikkyoku, produced by DKS Co., Ltd.), 25.0 g of crystalline cellulose-carmellose sodium (trade name: Ceolus RC-A591NF, produced by Asahi Kasei Corp.), 50.0 g of sodium starch glycolate (trade name: Primojel, produced by DFE Pharma), 25.0 g of croscarmellose sodium (trade name: Kiccolate ND-2HS, produced by Nichirin Chemical Industries, Ltd.), 75.0 g of succinic acid (produced by Merck Millipore), 10.0 g of colloidal silicon dioxide (trade name: Aerosil 200 Pharma, produced by Evonik Industries AG), 5.0 g of sucralose (produced by San-Ei Gen F.F.I., Inc.), 25.0 g of sodium benzoate (produced by FUJIFILM Wako Pure Chemical Corporation), 0.5 g of sodium edetate (produced by FUJIFILM Wako Pure Chemical Corporation), and 1.0 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were each weighed and placed in a polyethylene bag, and mixed inside the bag. After the mixture was passed through a No. 18 sieve (850 μm) with a diameter of 30 cm, the total amount of the resulting product was placed in an NSK-150 mini kneader (produced by Okada Seiko Co., Ltd.) and mixed at 300 rpm for 5 minutes. The resulting mixture was fed into the feeder of a TF-Mini roller compactor (produced by Freund Corporation) to perform dry granulation under the conditions of a roll pressure of 7 MPa, a roll speed of 6 rpm, and a feeder screw speed of 15 rpm. The resulting ribbon-like flakes were directly fed into a crusher equipped with an 850-μm mesh screen, thereby obtaining granules (weight: 583.0 mg) containing 50 mg of tolvaptan. The mean particle size of the resulting product was about 194 μm.

Tables 1 to 4 show the formulations of the granules of the Examples. In these tables, the value of each component is expressed in grams.

Examination of Effect of Sodium Carboxymethyl Cellulose
Suspensions were prepared using the granules of Example A, Example B, and Example 1, and their suspension durability and component stability were evaluated. The following table shows the results. The table shows the amounts of the components in the suspensions in terms of the ratio of parts by mass when the amounts of the active ingredient (tolvaptan) and antiseptic (sodium benzoate) contained in the granules used in this examination were each 100 parts by mass. The value on the left represents the amount of parts by mass of tolvaptan, and the value on the right represents the amount of parts by mass of sodium benzoate. The same applies to the tables described later that show the results of component stability evaluation, unless otherwise noted.

Amorphous tolvaptan is basically undissolved and exists in a solid state in a suspension, whereas sodium benzoate is a water-soluble substance and is thus dissolved in water. Since Example A, Example B, and Example 1 contain xanthan gum, which is necessary to maintain the suspension state when the suspensions were left to stand for 15 minutes, the slight decreases in concentration in Example A were considered to be due to adhesion to the container. The results of Example B, in which starch sodium octenyl succinate (SSOS) is added instead of sodium carboxymethyl cellulose (CMC-Na), show that both tolvaptan and sodium benzoate were sufficiently recovered, indicating an improvement in terms of adsorption to the container. The results of Example 1, in which CMC-Na is used instead of SSOS, show that both tolvaptan and sodium benzoate were sufficiently recovered (almost as theoretically). Thus, CMC-Na was considered to have an improvement effect in terms of adsorption to the container that is equivalent to or higher than that of SSOS.

The suspension durability was good in all of Example A, Example B, and Example 1, and it was found visually and from the above results that the suspension state was maintained even after the suspensions were left to stand for 15 minutes.

Examination of Effect of Xanthan Gum
To examine the effect of incorporating xanthan gum into granules, the shaking time required to prepare a suspension from granules containing xanthan gum was investigated.

Example E, Example F, and Example C each have a formulation in which granules equivalent to 50 mg of tolvaptan contains 100 mg of xanthan gum, and Example D has a formulation in which granules equivalent to 50 mg of tolvaptan contains 75 mg of xanthan gum. Due to xanthan gum contained in the granules, the time required for suspension was considered to be in the practical range in all of these Examples.
Further analysis was performed. Example E does not contain croscarmellose sodium as a disintegrant, and Example F does not contain croscarmellose sodium as a disintegrant or crystalline cellulose-carmellose sodium as an excipient. The time required for suspension preparation is 30 seconds longer in Examples E and F than in Example C. Thus, the presence of the disintegrant and/or excipient was considered to be effective in shortening the suspension preparation time. Furthermore, the amount of xanthan gum in Example C and Example D is different from eath other, and the suspension preparation time was shortened by 50 seconds in Example D, which contains a smaller amount of xanthan gum, suggesting that adjusting the amount of xanthan gum (reducing the amount in this example) may also be effective in shortening the suspension preparation time.

