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WO2017111178A1 - Solid preparation - Google Patents

Solid preparation Download PDF

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Publication number
WO2017111178A1
WO2017111178A1 PCT/JP2016/089222 JP2016089222W WO2017111178A1 WO 2017111178 A1 WO2017111178 A1 WO 2017111178A1 JP 2016089222 W JP2016089222 W JP 2016089222W WO 2017111178 A1 WO2017111178 A1 WO 2017111178A1
Authority
WO
WIPO (PCT)
Prior art keywords
tablet
blended
compound
hydrochloride
outer shell
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2016/089222
Other languages
French (fr)
Inventor
Shiro Ishii
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda Pharmaceutical Co Ltd
Original Assignee
Takeda Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Takeda Pharmaceutical Co Ltd filed Critical Takeda Pharmaceutical Co Ltd
Publication of WO2017111178A1 publication Critical patent/WO2017111178A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to a solid preparation containing N-methyl-N- (1-methylethyl) -6, 7,8,9- tetrahydropyrazino [2, 3-f] [1, ] oxazepin-3-amine or a salt thereof, which may release the compound in a sustained manner.
  • N-methyl-N- (1-methylethyl) -6, 7, 8, 9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine and salts thereof exhibit serotonin 5-HT 2c receptor-activating action, and are known to be useful as prophylactic or therapeutic agents for lower urinary tract symptoms, obesity, and/or organ prolapse (patent document 1) .
  • Patent document 2 discloses a nifedipine-containing dry coated tablet comprising a core containing nifedipine and a hydrophilic gel-forming polymer substance and exhibiting delayed release of nifedipine, and an outer shell formed by compression coating the core, which contains nifedipine, a hydrophilic gel-forming polymer substance, and a
  • disintegration-suppressive substance composed of a water- insoluble polymer that forms a pH-independent matrix with nifedipine and the hydrophilic gel-forming polymer substance.
  • Patent document 3 discloses a dry coated tablet
  • Patent document 4 discloses a dry coated tablet
  • a core containing nifedipine and a hydrophilic gel- forming polymer substance comprising a core containing nifedipine and a hydrophilic gel- forming polymer substance, and an outer shell containing nifedipine, a hydrophilic gel-forming polymer substance, and a disintegration-suppressive substance composed of a water- insoluble polymer.
  • N-methyl-N- ( 1-methylethyl) -6, 7, 8, 9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine and salts thereof have high solubility and a short half-life, three doses per day are anticipated to avoid an adverse event in a typical rapid release tablet.
  • an object of the present invention is to provide a preparation which may release N-methyl-N- ( 1-methylethyl) - 6, 7, 8, 9-tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof in a sustained manner, which may permit
  • Another object of the present invention is to provide a preparation that may reduce the amount of additive to be used, which in turn may suppress a decrease in the stability of N-methyl-N- (1-methylethyl) -6, 7,8, 9-tetrahydropyrazino [2, 3- f] [1, 4 ] oxazepin-3-amine or a salt thereof.
  • the present inventor has conducted intensive studies in an attempt to solve the aforementioned problems and found that N-methyl-N- (1-methylethyl) -6, 7,8, 9-tetrahydropyrazino [2, 3- f] [ 1 , 4 ] oxazepin-3-amine and a salt thereof may be released in a sustained manner by using a hydrophilic gel-forming polymer.
  • the present inventor has also found that, in a solid preparation (such as a tablet) comprising a core, an outer shell, a hydrophilic gel-forming polymer in the core and the outer shell, and N-methyl-N- (1-methylethyl) -6, 7, 8, 9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof in the core and/or the outer shell, the release of a solid preparation (such as a tablet) comprising a core, an outer shell, a hydrophilic gel-forming polymer in the core and the outer shell, and N-methyl-N- (1-methylethyl) -6, 7, 8, 9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof in the core and/or the outer shell, the release
  • N-methyl-N- (1-methylethyl) -6, 7, 8, 9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof may be controlled by adjusting the content thereof in the core and/or the outer shell, whereby the compound may be released in a sustained manner.
