TW201729814A - Solid preparation - Google Patents

Abstract

The problem of the present invention is provision of a solid preparation containing N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepin-3-amine or a salt thereof, which may release the compound in a sustained manner. A solid preparation containing N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazep in-3-amine or a salt thereof, and a hydrophilic gel-forming polymer.

Description

Solid preparation

The present invention relates to a N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxaza heterocycle A solid preparation of heptane-3-amine or a salt thereof which releases the compound in a sustained manner.

N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine- The 3-amine and its salt exhibit serotonin 5-HT _2C receptor activation, and are conventionally used as a prophylactic or therapeutic agent for lower urinary tract symptoms, obesity, and/or organ prolapse (Patent Document 1).

Patent Document 2 discloses a dry coated lozenge containing nifedipine, which comprises a core containing nifedipine and a polymer material forming a hydrophilic gel and exhibits delayed release of nifedipine, and An outer casing formed by press-coating the core, the outer shell comprising nifedipine, a polymeric substance forming a hydrophilic gel, and a polymer material composed of a water-insoluble polymer and nifedipine and a hydrophilic gel A disintegration inhibitor of a pH-independent matrix.

Patent Document 3 discloses a dry coating tablet comprising a polymerization-forming gel comprising 8 to 80% by weight of nifedipine and 15 to 80% by weight of a cellulose derivative or the like. Material and 2 to 30 weight a core of a disintegration inhibiting substance composed of a water-insoluble polymer, and a hydrophilic gel composed of 5 to 50% by weight of nifedipine and 30 to 90% by weight of a cellulose derivative or the like A polymer material and an outer shell of 5 to 50% by weight of a disintegration inhibiting substance composed of a water-insoluble polymer.

Patent Document 4 discloses a dry coating tablet comprising a core containing nifedipine and a polymer material forming a hydrophilic gel, and a polymer material containing nifedipine and forming a hydrophilic gel and An outer shell of a disintegration inhibiting substance composed of a water-insoluble polymer.

[Document list] [Patent Literature]

Patent Document 1: WO 2010/147226

Patent Document 2: JP-A-9-143073

Patent Document 3: JP-A-2004-2348

Patent Document 4: JP-A-2009-120600

Because N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine 3-Amines and their salts have high solubility and short half-life, so 3 doses per day are expected to avoid adverse events with typical rapid release tablets.

From the standpoint of patient convenience and medication compliance, there is a need for a formulation that reduces the number of doses.

Accordingly, it is an object of the present invention to provide a sustained release of N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f] A solid preparation of [1,4]oxazepine-3-amine or a salt thereof, which can be administered once or twice a day.

In addition, it contains N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine The preparation of trien-3-amine or a salt thereof as an active ingredient has a problem of stability of the active ingredient due to an increase in the amount of the additive. Therefore, it is desirable to use less additives.

Accordingly, it is another object of the present invention to provide a formulation which can reduce the amount of additives used, which in turn can inhibit N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydrogen The decrease in the stability of pyrazolo[2,3-f][1,4]oxazepine-3-amine or a salt thereof.

The inventors conducted intensive studies to solve the above problems and found that N-methyl-N-(1-methylethyl)-6,7,8 can be released in a sustained manner via the use of a polymer which forms a hydrophilic gel. , 9-tetrahydropyrazino[2,3-f][1,4]oxazepan-3-enylamine and salts thereof.

The inventors have also discovered that a core, an outer shell, a polymer forming a hydrophilic gel in the core and the outer shell, and N-methyl-N-(1-methylethyl) in the core and/or outer shell are also included. a solid preparation (such as a tablet) of -6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine-3-amine or a salt thereof, N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine- The release behavior of the 3-amine or its salt can be modulated by adjusting its content in the core and/or outer shell to release the compound in a sustained manner.

The inventors have further found that the use of a polymer forming a hydrophilic gel can maintain moldability even when the amount of additives other than the polymer forming the hydrophilic gel is reduced. It has been found that when the amount of the additive is increased, it affects N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1, 4] Chemical stability of oxazepine-3-amine and its salts. Therefore, it is expected that the decrease in the stability of the compound can be suppressed by reducing the additive.

The present inventors conducted further studies based on the above findings and completed the present invention.

Accordingly, the present invention provides the following.

[1] includes N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxaza heterocycle A solid preparation of heptane-3-amine or a salt thereof and a polymer forming a hydrophilic gel.

[2] The solid preparation of the above [1], comprising: (1) a core comprising N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazin[2] , 3-f][1,4]oxazet-3-enylamine or a salt thereof, and a first polymer forming a hydrophilic gel; and (2) an outer shell comprising N-methyl- N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepan-3-ene or its a salt, and a second polymer forming a hydrophilic gel.

[2-1] The solid preparation of the above [1], comprising: (1) a core comprising N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazine and [2,3-f][1,4]oxazepine-3-amine or a salt thereof, and a first polymer forming a hydrophilic gel; and (2) an outer shell comprising a second formation Polymer of hydrophilic gel and does not include N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4 Oxazepine-3-amine or a salt thereof.

[3] The solid preparation of the above [2] or [2-1], wherein the first polymer forming the hydrophilic gel and the second polymer forming the hydrophilic gel are the same or different, and each is selected from the group consisting of polyoxidation Groups of ethylene, hydroxypropylmethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carboxyvinyl polymer, methylcellulose, and sodium carboxymethylcellulose.

[4] The solid preparation of the above [2], wherein, in the preparation, N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazazine in the core [ The content (by weight) of 2,3-f][1,4]oxazepine-3-amine or its salt is the same as or higher than N-methyl-N-(1 in the outer shell) -Methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepan-3-enylamine or a salt thereof ( Weight meter).

The present invention can provide N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxaza A solid preparation of ghlytrien-3-amine or a salt thereof as an active ingredient which can release a compound in a sustained manner by using a polymer which forms a hydrophilic gel.

In particular, according to the present invention, N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazine[2,3-f][1,4 can be adjusted. The content of the oxazepine-3-amine or a salt thereof in the core and/or the outer shell provides a solid preparation (such as a tablet) comprising a core, an outer shell, and a formation in the core and the outer shell a polymeric substance of a hydrophilic gel, and N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazine in the core and/or outer shell [2, 3-f][1,4]oxazet-3-enylamine or a salt thereof which releases the compound in a sustained manner.

Further, the present invention can provide a preparation which can be administered once or twice a day.

Furthermore, the present invention can provide a polymer even forming a hydrophilic gel. When the amount of the additive other than is reduced, the present invention can provide N-methyl-N-(1-A) because a formulation which exhibits good moldability by forming a hydrophilic gel polymer is used, and since the amount of the additive used can be reduced. Decreased stability of hydroxyethyl-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine-3-amine or its salt Inhibitory preparation.

Fig. 1 shows the results of Experimental Example 1.

Fig. 2 shows the results of Experimental Example 2.

Fig. 3 shows the results of Experimental Example 3.

Fig. 4 shows the results of Experimental Example 4.

Fig. 5 shows the results of Experimental Example 5.

Fig. 6 shows the results of Experimental Example 6.

Fig. 7 shows the results of Experimental Example 7.

Fig. 8 shows the results of Experimental Example 8.

Fig. 9 shows the results of Experimental Example 9.

Fig. 10 shows the results of Experimental Example 10.

Fig. 11 shows the results of Experimental Example 11.

Fig. 12 shows the results of Experimental Example 12.

The invention is described in detail below.

The solid preparation of the invention contains N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxaza Cyclohepten-3-amine or a salt thereof is used as an active ingredient.

N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine- Examples of the salt of the 3-amine include a mineral acid salt, an organic acid salt, and a basic or acidic amino acid salt.

Examples of inorganic acid salts include hydrochlorides, hydrobromides, nitrates, sulfates, and phosphates.

Examples of organic acid salts include formates, acetates, trifluoroacetates, fumarates, oxalates, tartrates, maleates, citrates, succinates, malates , methanesulfonate, besylate and p-toluenesulfonate.

Examples of the basic amino acid salt include salts with arginine, lysine, and ornithine.

Examples of acidic amino acid salts include aspartate and glutamine.

Among them, pharmacologically acceptable salts are preferred.

As N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine a salt of 3-amine, N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxa Azacyclotrien-3-amine hydrochloride is particularly preferred.

N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxygen in free form in the solid preparation of the present invention The amount of the azacyclotrien-3-amine or a salt thereof is usually from 1 to 1,000 mg, preferably from 5 to 800 mg, more preferably from 10 to 500 mg.