Examination of Effect of Xanthan Gum (Grade of Xanthan Gum)
Whether the difference in grade of xanthan gum makes differences in shaking time and stability when suspensions are prepared from granules was examined. The following tables show the results.

The viscosities of xanthan gum (1% aqueous solution containing 1% KCl, 25±0.5℃, measured with a Brookfield viscometer, based on the Japanese Pharmaceutical Excipients) are as follows.
(Example 1) San Ace PH: 1,724 mPa・s
(Example 2) KELTROL CG-T: 1,200-1,600 mPa・s
(Example 3) KELTROL CG-SFT: 800-1,200 mPa・s
(Example 4) KELTROL CG: 1,200-1,600 mPa・s
Considering that the suspensions are prepared at the time of use, it can be said that examining the stability of the suspensions 5 minutes after being left to stand is sufficient. However, analysis in terms of durability of the suspension state indicates that in the example using CG-SFT, which has low viscosity, the quantitative values slightly decreased 15 minutes after the suspension was left to stand, confirming durability corresponding to the viscosity of xanthan gum. On the other hand, the time required to prepare the suspension was about half that of the examples using the other grades of xanthan gum.

Examination of Concentration of Xanthan Gum Added and Suspension Stability
Whether the shaking time and suspension durability in preparing suspensions from granules vary depending on the concentration of xanthan gum added was examined using the granules of Examples 5 to 8. The following tables show the results.

In all of the Examples, there was no deterioration of the suspension state that was considered to be a problem. However, in Examples 7 and 8, in which the amount of xanthan gum is relatively high, a slight tendency toward a decrease in the content of the antiseptic (sodium benzoate) was observed. In addition, the recovery of the quantitative values after shaking again was slightly poor. Thus, in order to make the suspension state more stable, it was considered preferable to add a relatively small amount of xanthan gum.

Examination of Combination of Xanthan Gum and Sodium Carboxymethyl Cellulose
The effect of the combination of xanthan gum and sodium carboxymethyl cellulose was examined using the granules of Examples 1 and 9, and Comparative Example 1. The following tables show the results.

In Examples 1 and 9, which contain xanthan gum and sodium carboxymethyl cellulose, the content of the active ingredient (tolvaptan) and the antiseptic (sodium benzoate) was maintained in the suspensions. Example 1 showed higher suspension stability 15 minutes after the suspension was left to stand. This was considered to be due to the relatively high xanthan gum content. In Comparative Example 1, which contains sodium carboxymethyl cellulose, but does not contain xanthan gum, the active ingredient was separated by sedimentation 5 minutes after the suspension was left to stand, and only 16% of the active ingredient was present in the suspension 15 minutes after the suspension was left to stand.

Examination of Storage Stability of Granules
The storage stability of granules was examined using the granules of Example 10 in the following manner.

Granules equivalent to 50 mg of tolvaptan (Example 10) were weighed, filled into empty packages with a width of about 15 mm and a length of about 90 mm formed in advance with a TM-10 aluminum stick packaging machine (produced by Toyo Machine Manufacturing Co., Ltd.), and sealed with a heat sealer. The aluminum stick single-dose packages were stored in a constant temperature and humidity chamber set at 25℃ and 40% RH (relative humidity) or 40℃ and 20% RH, and a stability test was performed. The storage period was 6 months, and sampling was performed at month 1, month 3, and month 6 to evaluate the stored products. The evaluation was performed by the suspension preparation time, pH measurement, quantification of the active ingredient (tolvaptan) and the antiseptic (sodium benzoate), a dissolution test, and powder X-ray diffraction analysis. The powder X-ray diffraction analysis was performed using the granules, and the pH measurement, the quantification, and the dissolution test were performed using a prepared suspension. The dissolution test of the suspension was performed after preparation of the suspension and after storage of the suspension in a refrigerator at about 5℃ for 4 weeks. The following tables show the results. The results of powder X-ray diffraction analysis are also shown in Fig. 1. In the part surrounded by the dashed line in Fig. 1, a crystal diffraction peak that is considered to be the peak of the active ingredient was confirmed near 4.7°. This result shows that the amorphous powder obtained by amorphization of the active ingredient with hydroxypropyl cellulose by a spray-drying method was highly likely to have transformed into crystals by being exposed to a temperature of 40℃ for a long period of time.