  • the present inventor has further found that use of a hydrophilic gel-forming polymer may enable maintenance of moldability even when the amount of additives other than the hydrophilic gel-forming polymer is reduced. It has been found that the chemical stability of N-methyl-N- (1-methylethyl) - 6, 7, 8, 9-tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine and salts thereof is affected when the amount of additive is increased. Therefore, the reduction of stability of the compound may be expected to be suppressed by decreasing the additives .
  • the present invention provides the following.
  • a solid preparation comprising N-methyl-N- (1-methylethyl) - 6, 7, 8, 9-tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof, and a hydrophilic gel-forming polymer.
  • a core comprising N-methyl-N- ( 1-methylethyl) - 6, 7, 8, 9-tetrahydropyrazino [2, 3-f] [1, ] oxazepin-3-amine or a salt thereof, and a first hydrophilic gel-forming polymer; and (2) an outer shell comprising N-methyl-N- (1-methylethyl) - 6, 7, 8, 9-tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof, and a second hydrophilic gel-forming polymer.
  • a core comprising N-methyl-N- (1-methylethyl) - 6, 7, 8, 9-tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof, and a first hydrophilic gel-forming polymer; and (2) an outer shell comprising a second hydrophilic gel-forming polymer and not comprising N-methyl-N- ( 1-methylethyl ) -6, 7 , 8 , 9- tetrahydropyrazino [2 , 3-f] [ 1 , 4 ] oxazepin-3-amine or a salt thereof.
  • each is selected from the group consisting of polyethylene oxide, hydroxypropyl methyl cellulose,
  • carboxymethyl cellulose hydroxypropyl cellulose, hydroxyethyl cellulose, carboxyvinyl polymer, methyl cellulose, and sodium carboxymethyl cellulose.
  • the present invention can provide a preparation
  • a solid preparation (such as a tablet) comprising a core, an outer shell, a hydrophilic gel-forming polymer in the core and the outer shell, and N-methyl-N- ( 1-methylethyl ) -6, 7 , 8 , 9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof in the core and/or the outer shell, which may release the compound in a sustained manner,
  • the present invention can provide a
  • the present invention can provide a
  • the present invention can provide a preparation that may suppress lowering of the stability of N-methyl-N- (1- methylethyl) -6, 7,8, 9-tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3- amine and a salt thereof.
  • 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 solid preparation of the present invention contains N-methyl-N- ( 1-methylethyl ) -6, 7,8, 9-tetrahydropyrazino [2, 3- f] [1, 4] oxazepin-3-amine or a salt thereof as an active
  • Examples of the salt of N-methyl-N- ( 1-methylethyl) - 6, 7, 8, 9-tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine include inorganic acid salts, organic acid salts, and basic or acidic amino acid salts.
  • Examples of the inorganic acid salt include
  • hydrochloride hydrobromate, nitrate, sulfate, and phosphate.
  • organic acid salt examples include formate, acetate, trifluoroacetate, fumarate, oxalate, tartrate, maleate, citrate, succinate, malate, methanesulfonate, benzenesulfonate, and p-toluenesulfonate .
  • Examples of the basic amino acid salt include salts with arginine, lysine, and ornithine.
  • Examples of the acidic amino acid salt include aspartate and glutamate.
  • N-methyl-N- (1-methylethyl) -6, 7, 8, 9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine N-methyl-N- (1- methylethyl) -6, 7,8, 9-tetrahydropyrazino [2, 3-f] [1,4] oxazepin-3- amine hydrochloride is especially preferable.
  • invention is generally 1-1000 mg, preferably 5-800 mg, more preferably 10-500 mg.
  • invention is generally 0.5-85% by weight, preferably 1-75% by weight, more preferably 1-65% by weight, relative to the weight of the bare preparation (uncoated tablet) .
  • the viscosity (25°C, 1% aqueous solution) of the hydrophilic gel-forming polymer is generally not less than 100 cP, preferably not less than 5500 cP, more preferably not less than 7500 cP. In the present invention, the viscosity (25°C, 1% aqueous solution) of the hydrophilic gel-forming polymer is generally not more than 500,000 cP.
  • the hydrophilic gel-forming polymer is not particular limited as long as it has the above- mentioned viscosity.