N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxygen in free form in the solid preparation of the present invention The amount of the azacyclotrien-3-amine or its salt, relative to the weight of the naked preparation (uncoated tablet), is generally From 0.5 to 85% by weight, preferably from 1 to 75% by weight, more preferably from 1 to 65% by weight.

The solid preparation of the present invention is characterized by containing a polymer forming a hydrophilic gel.

In the present invention, the viscosity (25 ° C, 1% aqueous solution) of the polymer forming the hydrophilic gel is generally not less than 100 cP, preferably not less than 5,500 cP, more preferably not less than 7,500 cP. In the present invention, the viscosity (25 ° C, 1% aqueous solution) of the polymer forming the hydrophilic gel is generally not more than 500,000 cP.

In the present invention, the polymer forming the hydrophilic gel is not particularly limited as long as it has the above viscosity. Examples include polyoxyethylene (e.g., Polyox ^TM WSR 303 Dow Chemical Company manufactured, or Sumitomo Seika Chemicals Co., Ltd. PEO -20NF manufactured), hydroxypropyl methylcellulose (e.g., Shin-etsu Chemical Co. , METOLOSE 90SH-100000SR manufactured by Ltd., carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carboxyvinyl polymer (for example, Carbopol 971PNF manufactured by Lubrizol Corporation), methylcellulose and Sodium carboxymethyl cellulose. Polyethylene oxide, hydroxypropylmethylcellulose and carboxyvinyl polymer are preferred, and polyethylene oxide is particularly preferred.

In the solid preparation of the present invention, it is preferred to use a highly gel-forming hydrophilic gel-forming polymer such as polyethylene oxide as a polymer for forming a hydrophilic gel because it can regulate N-methyl-N-(1) -Methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine-3-amine or a salt thereof.

In the solid preparation of the present invention, the content of the polymer forming the hydrophilic gel is generally 15 to 95% by weight, preferably 25 to 85% by weight, more preferably the weight of the naked preparation (uncoated tablet). It is 35 to 75% by weight.

In the present specification, the "bare preparation (uncoated tablet)" means a preparation (tablet) before application of a solid preparation as described below, or a solid preparation (tablet) itself when not coated with a solid preparation.

For example, the solid preparation of the present invention is a tablet.

Specific examples of the solid preparation of the present invention include the following specific examples (A), (B) and (C).

(A) a single-layer solid preparation (eg, a tablet) containing N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f [1,4]oxazepine-3-amine or a salt thereof and a polymer forming a hydrophilic gel (hereinafter also referred to as a single layer tablet of the present invention).

(B) a solid preparation (e.g., a tablet) comprising: (1) containing N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazin[2, 3-f][1,4]oxazet-3-enylamine or a salt thereof and a core of a first hydrophilic gel-forming polymer; and (2) containing N-methyl-N- (1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine-3-amine or a salt thereof The second outer shell of the polymer forming the hydrophilic gel.

(C) a solid preparation (e.g., a tablet) comprising: (1) containing N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazin[2, 3-f][1,4]oxazet-3-enylamine or a salt thereof and first forming a hydrophilic The core of the polymer of the gel; and (2) the polymer containing the second hydrophilic gel and not containing N-methyl-N-(1-methylethyl)-6,7,8,9 - an outer shell of tetrahydropyrazino[2,3-f][1,4]oxazepine-3-amine or a salt thereof.

(The following (B) and (C) are also referred to as dry coated tablets of the present invention.)

In the monolayer tablet of the present invention, N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxy The content of the azacyclotrien-3-amine or a salt thereof and the polymer forming the hydrophilic gel is as specified above.

As described below, the single layer tablet of the present invention may be a film coating.

When the single-layer tablet of the present invention is coated with a coating film, the content of the polymer forming the hydrophilic gel is the content in the uncoated tablet before the film coating.

In the present invention, an outer shell may be formed on the outside of the single-layer tablet, which has a polymer forming a hydrophilic gel without N-methyl-N-(1-methylethyl)-6, 7,8. 9-Tetrahydropyrazino[2,3-f][1,4]oxazepine-3-amine and its salts. It will be explained later that this shell does not contain N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4] Specific examples of dry coated tablets of oxazepine-3-amine or a salt thereof.

In the dry coated tablet of the present invention, the core may be a tablet (in the specification, the tablet is referred to as a core as a core tablet).

In the dry coated tablet of the present invention, N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f in free form in the core. The content of [1,4]oxazepine-3-amine or a salt thereof is usually from 0.5 to 1000 mg, preferably from 2.5 to 800 mg, more preferably from 5 to 500 mg.

In the dry coated tablet of the present invention, the free form of N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f in the outer shell The content of [1,4]oxazepine-3-amine or a salt thereof is usually from 0 to 500 mg, preferably from 0 to 400 mg, more preferably from 0 to 250 mg.

The dry coated tablet of the present invention may comprise N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazine in the core and the outer shell or only in the core [ 2,3-f][1,4]oxazet-3-en-3-amine or a salt thereof.

For example, the solid preparation of the present invention also contains N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f] in the core. 1,4] oxazepine-3-amine or a salt thereof, and does not contain N-methyl-N-(1-methylethyl)-6,7,8,9-tetra in the outer shell A dry coated lozenge of hydrogenpyrazino[2,3-f][1,4]oxazepine-3-amine or a salt thereof.

In the dry coated tablet of the present invention, N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1 in the core The content (by weight) of 4, oxazepine-3-amine or its salt is preferably equal to or higher than N-methyl-N-(1-methylethyl)- in the outer shell. The content (by weight) of 6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine-3-amine or a salt thereof, thereby Delayed and sustained release of further active ingredients is contemplated.

The dry coated tablet of the present invention is a solid preparation (such as a tablet) comprising a core, an outer shell, a polymer forming a hydrophilic gel in the core and the outer shell, and an active ingredient in the core and/or outer shell. The solid preparation can modulate the release behavior of the active ingredient by adjusting the content of the active ingredient in the core and/or the outer shell, thereby releasing the active ingredient in a sustained manner.

According to the paddle method described in the 16th edition of the Japanese Pharmacopoeia (Japanese Pharmacopoeia dissolves The test, the second fluid, 100 rpm, 900 mL), the dissolution rate of the active ingredient is generally 0 to 30% after 2 hr; 15 to 55% after 6 hr; 35 to 80% after 9 hr, preferably 5 to 5 after 2 hr. 25%; 20 to 50% after 6 hr; 40 to 75% after 9 hr, more preferably 5 to 20% after 2 hr; 25 to 45% after 6 hr; 45 to 70% after 9 hr.

In another specific example, it is generally 10 to 45% after 2 hr; 40 to 80% after 6 hr; 60 to 100% after 9 hr, preferably 15 to 40% after 2 hr; and 45 to 75% after 6 hr; It is then 65 to 95%, more preferably 20 to 35% after 2 hr; 50 to 70% after 6 hr; and 70 to 95% after 9 hr.

Examples of the first and second hydrophilic gel-forming polymers in the dry-coated tablet of the present invention include those described above as the polymer forming the hydrophilic gel in the solid preparation of the present invention.

The first polymer forming the hydrophilic gel and the second polymer forming the hydrophilic gel may be the same or different.

In the dry coated tablet of the present invention, the first and second hydrophilic gel-forming polymers are each preferably polyethylene oxide.

In the dry coated tablet of the present invention, the polymer content of the first hydrophilic gel formed in the core is generally from 0.01 to 90% by weight, preferably from 5 to 70% by weight, based on the weight of the core, more preferably 10 to 50% by weight.

In the dry coated tablet of the present invention, the content of the second hydrophilic polymer forming the polymer in the outer shell is generally from 20 to 100% by weight, preferably from 30 to 95% by weight, based on the weight of the outer shell, more preferably 40 to 90% by weight.

The dry coated tablet of the present invention may be a coating film as described below.

When the dry coating tablet of the present invention is coated with a coating film, the content of the polymer forming the hydrophilic gel is the content in the pre-film coating preparation (uncoated tablet).

In the dry coated tablet of the present invention, the weight ratio of the core and the outer shell (core: outer shell) is generally from 1:1.5 to 3.5, preferably from 1:1.5 to 3.0, more preferably from 1:2 to 2.5, and even more preferably. It is about 1:2.

The solid preparation of the present invention (single layer tablet, dry coated tablet) may further contain additives commonly used in the field of preparation.