In the suspension prepared using the granules stored at 25℃ and 40% RH for 6 months, no influence on the dissolution property was observed even when the suspension was stored in a refrigerator for 4 weeks after preparation.

Examination of Organic Acid
The granules of Examples 11, 12, and 13, which use succinic acid, anhydrous citric acid, or dl-malic acid as the organic acid contained in the granules were compared. Specifically, 1 g of the granules of each Example was collected and placed in airtight glass containers (trade name: Maruemu Screw Tube No. 2, produced by Maruemu Corporation), and the containers were tightly capped and stored in constant-temperature chambers set at 40℃ and 50℃. The storage period was 3 months. Sampling of the products stored at 40℃ was performed at the beginning, month 1, month 2, and month 3, and sampling of the products stored at 50℃ was performed at month 0.5, month 1, month 2, and month 3. The times required to prepare suspensions using these granules, the pH of the prepared suspensions, and the stability of the components of the prepared suspensions were examined.
The following tables show the results.

Slight tendencies toward a decrease in the dissolution rate from that at the beginning were acceptable in all of the formulations, and the degree of decrease was the smallest in Example 12, which uses anhydrous citric acid. The degree of decrease in dissolution in Example 11, in which the same succinic acid as in Example 10 is used, but the proportion thereof is reduced to 1/10 of that in Example 10, was smaller than that of the product of Example 10 stored at 40℃ and 20% RH for 3 months. Moreover, although data are omitted here, no crystalline peaks that are considered to be derived from tolvaptan were observed by powder X-ray diffraction of the products of Examples 11, 12, and 13 stored at 40℃ for 3 months and at 50℃ for 3 months. That is, crystallization of tolvaptan was not confirmed.

In addition, slight yellowing of the granules of Examples 12 and 13 was observed when stored at 50℃, although it was within the acceptable range.

Investigation of Suitable Amount of Organic Acid
In general, the antimicrobial activity of antiseptics depends on pH. For example, benzoic acid and its sodium salt are effective against a wide range of microorganisms in a low pH range, but lose their effect at a pH of 6 or more. Sorbic acid not only loses its effect but is also easily decomposed by light at a pH of 6.5 or more. Although variations in the antimicrobial properties of p-hydroxybenzoic acid esters due to pH are small, p-hydroxybenzoic acid esters are adsorbed to plastics with polar groups; thus, the decrease in concentration due to adsorption affects the antimicrobial properties.

The more acidic the pH of a suspension, the higher the preservative effectiveness; however, the strong sourness may impair the taste, making the suspension difficult to take. In such a case, it is effective to mask the strong sourness using a flavor. However, flavors, which have food flavors, themselves may stress subjects who have not yet had weaning food, such as newborns, when such a suspension is taken.
Thus, it is reasonable to think that tastelessness and odorlessness are ideal when a drug is to be administered to subjects including newborns. In order to investigate a superior preparation that has preservative effectiveness and is also tasteless and odorless, the concentrations of organic acids (pH adjusters) added, the pH of aqueous solutions thereof, and their tastes were examined.

- pH and Sensory Test of Succinic Acid Aqueous Solution
50 mg and 150 mg of succinic acid were precisely weighed and dissolved in purified water to dilute them in specific ratios, thereby preparing succinic acid aqueous solutions with the concentrations shown in the table below. The pH of each solution was measured. In addition, volunteers were asked to monitor the taste of each succinic acid aqueous solution.

The volunteers detected the taste particular to the organic acid at a pH of less than 4.

Next, suspensions were prepared using the granules of Examples 14, 15, 16, and 19, which have different concentrations of succinic acid, and the pH of each suspension was measured.

A comparison of the above tables reveals that the pH shifted 1 value or more higher due to the influence of the other components, even when succinic acid was used in the same concentrations.

- pH and Sensory Test of Citric Acid Aqueous Solution
50 mg and 150 mg of anhydrous citric acid were precisely weighed and dissolved in purified water to dilute them in specific ratios, thereby preparing citric acid aqueous solutions with the concentrations shown in the table below. The pH of each solution was measured. In addition, volunteers were asked to monitor the taste of each citric acid aqueous solution.