  • examples include polyethylene oxide (for example, PolyoxTM WSR 303 produced by The Dow Chemical Company, or PEO-20NF produced by Sumitomo Seika Chemicals Co., Ltd.), hydroxypropyl methyl cellulose (for example, METOLOSE 90SH- 100000SR produced by Shin-etsu Chemical Co., Ltd.),
  • carboxymethyl cellulose hydroxypropyl cellulose, hydroxyethyl cellulose, carboxyvinyl polymer (for example, Carbopol 971PNF produced by the Lubrizol Corporation) , methyl cellulose, and sodium carboxymethyl cellulose.
  • carboxyvinyl polymer for example, Carbopol 971PNF produced by the Lubrizol Corporation
  • hydroxypropyl methyl cellulose, and carboxyvinyl polymer are preferable, and polyethylene oxide is especially preferable.
  • a highly viscous hydrophilic gel-forming polymer such as polyethylene oxide
  • the hydrophilic gel- forming polymer may control dissolution of N- methyl-N- (1-methylethyl) -6, 7,8, 9-tetrahydropyrazino [2, 3- f] [1, 4 ] oxazepin-3-amine or salt thereof.
  • the content of the hydrophilic gel-forming polymer is generally 15- 95% by weight, preferably 25-85% by weight, more preferably 35- 75% by weight, relative to the weight of the bare preparation (uncoated tablet) .
  • uncoated tablet refers to a preparation (tablet) prior to coating when the solid preparation is to be coated as described below, or a solid preparation (tablet) itself when the solid preparation is not coated.
  • invention is a tablet.
  • solid preparation of the present invention include the following embodiments (A) , (B) and (C) .
  • a single-layered solid preparation e.g., tablet
  • a solid preparation (e.g., tablet) comprising:
  • a solid preparation (e.g., tablet) comprising:
  • the contents of N-methyl-N- (1-methylethyl) -6, 7, 8, 9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof and the hydrophilic gel-forming polymer are as
  • the single-layered tablet of the present invention may be film-coated, as described below.
  • the content of the hydrophilic gel-forming polymer is the content thereof in the uncoated tablet before film coating.
  • a shell of a hydrophilic gel- forming polymer and free of N-methyl-N- (1-methylethyl) -6, 7, 8, 9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine and a salt thereof may be formed on the outside of the single-layered tablet.
  • This embodiment is to be described later as a dry coated tablet with a shell not containing N-methyl-N- (1- methylethyl) -6, 7,8, 9-tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3- amine or a salt thereof.
  • the core may be a tablet (in the DESCRIPTION, a tablet as a core is referred to as a core tablet) .
  • the content of N-methyl-N- (1-methylethyl) -6, 7, 8, 9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or salt thereof in a free form in the core is generally 0.5-1000 mg, preferably 2.5-800 mg, more preferably 5—500 mg.
  • the content of N-methyl-N- (1-methylethyl) -6, 7, 8, 9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or salt thereof in a free form in the outer shell is generally 0-500 mg, preferably 0-400 mg, more preferably 0-250 mg.
  • the dry coated tablet of the present invention may contain N-methyl-N- (1-methylethyl) -6, 7,8,9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof in both the core and the outer shell, or only in the core .
  • the content (by weight) of N-methyl-N- (1-methylethyl) -6, 7, 8, 9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof in the core is preferably equal to or higher than the content (by weight) of N-methyl-N- (1-methylethyl) -6, 7, 8, 9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof in the outer shell, since further delayed and sustained release of the active ingredient can be expected. [0024]
  • the dry coated tablet of the present invention is a solid preparation (such as a tablet) comprising a core, an outer shell, a hydrophilic gel-forming polymer in the core and the outer shell, and the active ingredient in the core and/or the outer shell, which may control the release behavior of the active ingredient by adjusting the content of the active ingredient in the core and/or the outer shell, thereby
  • the dissolution ratio of the active ingredient is generally 0- 30% after 2 hr; 15-55% after 6 hr; 35-80% after 9 hr,
  • it is generally 10-45% after 2 hr; 40-80% after 6 hr; 60-100% after 9 hr, preferably 15-40% after 2 hr; 45-75% after 6 hr; 65-95% after 9 hr, more preferably 20- 35% after 2 hr; 50-70% after 6 hr; 70-95% after 9 hr.
  • first and second hydrophilic gel-forming polymers in the dry coated tablet of the present invention include those recited above as the hydrophilic gel-forming polymer in the solid preparation of the present invention.