Examples of the additive include excipients (e.g., mannitol, spray-dried mannitol, starch, lactose, sucrose, calcium carbonate, calcium phosphate, crystalline cellulose), binders (e.g., starch, gum arabic, alginic acid, gelatin) , polyvinylpyrrolidone and hydroxypropylcellulose (having a low viscosity preventing function as a polymer for forming a hydrophilic gel, such as HPC-SL and PC-L, manufactured by Nippon Soda Co., Ltd.), and a lubricant (eg, stearic acid, magnesium stearate, calcium stearate, and talc).

The use of a polymer forming a hydrophilic gel in the present invention can reduce the amount of additives other than the polymer forming the hydrophilic gel.

In the solid preparation of the present invention, the total content of the additive other than the polymer forming the hydrophilic gel is generally 5 to 95% by weight, preferably 15 to 75% by weight, more preferably the weight of the uncoated tablet. It is 25 to 65% by weight.

The solid preparation of the present invention (single layer tablet, dry coated tablet) can be produced using the various components described above and according to methods commonly used in the art of formulation.

For example, by blending N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxa nitrogen Heterocyclic heptane-3-amine Or a salt thereof, a polymer forming a hydrophilic gel (eg, polyethylene oxide, hydroxypropylmethylcellulose, carboxyvinyl polymer, etc.) and optionally added additives (eg, excipients (eg, Mannitol), a lubricant (e.g., magnesium stearate), a binder, and the mixture is compression molded (pressed) to produce a single layer tablet of the present invention.

For example, the dry coated tablet of the present invention can be produced according to the following method.

Blending N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine An olefin-3-amine or a salt thereof, a polymer forming a hydrophilic gel (e.g., polyethylene oxide, hydroxypropylmethylcellulose, carboxyvinyl polymer, etc.) and an additive added as needed (for example, A flux (e.g., mannitol), a lubricant (e.g., magnesium stearate), a binder, and the mixture is compression molded to obtain a core (core tablet).

In addition, blending N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxaza heterocycle a heptane-3-amine or a salt thereof, a polymer forming a hydrophilic gel (for example, polyethylene oxide, hydroxypropylmethylcellulose, carboxyvinyl polymer, etc.) and an additive added as needed (for example) An excipient (e.g., mannitol), a lubricant (e.g., magnesium stearate), a binder, to obtain an outer shell blending powder (i.e., a powder mixture of the components forming the outer shell).

The core tablet and the outer shell are blended into a powder to form a dry coated tablet.

No N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazine can be added during the process of producing the shell-blended powder in the above manufacturing method. [2,3 -f][1,4]oxazepine-3-amine or a salt thereof The shell does not contain N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxaza heterocycle A dry coated lozenge of heptane-3-amine or a salt thereof.

Blending can be carried out using a mixer such as a V-blender or a drum mixer. Molding can be carried out by using, for example, a single press ingot, a rotary press, or the like.

The solid preparation of the present invention (single layer tablet, dry coated tablet) can be applied as needed via methods commonly used in the art of formulation. For example, the following films can be used to coat substrates and coating additives.

Examples of the film-coated substrate include hydroxypropylmethylcellulose (TC-5E, TC-5R; manufactured by Shin-etsu Chemical Co., Ltd.), hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, methyl Cellulose and hydroxyethyl methylcellulose.

Examples of the coating additive include a light blocking agent such as titanium oxide; a fluidizing agent such as talc, sterile talc; a coloring agent such as iron oxide and yellow iron oxide; a plasticizer such as polyethylene glycol (e.g., Macrogol 6000), citric acid three Ethyl ester, castor oil and polysorbate; and organic acids such as citric acid, tartaric acid, malic acid and ascorbic acid.

When the solid preparation of the present invention is a coating film, the amount of film coating is generally from 1% to 8%, preferably from 2% to 6%, based on the weight of the naked preparation (uncoated tablet).

The solid preparation of the present invention generally has a weight of from 100 mg to 1,500 mg, preferably from 200 mg to 1,000 mg.

The single layer tablet of the present invention typically has a size of from 6 mm to 20 mm, preferably from 8 mm to 15 mm.

The dry coated tablet of the present invention generally has a size of from 4.5 mm to 17 mm, preferably from 5 mm to 12 mm, and the core of the dry coated tablet (core tablet) generally has a size of from 7.5 mm to 20 mm, preferably from 8 mm to 15mm.

The shape of the solid preparation of the present invention is not particularly limited and may be any shape such as a circular shape, a capsule shape, a ring shape, an oblong shape, or the like.

The solid preparation of the present invention is suitable for use in improving, preventing or treating serotonin 5-HT _2C correlation in mammals such as human, monkey, cow, horse, pig, mouse, rat, hamster, rabbit, cat, dog, sheep and goat. A drug such as a lower urinary tract symptom (eg, stress urinary incontinence). The solid preparation of the present invention can be administered orally safely.

Although N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxa nitrogen in the solid preparation of the present invention The dose of the heterocyclic p-trien-3-amine or its salt varies depending on the subject to be administered, the symptoms, and the like, and is orally administered to a patient having an acute urinary tract symptom (adult; body weight: about 60 kg), and the usual amount is about 0.01667 to Approximately 16.67 mg/kg body weight, preferably from about 0.08333 to about 13.33 mg/kg body weight, more preferably from about 0.1667 to about 8.333 mg/kg body weight, may be administered from one to several times per day depending on the symptoms.

The solid preparation of the present invention can release the active ingredient in a sustained manner, which can reduce the number of doses per day (1 or 2 doses/day). As a result, it is expected to increase patient convenience and improve medication compliance.

The solid preparation of the invention can be combined with N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxa nitrogen The active ingredient other than the heterocyclic p-trien-3-amine or a salt thereof is used in combination (hereinafter simply referred to as "combined drug"). In this case, N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyridyl The administration time of the pyrazolo[2,3-f][1,4]oxazepine-3-amine or a salt thereof and the combined use thereof is not limited, and they may be administered simultaneously or in a staggered manner. Object. Further, the solid preparation and the concomitant drug of the present invention may be administered in two formulations containing the respective active ingredients, or may be administered as a single preparation containing the two active ingredients.

The dose of the combined drug can be appropriately determined based on the dose used in the clinical situation.

Examples of combined medications include other therapeutic agents for stress urinary incontinence.

[Examples]

The invention will be described in more detail below with reference to examples, and the examples should not be construed as limiting.

Use the Japanese Pharmacopoeia 16th Edition compatible product, Japanese Pharmaceutical Excipient 2003 compatible product, US Pharmacopoeia (USP) compatible product, and US National Formulary compatible product as the formulation additive used in the following examples (eg, polyethylene oxide) , mannitol, magnesium stearate, hydroxypropyl cellulose, crystalline cellulose, carboxyvinyl polymer, yellow iron oxide, spray dried mannitol, hydroxypropyl methylcellulose, talc).

In the following examples, the dissolution test was carried out in accordance with the paddle method described in the 16th edition of the Japanese Pharmacopoeia. The dissolution test second fluid can be prepared as a test liquid according to a known method. The amount of the second fluid as the dissolution test of the test liquid is generally 900 mL.

The compound X used in the following formulation examples is N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4] Oxazepine-3- amine. The dissolution properties of the preparations obtained in Examples 1 to 27 were evaluated by a paddle method (Japanese Pharmacopoeia dissolution test, second fluid, 50 rpm, 900 mL) using a Varian dissolution tester. The dissolution properties of the preparations obtained in Examples 34 to 39 were evaluated using a dissolution tester manufactured by Toyama Sangyo Co., Ltd. and according to the paddle method (Japanese Pharmacopoeia dissolution test, second fluid, 100 rpm, 900 mL).

Example 1

Blending hydrochloride Compound X (5.82g), polyethylene oxide (Polyox ^TM WSR 303,2.5g), mannitol (0.095 g) and magnesium stearate (0.085 g) and using a manual tablet press (HANDTAB, Ichihashi Seiki Manufacture) A core tablet (170 mg per spindle) was produced using a 7 mm Φ punch press.

Blending polyoxyethylene (Polyox ^TM WSR 303,15g), mannitol (1.83 g of) and magnesium stearate (0.17 g of) the housing blended powder produced. A dry coated lozenge containing Compound X hydrochloride (100 mg of Compound X) shown in Table 1 was produced by blending a core tablet and a 340 mg shell with a 11 mm Φ punch using an autograph tablet press (AG-IS, Shimadzu). (510 mg per spindle).

Example 2

Blending hydrochloride Compound X (5.82g), polyethylene oxide (Polyox ^TM WSR 303,2.5g), mannitol (0.095 g) and magnesium stearate (0.085 g) and using a manual tablet press (HANDTAB, Ichihashi Seiki Manufacture) A core tablet (170 mg per spindle) was produced using a 7 mm Φ punch press.