A comparison of the above tables reveals that although citric acid had a greater pH-lowering effect than succinic acid at the same concentrations, citric acid had a milder taste than succinic acid, and citric acid was superior to succinic acid in terms of acceptable margin for taste.
These results show that the use of citric acid has less effect on the taste, even at the same concentrations.

Investigation of Suitable pH of Suspension and Suitable Concentration of Antiseptic
The higher the pH, the better the taste; however, a lower pH is preferred for preservation effectiveness. In particular, when used as a pediatric formulation, a suspension is required to have a taste that is easy to take and to have a minimally required antiseptic concentration.
Suspensions were prepared using the five types of granules of Examples 17, 18, 20, 21, and 22, and a preliminary test of the preservative effectiveness of the suspensions against five kinds of microorganisms (i.e., Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans, and Aspergillus brasiliensis) was performed according to Preservatives-Effectiveness Tests described in the Japanese Pharmacopoeia, General Information, in accordance with the criteria in the section for oral suspensions of EP 5.1.3. The organic acid in the granules used was succinic acid. The concentration of succinic acid was a concentration necessary to adjust the pH of the suspensions to around 5 (i.e., 15 mg/50 mL suspensions). The following table shows the results of the preservative effectiveness test on day 28 (at the completion of the test).

As can be seen from the above table, particularly preferable preservative effectiveness was obtained when the concentration of sodium benzoate in the suspensions was 0.25% or more. Basically, the preservative effectiveness strongly depends on the concentration of an antiseptic and pH. Thus, even when organic acids other than succinic acid are used, if the pH of the suspension is similar, a similar level of preservative effectiveness can be expected.

Division of Granules into Two Parts
In view of the comparative examination of the organic acids, the results of the pH and sensory evaluation of the organic acid aqueous solutions, and an actual performance of use in commercial products of pediatric formulations, citric acid was considered to be particularly preferable as an organic acid. In addition, the granules were divided into two parts, taking into consideration the risks of changes upon mixing an organic acid and a suspending agent and appearance changes such as yellowing. Granules A contained an amorphous powder of tolvaptan, a suspending agent, an excipient, a cellulose-based disintegrant, and sodium benzoate, and granules B contained anhydrous citric acid, a starch-based disintegranta pH adjuster, and a sweetening agent. A fluidizer and a lubricant were equally contained in granules A and granules B.
This division ensured long-term storage stability. The results of the suspension preparation time and pH of Examples 23 to 26 are shown below. Suspensions were prepared by placing granules A and granules B in the same container and then adding water for suspension.

The use of the divided granules further shortened the suspension preparation time, making the preparation easier to prepare. Moreover, since all of these Examples contain the same amount of sodium benzoate as in Example 22, and the resulting suspensions had a pH of 4.9 to 5.2, it can be said that the suspensions had sufficient preservative effectiveness.

Stability in Use
To carry out a study to examine stability during 4 weeks of use, assuming multiple uses, 50 mL of a suspension was prepared from the granules of Example 26 using a 75-mL PET bottle and purified water and stored in a refrigerator for 4 weeks (storage temperature: 5±3℃). More specifically, the granules of Example 26 (equivalent to 50 mg of tolvaptan) were added to 50 mL of water for suspension to prepare a suspension. Thus, the concentration of tolvaptan in the resulting suspension was 1 mg/ml.
Sampling was performed at the beginning of the study, after 2 weeks, and after 4 weeks for examination of the properties, pH of the suspension, and related substances and impurities, a dissolution test, and quantification. The dissolution test was performed using a 0.22% sodium lauryl sulfate solution, which is applied to commercially available tolvaptan tablets, and the dissolution rate after 30 minutes was measured by HPLC.

As shown in the table above, the suspension stored under refrigeration met the criteria in all of the test items.

Examination of Administration via Nasogastric Tube
A study of administration via a nasogastric tube was performed using a suspension prepared from the granules of Example 26.
50 mL of a suspension was prepared from the granules of Example 26 using a 75-mL PET bottle and purified water. More specifically, the granules of Example 26 (equivalent to 50 mg of tolvaptan) were added to 50 mL of water for suspension to prepare a suspension. Thus, the concentration of tolvaptan in the resulting suspension was 1 mg/ml. When the suspension is used as a suspension for oral administration, an oral dispenser for oral administration is preferably used for collecting and administering the suspension. Thus, the accuracy of collection and administration using an oral dispenser available in the medical field was confirmed at first, and then a test of administration via a nasogastric tube was performed.