Blending polyoxyethylene (Polyox ^TM WSR 303,12.5g), mannitol (4.33 g of) and magnesium stearate (0.17 g of) the housing blended powder produced. A dry coated lozenge containing Compound X hydrochloride (100 mg of Compound X) shown in Table 2 was produced by blending a core tablet and a 340 mg shell with a 11 mm Φ punch using an autograph tablet press (AG-IS, Shimadzu). (510 mg per spindle).

Example 3

Blending hydrochloride Compound X (5.82g), polyethylene oxide (Polyox ^TM WSR 303,17.5g), mannitol (1.925g) and magnesium stearate (0.255 g) produced powder mixture. A single layer tablet containing Compound X hydrochloride (100 mg of Compound X) shown in Table 3 was produced using an autograph tablet press (AG-IS, Shimadzu) using a 11 mm Φ punch to compress 510 mg of the powder mixture into tablets (510 mg per tablet) ).

Example 4

Blending hydrochloride Compound X (5.82g), polyethylene oxide (Polyox ^TM WSR 303,2.5g), mannitol (0.095 g) and magnesium stearate (0.085 g) and using a manual tablet press (HANDTAB, Ichihashi Seiki Manufacture) A core tablet (170 mg per spindle) was produced using a 7 mm Φ punch press.

Blending polyoxyethylene (Polyox ^TM WSR 303,10g), mannitol (6.83 g) and magnesium stearate (0.17 g of) the housing blended powder produced. A dry coated lozenge containing Compound X hydrochloride (100 mg of Compound X) shown in Table 4 was produced by blending a core tablet and a 340 mg shell with a 11 mm Φ punch using an autograph tablet press (AG-IS, Shimadzu). (510 mg per spindle).

Example 5

Blending hydrochloride Compound X (5.82g), polyethylene oxide (Polyox ^TM WSR 303,2.5g), mannitol (0.095 g) and magnesium stearate (0.085 g) and using a manual tablet press (HANDTAB, Ichihashi Seiki Manufacture) A core tablet (170 mg per spindle) was produced using a 7 mm Φ punch press.

Blending polyoxyethylene (Polyox ^TM WSR 303,7.5g), mannitol (9.33 g) and magnesium stearate (0.17 g of) the housing blended powder produced. A dry coated lozenge containing Compound X hydrochloride (100 mg of Compound X) shown in Table 5 was produced by blending a core tablet and a 340 mg shell with a 11 mm Φ punch using an autograph tablet press (AG-IS, Shimadzu). (510 mg per spindle).

[table 5]

Example 6

X blending compound hydrochloride (5.238g), polyethylene oxide (Polyox ^TM WSR 303,2.5g), mannitol (0.677 g) and magnesium stearate (0.085 g) and using a manual tablet press (HANDTAB, Ichihashi Seiki Manufacture) A core tablet (170 mg per spindle) was produced using a 7 mm Φ punch press.

X blending compound hydrochloride (0.582g), polyethylene oxide (Polyox ^TM WSR 303,12.5g), mannitol (3.748g) and magnesium stearate (0.17 g of) the housing blended powder produced. A dry coated lozenge containing Compound X hydrochloride (100 mg of Compound X) shown in Table 6 was produced by blending a core tablet and a 340 mg shell with a 11 mm Φ punch using an autograph tablet press (AG-IS, Shimadzu). (510 mg per spindle).

Example 7

X blending compound hydrochloride (4.074g), polyethylene oxide (Polyox ^TM WSR 303,2.5g), mannitol (1.841g) and magnesium stearate (0.085 g) and using a manual tablet press (HANDTAB, Ichihashi Seiki Manufacture) A core tablet (170 mg per spindle) was produced using a 7 mm Φ punch press.

X blending compound hydrochloride (1.746g), polyethylene oxide (Polyox ^TM WSR 303,12.5g), mannitol (2.584g) and magnesium stearate (0.17 g of) the housing blended powder produced. A dry coated lozenge containing Compound X hydrochloride (100 mg of Compound X) shown in Table 7 was produced by blending a core tablet and a 340 mg shell with a 11 mm Φ punch using an autograph tablet press (AG-IS, Shimadzu). (510 mg per spindle).

Example 8

X blending compound hydrochloride (4.074g), polyethylene oxide (Polyox ^TM WSR 303,2.5g), mannitol (0.356 g) and magnesium stearate (0.07 g of) and using a manual tablet press (HANDTAB, Ichihashi Seiki Manufactured) A core tablet (140 mg per spindle) was produced using a 6.5 mm Φ punch press.

X blending compound hydrochloride (1.746g), polyethylene oxide (Polyox ^TM WSR 303,12.5g), mannitol (0.109 g) and magnesium stearate (0.145 g of) the housing blended powder produced. A dry coated ingot containing Compound X hydrochloride (100 mg of Compound X) shown in Table 8 was produced by blending a core tablet and a 290 mg shell with a 10.5 mm Φ punch using an autograph tablet press (AG-IS, Shimadzu). Agent (430mg per ingot).

Example 9

X blending compound hydrochloride (4.074g), polyethylene oxide (Polyox ^TM WSR 303,1.75g), mannitol (0.116 g) and magnesium stearate (0.06 g of) and using a manual tablet press (HANDTAB, Ichihashi Seiki Manufactured) A core tablet (120 mg per spindle) was produced using a 6.5 mm Φ punch press.

X blending compound hydrochloride (1.746g), polyethylene oxide (Polyox ^TM WSR 303,10g), mannitol (0.134 g) and magnesium stearate (0.12 g of) the housing blended powder produced. A dry coated lozenge containing Compound X hydrochloride (100 mg of Compound X) shown in Table 9 was produced by blending a core tablet and a 240 mg shell with a 10 mm Φ punch using a autograph press (AG-IS, Shimadzu). (360mg per spindle).

Example 10

X blending compound hydrochloride (3.492g), polyethylene oxide (Polyox ^TM WSR 303,1.5g), mannitol (0.057g) and magnesium stearate (0.051 g) and using a manual tablet press (HANDTAB, Ichihashi Seiki Manufacture) A core tablet (102 mg per spindle) was produced using a 6 mm Φ punch press.

X blending compound hydrochloride (2.328g), polyethylene oxide (Polyox ^TM WSR 303,7.5g), mannitol (0.072 g) and magnesium stearate (0.1 g of) the housing blended powder produced. A dry coated ingot containing Compound X hydrochloride (100 mg of Compound X) shown in Table 10 was produced by blending a core tablet and a 200 mg shell with a 9.5 mm Φ punch using an autograph tablet press (AG-IS, Shimadzu). Agent (302mg per ingot).

Example 11

Blending hydrochloride Compound X (2.91g), polyethylene oxide (Polyox ^TM WSR 303,1.25g), mannitol (0.0475 g) and magnesium stearate (0.0425g) and using a manual tablet press (HANDTAB, Ichihashi Seiki Manufacture) A core tablet (85 mg per spindle) was produced by pressing a 5.5 mm Φ punch.

Blending hydrochloride Compound X (2.91g), polyethylene oxide (Polyox ^TM WSR 303,6g) and magnesium stearate (0.09 g of) the housing blended powder produced. A dry coated lozenge containing Compound X hydrochloride (100 mg of Compound X) shown in Table 11 was produced by blending a core tablet and a 180 mg shell with a 9 mm Φ punch using a autograph tablet press (AG-IS, Shimadzu). (265mg per ingot).

Example 12

Blending compound X hydrochloride (4.074 g), hydroxypropyl methylcellulose (METOLOSE 90SH-100000SR, 1.75 g), mannitol (0.116 g) and magnesium stearate (0.06 g) and using a manual tablet press ( HANDTAB, manufactured by Ichihashi Seiki), a core tablet (120 mg per spindle) was produced using a 6.5 mm Φ punch press.

The shell-mixed powder was produced by blending compound X hydrochloride (1.746 g), hydroxypropyl methylcellulose (METOLOSE 90SH-100000SR, 10 g), mannitol (0.134 g), and magnesium stearate (0.12 g). A dry coated lozenge containing Compound X hydrochloride (100 mg of Compound X) shown in Table 12 was produced by blending a core tablet and a 240 mg shell with a 10 mm Φ punch using an autograph tablet press (AG-IS, Shimadzu). (360mg per spindle).

Example 13

Compound X hydrochloride (366.8 g) and crystalline cellulose (22.5 g) were charged into a fluidized bed granulator (LAB-1, Powrex Corp.) while being sprayed into purified water to dissolve hydroxypropylcellulose ( The obtained aqueous solution of HPC-L, 18.9 g) was granulated and dried to produce a granulated powder. The granulated powder (362.8 g) was blended with polyethylene oxide (Polyox ^TM WSR 303, 152 g) and magnesium stearate (5.2 g) and a spindle was pressed with a 7 mm Φ punch using a rotary press (Correct 19K, Kikusui Seisakusho). Agent (130mg per tablet).

Compound X hydrochloride (279.2 g), mannitol (60.8 g) and crystalline cellulose (20.8 g) were charged into a fluidized bed granulator (LAB-1, Powrex Corp.) while being sprayed into purified water. The aqueous solution obtained by dissolving hydroxypropylcellulose (HPC-L, 17.6 g) was granulated and dried to produce a granulated powder. Blended granulated powder (189.2 g) and polyethylene oxide (Polyox ^TM WSR 303,880g) and magnesium stearate (10.8 g of) the housing blended powder produced. A dry-coated lozenge containing the compound X hydrochloride (100 mg of the compound X) shown in Table 13 was produced by using a rotary tablet press (manufactured by Kikusui Seisakusho) using a 10 mm Φ punch to blend the core tablet and 270 mg of the outer shell into a powder tablet. Ingot 400mg).

Example 14

X blending compound hydrochloride (1.746g), polyethylene oxide (Polyox ^TM WSR 303,2.74g), mannitol (4.724g) and magnesium stearate (0.09 g of) and using a manual tablet press (HANDTAB, Ichihashi Seiki Manufacture) A core tablet (93 mg per spindle) was produced by pressing a 6 mm Φ punch.

X blending compound hydrochloride (1.746g), polyethylene oxide (Polyox ^TM WSR 303,13g), mannitol (4.754g) and magnesium stearate (0.2g) produced a housing blended powder. A dry-coated lozenge containing the compound X hydrochloride (30 mg of the compound X) shown in Table 14 was produced by blending a core tablet and a 340 mg outer shell with a 9 mm Φ punch using a manual press (manufactured by HANDTAB, manufactured by Ichihashi Seiki). (290mg per spindle).

Example 15

X blending compound hydrochloride (2.094g), polyethylene oxide (Polyox ^TM WSR 303,3.3g), mannitol (5.696g) and magnesium stearate (0.11 g of) and using a manual tablet press (HANDTAB, Ichihashi Seiki Manufacture) A core tablet (112 mg per spindle) was produced using a 6 mm Φ punch press.

X blending compound hydrochloride (1.398g), polyethylene oxide (Polyox ^TM WSR 303,17.55g), mannitol (4.622g) and magnesium stearate (0.23 g of) the housing blended powder produced. A dry-coated lozenge containing the compound X hydrochloride (30 mg of the compound X) shown in Table 15 was produced by blending a core tablet and a 238 mg outer shell with a 9 mm Φ punch using a manual press (manufactured by HANDTAB, manufactured by Ichihashi Seiki). (350mg per spindle).

Example 16

X blending compound hydrochloride (2.445g), polyethylene oxide (Polyox ^TM WSR 303,3.8g), mannitol (5.705g), hydroxypropyl cellulose (HPC-L, 0.42g), crystalline cellulose ( 0.5 g) and magnesium stearate (0.13 g) were used to produce a core tablet (130 mg per ingot) using a 7 mm Φ punch press using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki).

X blending compound hydrochloride (1.047g), polyethylene oxide (Polyox ^TM WSR 303,22g), mannitol (3.203g), hydroxypropyl cellulose (HPC-L, 0.22g), crystalline cellulose (0.26 g) and magnesium stearate (0.27 g) to produce a shell blend powder. A dry-coated lozenge containing the compound X hydrochloride (30 mg of the compound X) shown in Table 16 was produced by blending a core tablet and a 270 mg outer shell with a 10 mm Φ punch using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki). (400mg per spindle).

Example 17

X blending compound hydrochloride (2.793g), polyethylene oxide (Polyox ^TM WSR 303,4.4g), mannitol (6.607g), hydroxypropyl cellulose (HPC-L, 0.45g), crystalline cellulose ( 0.6 g) and magnesium stearate (0.15 g) were used to produce a core tablet (150 mg per tablet) using a 75% Φ punch press using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki).

X blending compound hydrochloride (0.699g), polyethylene oxide (Polyox ^TM WSR 303,26g), mannitol (3.431g), hydroxypropyl cellulose (HPC-L, 0.25g), crystalline cellulose (0.31 g) and magnesium stearate (0.31 g) to produce an outer shell blend powder. A dry-coated lozenge containing the compound X hydrochloride (30 mg of the compound X) shown in Table 17 was produced by blending a core tablet and a 310 mg outer shell with a 10 mm Φ punch using a manual press (manufactured by HANDTAB, manufactured by Ichihashi Seiki). (460 mg per ingot).

Example 18

X blending compound hydrochloride (3.144g), polyethylene oxide (Polyox ^TM WSR 303,5g), mannitol (7.496g), hydroxypropyl cellulose (HPC-L, 0.51g), crystalline cellulose (0.68 g) and magnesium stearate (0.17 g) and a core tablet (170 mg per spindle) was produced using a manual press (HANDTAB, manufactured by Ichihashi Seiki) with an 8 mm Φ punch.

X blending compound hydrochloride (0.348g), polyethylene oxide (Polyox ^TM WSR 303,30g), mannitol (3.672g), hydroxypropyl cellulose (HPC-L, 0.28g), crystalline cellulose (0.35 g) and magnesium stearate (0.35 g) to produce a shell blend powder. A dry-coated lozenge containing the compound X hydrochloride (30 mg of the compound X) shown in Table 18 was produced by blending a core tablet and a 350 mg outer shell with a 11 mm Φ punch using a manual press (manufactured by HANDTAB, manufactured by Ichihashi Seiki). (520mg per ingot).

Example 19

X blending compound hydrochloride (1.746g), polyethylene oxide (Polyox ^TM WSR 303,7.87g), mannitol (4.739g) and magnesium stearate (0.145 g of) produced powder mixture. A 290 mg powder mixture was tableted with a 9 mm Φ punch using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki) to produce a single layer tablet (290 mg per tablet) containing the compound X hydrochloride (30 mg of the compound X) shown in Table 19.

Example 20

Blending hydrochloride Compound X (8.15g), polyethylene oxide (Polyox ^TM WSR 303,3.8g), hydroxypropyl cellulose (HPC-L, 0.42g), crystalline cellulose (0.5g) and stearic acid Magnesium (0.13 g) was used to produce a core tablet (130 mg per spindle) using a manual press (HANDTAB, manufactured by Ichihashi Seiki) with a 7 mm Φ punch.

Blending hydrochloride Compound X (3.49g), polyethylene oxide (Polyox ^TM WSR 303,22g), mannitol (0.76g), hydroxypropyl cellulose (HPC-L, 0.22g), crystalline cellulose (0.26 g) and magnesium stearate (0.27 g) to produce a shell blend powder. A dry-coated lozenge containing the compound X hydrochloride (100 mg of the compound X) shown in Table 20 was produced by blending a core tablet and a 270 mg outer shell with a 10 mm Φ punch using a manual press (manufactured by HANDTAB, manufactured by Ichihashi Seiki). (400mg per spindle).

Example 21

Blending compound X hydrochloride (8.15 g), carboxyvinyl polymer (Carbopol 971 PNF, 3.8 g), hydroxypropyl cellulose (HPC-L, 0.42 g), crystalline cellulose (0.5 g) and stearic acid Magnesium (0.13 g) was used to produce a core tablet (130 mg per spindle) using a manual press (HANDTAB, manufactured by Ichihashi Seiki) with a 7 mm Φ punch.

Blending Compound X Hydrochloride (3.49g), Carboxyvinyl Polymer (Carbopol 971PNF, 22g), mannitol (0.76g), hydroxypropylcellulose (HPC-L, 0.22g), crystalline cellulose (0.26g) and magnesium stearate (0.27g) to produce shell blend powder . A dry-coated lozenge containing the compound X hydrochloride (100 mg of the compound X) shown in Table 21 was produced by blending a core tablet and a 270 mg outer shell with a 10 mm Φ punch using a manual press (manufactured by HANDTAB, manufactured by Ichihashi Seiki). (400mg per spindle).