- Preliminary Experiment (Test of Accuracy of Collection of Suspension by Oral Dispenser)
3-mL and 5-mL Comar oral dispensers, which are available in the medical field in Europe and the United States, were obtained, and the suspension prepared from the granules of Example 26 was collected according to the scale lines, and the entire amount was discharged and recovered. The concentration of tolvaptan in the recovered suspension was measured by HPLC.

- Main Experiment (Test of Administration of Suspension via Nasogastric Tube)
Commercially available Cardinal Health vinyl chloride nasogastric tubes (inner diameter: 8 Fr. Gauge), which are available in the medical field in Europe and the United States, were obtained. This inner diameter is the thinnest on the market and can be used as an aid during administration (oral administration) to newborns. The minimum amount of rinse required to administer the entire amount of suspension retained in each of the nasogastric tubes with different lengths into the stomach after discharging the entire amount of suspension collected with each oral dispenser into the nasogastric tubes was investigated. The nasogastric tubes were those having two different lengths of 16 inches and 42 inches, and the oral dispensers had sizes of 3 mL and 5 mL.
An oral dispenser was connected to the connector of a nasogastric tube. The entire amount of the suspension was discharged, and then 2, 3, or 5 mL of purified water was immediately supplied to the tube to recover the entire amount. The content of tolvaptan in the recovered sample was quantified by HPLC and calculated as the recovered amount.

The following table shows the results of the preliminary experiment.

Both of the oral dispensers of the above sizes could be used to accurately collect the suspension according to the scale lines, and the entire amount was recovered without being affected by adhesion or adsorption to the containers. Furthermore, the criteria of the preparation uniformity test of the European Pharmacopoeia were met.

The following table shows the results of the main experiment.

The tubes with an inner diameter of 8 Fr. G. are the thinnest nasogastric tubes on the market.
The entire amount of the suspension prepared from the granules of Example 26 of the present invention was easily discharged into each tube having this inner diameter without tube blockage or significant resistance. The amount of tolvaptan in each sample recovered after addition and discharge of the rinse was 97 to 102%, which is almost as theoretically. The above results show that the suspension can also be administered to newborns. This is because, as can be seen in the table above, the suspension is excellent in terms of handling since it has low viscosity and does not remain in the oral dispensers.

Claims

A composition for preparing a suspension, comprising:
(a) particles containing amorphous tolvaptan;
(b) xanthan gum; and
(c) benzoic acid or a salt thereof.
The composition according to claim 1, further comprising (d) at least one organic acid selected from the group consisting of succinic acid, citric acid, malic acid, and mixtures of two or more thereof.
The composition according to claim 1 or 2, further comprising (e) carboxymethyl cellulose or a salt thereof.
The composition according to any one of claims 1 to 3, further comprising (f) starch glycolic acid or a salt thereof.
The composition according to any one of claims 1 to 4, which is in the form of granules.
The composition according to claim 4, which is in the form of granules comprising:
(a) particles containing amorphous tolvaptan;
(b) xanthan gum;
(c) sodium benzoate;
(d) at least one organic acid selected from the group consisting of succinic acid, citric acid, malic acid, and salts thereof, and mixtures of two or more thereof;
(e) sodium carboxymethyl cellulose; and
(f) sodium starch glycolate.
The granule kit for preparing a suspension, comprising:
(a) particles containing amorphous tolvaptan;
(b) xanthan gum;
(c) sodium benzoate;
(d) at least one organic acid selected from the group consisting of succinic acid, citric acid, malic acid, and salts thereof, and mixtures of two or more thereof;
(e) sodium carboxymethyl cellulose; and
(f) sodium starch glycolate,
wherein the kit comprises at least two granule packaging bags,
a first packaging bag comprises first granules containing components (a), (b), (c), and (e), and
a second packaging bag comprises second granules containing components (d) and (f).
The kit according to claim 7, wherein the composition according to claim 6 is prepared by combining the first granules and the second granules.
A suspension prepared from the composition according to any one of claims 1 to 6 or the kit according to claim 7 or 8.