Example 22

Compound X hydrochloride (97.9 g), mannitol (329 g) and polyethylene oxide (PEO-20NF, 44 g) were charged into a fluidized bed granulator (MP-01, Powrex Corp.) while being sprayed and purified. Granulation with water and drying to obtain a granulated powder. A granulated powder (353.1 g) was blended with polyethylene oxide (PEO-20NF, 33 g) and magnesium stearate (3.9 g) and a 6.5 mm Φ punch was used to produce a core tablet using a rotary press (Kikusui Seisakusho). 130 mg per ingot).

Compound X hydrochloride (36.7 g), mannitol (128.9 g) and polyethylene oxide (PEO-20NF, 385 g) were charged into a fluidized bed granulator (MP-01, Powrex Corp.) while being sprayed The water was purified, granulated, and dried to obtain a granulated powder. A granulated powder (393.3 g) was blended with polyethylene oxide (PEO-20NF, 275 g) and magnesium stearate (6.75 g) to produce an outer shell blend powder. A core tablet and a 270 mg shell were blended into a powder tablet using a rotary press (Kikusui Seisakusho) to produce a dry coated tablet (400 mg per tablet) containing Compound X hydrochloride (30 mg of Compound X). The dry coated tablet was loaded into a coating machine (DRC-300, Powrex Corp.), and water was dissolved by dissolving hydroxypropylmethylcellulose (TC-5E) and dispersing yellow iron oxide therein. The suspension was applied and dried to produce a coating dry-coated tablet as shown in Table 22.

Example 23

Compound X hydrochloride (87.3 g), mannitol (300.7 g) and polyethylene oxide (PEO-20NF, 36.25 g) were charged into a fluidized bed granulator (MP-01, Powrex Corp.) while spraying The purified water was granulated and dried to obtain a granulated powder. The granulated powder (339.4 g) was blended with polyethylene oxide (PEO-20NF, 29 g) and magnesium stearate (3.6 g) and compressed with a 5.5 mm Φ punch using a rotary press (Kikusui Seisakusho) to obtain a core tablet ( 93mg per ingot).

Compound X hydrochloride (69.84 g), mannitol (190.2 g) and polyethylene oxide (PEO-20NF, 260 g) were charged into a fluidized bed granulator (MP-1, Powrex Corp.) while being sprayed The water was purified, granulated, and dried to obtain a granulated powder. A granulated powder (455 g) was blended with polyethylene oxide (PEO-20NF, 227.5 g) and magnesium stearate (7 g) to produce an outer shell blend powder. A dry tablet tablet (290 mg per tablet) containing Compound X hydrochloride (30 mg of Compound X) was produced by blending a core tablet and a 197 mg shell with a 9 mm Φ punch using a rotary press (Kikusui Seisakusho). The dry coated tablet was loaded into a coating machine (DRC-300, Powrex Corp.), and water was dissolved by dissolving hydroxypropylmethylcellulose (TC-5E) and dispersing yellow iron oxide therein. The suspension was applied and dried to produce a coating dry-coated tablet as shown in Table 23.

Example 24

Compound X hydrochloride (104.8 g), mannitol (284.4 g) and polyethylene oxide (PEO-20NF, 236.1 g) were charged into a fluidized bed granulator (MP-01, Powrex Corp.) while spraying It is granulated by adding to purified water, and dried to obtain a granulated powder. Blending granulated powder (521 g) with polyethylene oxide (PEO-20NF, 196.75 g) and magnesium stearate (7.25 g) and using a rotary press (Kikusui Seisakusho) with a 9 mm Φ punch to produce a compound containing hydrochloric acid salt Uncoated tablets (30 mg of compound X) (290 mg per ingot). The uncoated tablet was charged into a coating machine (DRC-300, Powrex Corp.), and the coating of the oxidized water and the yellow iron oxide dispersed therein was sprayed by dissolving hydroxypropylmethylcellulose (TC-5E). The suspension was applied and dried to produce a coated single-layer tablet as shown in Table 24.

Example 25

X blending compound hydrochloride (0.815g), polyethylene oxide (Polyox ^TM WSR 303,2.3g), mannitol (9.855g) and magnesium stearate (0.13 g of) and using a manual tablet press (HANDTAB, Ichihashi Seiki Manufacture) A core tablet (130 mg per spindle) was produced using a 7 mm Φ punch press.

X blending compound hydrochloride (0.349g), polyethylene oxide (Polyox ^TM WSR 303,22g), mannitol (4.381g) and magnesium stearate (0.27 g of) the housing blended powder produced. A dry-coated lozenge containing the compound X hydrochloride (10 mg of the compound X) shown in Table 25 was produced by blending a core tablet and a 270 mg outer shell with a 10 mm Φ punch using a manual press (manufactured by HANDTAB, manufactured by Ichihashi Seiki). (400mg per spindle).

Example 26

X blending compound hydrochloride (0.582g), polyethylene oxide (Polyox ^TM WSR 303,1.45g), mannitol (7.178g) and magnesium stearate (0.09 g of) and using a manual tablet press (HANDTAB, Ichihashi Seiki Manufacture) A core tablet (93 mg per spindle) was produced by pressing a 6 mm Φ punch.

X blending compound hydrochloride (0.582g), polyethylene oxide (Polyox ^TM WSR 303,13g), mannitol (5.918g) and magnesium stearate (0.2g) produced a housing blended powder. A dry-coated lozenge containing Compound X hydrochloride (10 mg of Compound X) shown in Table 26 was produced by blending a core tablet and a 197 mg outer shell with a 9 mm Φ punch using a manual press (manufactured by HANDTAB, manufactured by Ichihashi Seiki). (290mg per spindle).

Example 27

X blending compound hydrochloride (1.164g), polyethylene oxide (Polyox ^TM WSR 303,14.5g), mannitol (13.046g) and magnesium stearate (0.29 g of) produced powder mixture. A 290 mg powder mixture was tableted with a 9 mm Φ punch using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki) to produce a single layer tablet (290 mg per tablet) containing the compound X hydrochloride (10 mg of the compound X) shown in Table 27.

Example 28

Compound X hydrochloride (125.82 g) and mannitol (125.82 g) were blended in a bag and passed through a 16 mesh screen. The blended and sieved powder was mixed with spray-dried mannitol (297.45 g), polyethylene oxide (PEO-20NF, 113.22 g) and magnesium stearate (6.69 g) in a bag using a rotary press (Kikusui Seisakusho). The core tablet was obtained by pressing a tablet with a 5.5 mm Φ punch (92.86 mg per spindle).

Compound X hydrochloride (69.84 g) and mannitol (69.84 g) were blended in a bag and passed through a 16 mesh screen. The blended and sieved powder was blended with spray-dried mannitol (297.45 g), polyethylene oxide (PEO-20NF, 113.22 g) and magnesium stearate (6.69 g) in a bag to obtain an outer shell blend powder. The core tablet and the 197.14 mg shell were blended into a powder ingot using a 9 mm Φ punch using a rotary press (Kikusui Seisakusho) to produce a compound X hydrochloride (30 mg compound). X) Dry coated lozenge (290 mg per tablet). The dry coated tablet was loaded into a coating machine (HICOATER LABO, Freund Corp.), and hydroxypropylmethylcellulose (TC-5E) was dissolved by spraying to purify water and disperse talc and yellow iron oxide therein. The coating was coated with a suspension and dried to produce a coating dry-coated tablet as shown in Table 28.

Example 29

Compound X hydrochloride (125.82 g) and mannitol (125.82 g) were blended in a bag and passed through a 16 mesh screen. The blended and sieved powder was mixed with spray-dried mannitol (297.45 g), polyethylene oxide (PEO-20NF, 113.22 g) and magnesium stearate (6.69 g) in a bag using a rotary press (Kikusui Seisakusho). A core tablet (130 mg per spindle) was obtained by pressing a tablet with a 6.5 mm Φ punch.

Compound X hydrochloride (41.88 g) and mannitol (41.88 g) were blended in a bag and passed through a 16 mesh screen. The blended and sieved powder was blended with spray-dried mannitol (105.44 g), polyethylene oxide (PEO-20NF, 880 g) and magnesium stearate (10.8 g) in a bag to obtain an outer shell blend powder. A core tablet and a 270 mg shell were blended into a powder tablet using a rotary press (Kikusui Seisakusho) to produce a dry coated tablet (400 mg per tablet) containing Compound X hydrochloride (30 mg of Compound X). The dry coated tablet was loaded into a coating machine (HICOATER LABO, Freund Corp.), and hydroxypropylmethylcellulose (TC-5E) was dissolved by spraying to purify water and disperse talc and yellow iron oxide therein. The suspension was coated with a coating and dried to produce a coating dry-coated tablet as shown in Table 29.

Example 30

Compound X hydrochloride (104.76 g) and mannitol (104.76 g) were blended in a bag and passed through a 16 mesh screen. The sifted powder and spray-dried mannitol (179.58 g), polyethylene oxide (PEO-20NF, 472.20 g) and Magnesium stearate (8.7 g) was blended in a bag and compressed with a 9 mm Φ punch using a rotary press (Kikusui Seisakusho) to obtain an uncoated tablet containing Compound X hydrochloride (30 mg of Compound X) (290 mg per tablet) . The uncoated tablet was loaded into a coating machine (HICOATER LABO, Freund Corp.), and hydroxypropylmethylcellulose (TC-5E) was dissolved by spraying to purify water and disperse talc and yellow iron oxide therein. The suspension was applied by coating, and dried to produce a coated single-layer tablet as shown in Table 30.

Example 31

Compound X hydrochloride (44.83 g) and mannitol (44.83 g) were blended in a bag and passed through a 16 mesh screen. Mixing the sieved powder with spray-dried mannitol (497.2 g), polyethylene oxide (PEO-20NF, 121 g) and magnesium stearate (7.15 g) were mixed in a bag and compressed with a 5.5 mm Φ punch using a rotary press (Kikusui Seisakusho) to obtain a core tablet (per Ingot 92.86mg).

Compound X hydrochloride (23.28 g) and mannitol (23.28 g) were blended in a bag and passed through a 16 mesh screen. The blended and sieved powder was blended with spray-dried mannitol (214.12 g), polyethylene oxide (PEO-20NF, 520 g) and magnesium stearate (7.88 g) in a bag to obtain an outer shell blend powder. A dry tablet tablet (290 mg per tablet) containing Compound X hydrochloride (10 mg of Compound X) was produced by blending a core tablet and a 197.14 mg shell with a 9 mm Φ punch using a rotary press (Kikusui Seisakusho). The dry coated tablet was loaded into a coating machine (HICOATER LABO, Freund Corp.), and hydroxypropylmethylcellulose (TC-5E) was dissolved by spraying to purify water and disperse talc and yellow iron oxide therein. The suspension was coated with a coating, and dried to produce a coating dry-coated tablet as shown in Table 31.

Example 32

Compound X hydrochloride (44.83 g) and mannitol (44.83 g) were blended in a bag and passed through a 16 mesh screen. The sieved powder was mixed with spray-dried mannitol (497.2 g), polyethylene oxide (PEO-20NF, 121 g) and magnesium stearate (7.15). g) A core tablet (130 mg per spindle) was obtained by blending in a bag using a rotary press machine (Kikusui Seisakusho) with a 6.5 mm Φ punch.

Compound X hydrochloride (13.96 g) and mannitol (13.96 g) were blended in a bag and passed through a 16 mesh screen. The blended and sieved powder was blended with spray-dried mannitol (161.28 g), polyethylene oxide (PEO-20NF, 880 g) and magnesium stearate (10.8 g) in a bag to obtain an outer shell blend powder. A core tablet and a 270 mg shell were blended into a powder tablet using a rotary press (Kikusui Seisakusho) to produce a dry coated tablet (400 mg per tablet) containing Compound X hydrochloride (10 mg of Compound X). The dry coated tablet was loaded into a coating machine (HICOATER LABO, Freund Corp.), and hydroxypropylmethylcellulose (TC-5E) was dissolved by spraying to purify water and disperse talc and yellow iron oxide therein. The coating was coated with a suspension and dried to produce a coating dry-coated tablet as shown in Table 32.

Example 33

Compound X hydrochloride (34.92 g) and mannitol (34.92 g) were blended in a bag and passed through a 16 mesh screen. The blended sieved powder and spray dried mannitol (319.26 g), polyethylene oxide (PEO-20NF, 472.20 g) and magnesium stearate (8.7 g) was mixed in a bag and pressed with a 9 mm Φ punch using a rotary press (Kikusui Seisakusho) to obtain an uncoated tablet (290 mg per tablet) containing the compound X hydrochloride (10 mg of the compound X). The uncoated tablet was loaded into a coating machine (HICOATER LABO, Freund Corp.), and hydroxypropylmethylcellulose (TC-5E) was dissolved by spraying to purify water and disperse talc and yellow iron oxide therein. The suspension was coated, coated, and dried to produce a coated single-layer tablet as shown in Table 33.

Example 34

Compound X hydrochloride (3422 g), mannitol (11520 g) and polyethylene oxide (PEO-20NF, 1540 g) were charged into a fluidized bed granulator (FD-WSG-30, Powrex Corp.) was simultaneously granulated by spraying purified water, and dried to obtain a granulated powder. The double-grain operation was carried out twice and the obtained granulated powder (32960 g) was blended with polyethylene oxide (PEO-20NF, 3080 g) and magnesium stearate (364 g) and pressed with a 6.5 mm Φ punch using a rotary press (Kikusui Seisakusho). A core tablet (130 mg per spindle) was obtained.

Compound X hydrochloride (1153 g), mannitol (4050 g) and polyethylene oxide (PEO-20NF, 12100 g) were charged into a fluidized bed granulator (FD-WSG-30, Powrex Corp.) while being sprayed The water was purified, granulated, and dried to obtain a granulated powder. The re-replicated granules were operated twice and the resulting granulated powder (34,600 g) was blended with polyethylene oxide (PEO-20NF, 24,200 g) and magnesium stearate (594 g) to produce an outer shell blend powder. A core tablet and a 270 mg outer shell were blended into a powder tablet using a rotary press (HATA TEKKOSHO CO., LTD.) to produce a dry coated tablet (400 mg per tablet) containing Compound X (30 mg). The dry coated tablet was loaded into a coating machine (DRC-900DS, Powrex Corp.), and hydroxypropylmethylcellulose (TC-5E) was dissolved by spraying to purify the water and disperse the sterile talc and yellow iron oxide. The coating suspension was applied thereto, and dried to produce a coating dry-coated tablet as shown in Table 34.

Example 35

Compound X hydrochloride (3754 g), mannitol (12630 g) and polyethylene oxide (PEO-20NF, 1689 g) were charged into a fluidized bed granulator (FD-WSG-30, Powrex Corp.) while being sprayed The water was purified, granulated, and dried to obtain a granulated powder. Blending the obtained granulated powder (18070 g) with polyethylene oxide (PEO-20NF, 1689 g) and magnesium stearate (200 g) and using a rotary press machine (Kikusui Seisakusho) A core tablet (92.86 mg per ingot) was obtained by pressing a 5.5 mm Φ punch.

Compound X hydrochloride (2270 g), mannitol (6202 g) and polyethylene oxide (PEO-20NF, 8450 g) were charged into a fluidized bed granulator (FD-WSG-30, Powrex Corp.) while being sprayed The water was purified, granulated, and dried to obtain a granulated powder. The re-replicated granules were operated twice and the resulting granulated powder (33840 g) was blended with polyethylene oxide (PEO-20NF, 16900 g) and magnesium stearate (512.2 g) to produce an outer shell blend powder. A core tablet and a 197.14 mg outer shell were blended into a powder compact using a 9 mm Φ punch using a rotary press (HATA TEKKOSHO CO., LTD.) to produce a dry coated tablet containing Compound X (30 mg) (290 mg per tablet). The dry coated tablet was loaded into a coating machine (DRC-900DS, Powrex Corp.), and hydroxypropylmethylcellulose (TC-5E) was dissolved by spraying to purify the water and disperse the sterile talc and yellow iron oxide. The coating suspension was applied thereto, and dried to produce a coating dry-coated tablet as shown in Table 35.

Example 36

Compound X hydrochloride (3492 g), mannitol (9478 g) and polyethylene oxide (PEO-20NF, 7870 g) were charged into a fluidized bed granulator (FD-WSG-30, Powrex Corp.) while being sprayed The water was purified, granulated, and dried to obtain a granulated powder. The heavy replicating operation was carried out twice and the obtained granulated powder (41680 g) was blended with polyethylene oxide (PEO-20NF, 15740 g) and magnesium stearate (580 g) and An uncoated tablet containing Compound X (30 mg) (290 mg per tablet) was produced by a rotary press (Kikusui Seisakusho) using a 9 mm Φ punch. The uncoated tablet was loaded into a coating machine (DRC-900DS, Powrex Corp.), and hydroxypropylmethylcellulose (TC-5E) was dissolved by spraying to purify the water and disperse the sterile talc and yellow iron oxide. The coating suspension was applied thereto, and dried to produce a coated single-layer tablet as shown in Table 36.

Example 37

Compound X hydrochloride (11410 g), mannitol (564.5 g) and polyethylene oxide (PEO-20NF, 5132 g) were charged into a fluidized bed granulator (FD-WSG-30, Powrex Corp.) while spraying The purified water was granulated and dried to obtain a granulated powder. Blending the obtained granulated powder (17110g) with nectar An alcohol (723.5 g), polyethylene oxide (PEO-20NF, 188 g) and magnesium stearate (182 g) were compressed with a 6.5 mm Φ punch using a rotary press (Kikusui Seisakusho) to obtain a core tablet (130 mg per spindle).

Compound X hydrochloride (10820 g), mannitol (535.4 g) and polyethylene oxide (PEO-20NF, 4866 g) were charged into a fluidized bed granulator (FD-WSG-30, Powrex Corp.) while spraying The purified water was granulated and dried to obtain a granulated powder. The obtained granulated powder (7849 g) was blended with mannitol (1601 g), polyethylene oxide (PEO-20NF, 30650 g) and magnesium stearate (405 g) to produce an outer shell blend powder. A core tablet and a 270 mg outer shell were blended into a powder compact using a rotary press (HATA TEKKOSHO CO., LTD.) to produce a dry coated tablet (400 mg per tablet) containing Compound X (100 mg). The dry coated tablet was loaded into a coating machine (DRC-900DS, Powrex Corp.), and hydroxypropylmethylcellulose (TC-5E) was dissolved by spraying to purify the water and disperse the sterile talc and yellow iron oxide. The coating suspension was applied thereto, and dried to produce a coating dry-coated tablet as shown in Table 37.

Example 38

Compound X hydrochloride (11060 g), mannitol (547 g) and polyethylene oxide (PEO-20NF, 4974 g) were charged into a fluidized bed granulator (FD-WSG-30, Powrex Corp.) while being sprayed The water was purified, granulated, and dried to obtain a granulated powder. Blending the obtained granulated powder (16580 g) with mannitol (682.3 g), polyethylene oxide (PEO-20NF, 232.4 g) and magnesium stearate (176.7 g) and using A rotary tablet press (Kikusui Seisakusho) was pressed with a 6 mm Φ punch to obtain a core tablet (93 mg per spindle).

Compound X hydrochloride (11060 g), mannitol (547 g) and polyethylene oxide (PEO-20NF, 4974 g) were charged into a fluidized bed granulator (FD-WSG-30, Powrex Corp.) while being sprayed The water was purified, granulated, and dried to obtain a granulated powder. The obtained granulated powder (16580 g) was blended with mannitol (750.7 g), polyethylene oxide (PEO-20NF, 19730 g), and magnesium stearate (374.3 g) to produce an outer shell blend powder. A core tablet and a 197 mg outer shell were blended into a powder compact using a 9 mm Φ punch using a rotary press (HATA TEKKOSHO CO., LTD.) to produce a dry coated tablet containing Compound X (100 mg) (290 mg per tablet). The dry coated tablet was loaded into a coating machine (DRC-900DS, Powrex Corp.), and hydroxypropylmethylcellulose (TC-5E) was dissolved by spraying to purify the water and disperse the sterile talc and yellow iron oxide. The coating suspension was applied thereto, and dried to produce a coating dry-coated tablet as shown in Table 38.

Example 39

Compound X hydrochloride (13970 g), mannitol (691.1 g) and polyethylene oxide (PEO-20NF, 6262 g) were charged into a fluidized bed granulator (FD-WSG-30, Powrex Corp.) while spraying The purified water was granulated and dried to obtain a granulated powder. Blending the obtained granulated powder (20940g) with mannitol (904.9g), polyethylene oxide (PEO-20NF, 12610g) and magnesium stearate (348 g) An uncoated tablet containing Compound X (100 mg) (290 mg per spindle) was produced by a rotary press (Kikusui Seisakusho) using a 9 mm Φ punch. The uncoated tablet was loaded into a coating machine (DRC-900DS, Powrex Corp.), and hydroxypropylmethylcellulose (TC-5E) was dissolved by spraying to purify the water and disperse the sterile talc and yellow iron oxide. The coating suspension was applied thereto, and dried to produce a coated single-layer tablet as shown in Table 39.

Experimental example 1

The dissolution properties of the preparations obtained in Examples 1, 2, 4 and 5 were evaluated by a paddle method (Japanese Pharmacopoeia dissolution test, second fluid, 50 rpm, 900 mL). The results are shown in Figure 1.

Experimental example 2

The dissolution properties of the preparations obtained in Examples 2, 3, 6, 9, 10 and 11 were evaluated by the paddle method (Japanese Pharmacopoeia dissolution test, second fluid, 50 rpm, 900 mL). The results are shown in Figure 2.

Experimental example 3

The dissolution properties of the preparations obtained in Examples 7, 8, and 9 were evaluated by a paddle method (Japanese Pharmacopoeia dissolution test, second fluid, 50 rpm, 900 mL). The results are shown in Figure 3.

Experimental example 4

The dissolution properties of the preparations obtained in Examples 9 and 12 were evaluated by a paddle method (Japanese Pharmacopoeia dissolution test, second fluid, 50 rpm, 900 mL). The results are shown in Figure 4.

Experimental example 5

The dissolution properties of the preparation obtained in Example 13 were evaluated by a paddle method (Japanese Pharmacopoeia dissolution test, second fluid, 50 rpm, 900 mL). The results are shown in Figure 5.

Experimental example 6

The dissolution properties of the preparations obtained in Examples 14, 15, 16, 17, 18 and 19 were evaluated by the paddle method (Japanese Pharmacopoeia dissolution test, second fluid, 50 rpm, 900 mL). The results are shown in Figure 6.

Experimental example 7

The dissolution properties of the preparation obtained in Example 20 were evaluated by a paddle method (Japanese Pharmacopoeia dissolution test, second fluid, 50 rpm, 900 mL). The results are shown in Figure 7.

Experimental Example 8

The dissolution properties of the preparation obtained in Example 21 were evaluated by a paddle method (Japanese Pharmacopoeia dissolution test, second fluid, 50 rpm, 900 mL). The results are shown in Fig. 8.

Experimental Example 9

The dissolution properties of the preparations obtained in Examples 22, 23 and 24 were evaluated by the paddle method (Japanese Pharmacopoeia dissolution test, second fluid, 50 rpm, 900 mL). The results are shown in Figure 9.

Experimental Example 10

The dissolution properties of the preparations obtained in Examples 25, 26, and 27 were evaluated by the paddle method (Japanese Pharmacopoeia dissolution test, second fluid, 50 rpm, 900 mL). The results are shown in Figure 10.

Experimental Example 11

The dissolution properties of the preparations obtained in Examples 34, 35 and 36 were evaluated by the paddle method (Japanese Pharmacopoeia dissolution test, second fluid, 100 rpm, 900 mL). The results are shown in Figure 11.

Experimental Example 12

The dissolution properties of the preparations obtained in Examples 37, 38 and 39 were evaluated by the paddle method (Japanese Pharmacopoeia dissolution test, second fluid, 100 rpm, 900 mL). The results are shown in Fig. 12.

The present application is based on Japanese Patent Application No. 2015-252657, the entire contents of which is incorporated herein.

Since the figure in this case is the embodiment data, it is not a representative figure of this case.

Therefore, there is no designated representative map in this case.

Claims (4)

A solid preparation comprising N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxygen Azazepine-3-amine or a salt thereof, and a polymer forming a hydrophilic gel. The solid preparation according to claim 1, wherein the solid preparation comprises: (1) a core comprising N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydrogen Pyrazino[2,3-f][1,4]oxazepine-3-amine or a salt thereof, and a first polymer forming a hydrophilic gel; and (2) an outer shell, including N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine- A 3-amine or a salt thereof, and a second polymer forming a hydrophilic gel. The solid preparation according to claim 2, wherein the first hydrophilic gel-forming polymer and the second hydrophilic gel-forming polymer are the same or different, and each is selected from the group consisting of polyethylene oxide A group of hydroxypropylmethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carboxyvinyl polymer, methylcellulose, and sodium carboxymethylcellulose. The solid preparation of claim 2, wherein in the preparation, N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazine in the core And the content of [2,3-f][1,4]oxazepine-3-amine or its salt is the same as or higher than N-methyl-N-(1-A in the outer shell The content of the ethylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine-3-amine or a salt thereof.