  • the first hydrophilic gel-forming polymer and the second hydrophilic gel-forming polymer may be identical or different.
  • each of the first and second hydrophilic gel-forming polymers is preferably polyethylene oxide.
  • the content of the first hydrophilic gel-forming polymer in the core is generally 0.01-90% by weight, preferably 5-70% by weight, more preferably 10-50% by weight, relative to the weight of the core.
  • the content of the second hydrophilic gel-forming polymer in the outer shell is generally 20-100% by weight, preferably 30-95% by weight, more preferably 40-90% by weight, relative to the weight of the outer shell.
  • the dry coated tablet of the present invention may be film-coated as described below.
  • the content of the hydrophilic gel-forming polymer is the content of the preparation (uncoated tablet) prior to film coating.
  • the weight ratio of the core and the outer shell is generally 1:1.5-3.5, preferably 1:1.5-3.0, more preferably 1:2-2.5, still more preferably about 1:2.
  • the solid preparation (single-layered tablet, dry coated tablet) of the present invention may further contain an
  • additives examples include excipients (e.g., mannitol, spray-dried mannitol, starch, lactose, sucrose, calcium carbonate, calcium phosphate, and crystalline materials.
  • excipients e.g., mannitol, spray-dried mannitol, starch, lactose, sucrose, calcium carbonate, calcium phosphate, and crystalline materials.
  • cellulose e.g., cellulose
  • binders e.g., starch, gum arabic, alginic acid, gelatin, polyvinyl pyrrolidone, and hydroxypropyl cellulose (having low viscosity preventing function as a hydrophilic gel- forming polymer, e.g., HPC-SL and HPC-L, produced by Nippon Soda Co., Ltd.
  • lubricants e.g., stearic acid, magnesium stearate, calcium stearate, and talc
  • hydrophilic gel-forming polymer in the present invention may reduce the amount of additives other than the hydrophilic gel-forming polymer.
  • the content of the total amount of the additive other than the hydrophilic gel-forming polymer is generally 5-95% by weight, preferably 15-75% by weight, more preferably 25-65% by weight, relative to the weight of the uncoated tablet.
  • the solid preparation (single-layered tablet, dry coated tablet) of the present invention can be produced using the above-mentioned various components and according to a
  • the single-layered tablet of the present invention can be produced, for example, by blending N-methyl-N- ( 1-methylethyl ) - 6, 7, 8, 9-tetrahydropyrazino [2, 3-f] [1, ] oxazepin-3-amine or a salt thereof, a hydrophilic gel-forming polymer (e.g.,
  • carboxyvinyl polymer etc.
  • additive to be optionally added for example, excipient (e.g., mannitol) , lubricant (e.g., magnesium stearate) , binder) , and compression-molding
  • the dry coated tablet of the present invention can be produced, for example, according to the following method.
  • hydrophilic gel-forming polymer e.g., polyethylene oxide, hydroxypropyl methyl cellulose, carboxyvinyl polymer, etc.
  • additive to be optionally added for example,
  • excipient e.g., mannitol
  • lubricant e.g., magnesium
  • hydrophilic gel-forming polymer e.g., polyethylene oxide, hydroxypropyl methyl cellulose, carboxyvinyl polymer, etc.
  • additive to be optionally added for example, excipient (e.g., mannitol) , lubricant (e.g., magnesium
  • an outer shell blended powder i.e., a powder mixture of components forming the outer shell
  • the core tablet and the outer shell blended powder are compression-molded to give a dry coated tablet.
  • a dry coated tablet not contain N-methyl-N- ( 1- methylethyl) -6, 7,8, 9-tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3- amine or a salt thereof in the outer shell can be produced by not adding N-methyl-N- (1-methylethyl) -6, 7, 8, 9- tetrahydropyrazino [2, 3-f] [1, 4 ] oxazepin-3-amine or salt thereof during the process of producing the outer shell blended powder in the above-mentioned production method.
  • Blending can be performed using a mixer such as V-mixer or tumbler mixer.
  • Compression molding can be performed by tableting using, for example, a single-punch tablet press, rotary tablet press, or the like.
  • the solid preparation (single-layered tablet, dry coated tablet) of the present invention may be coated as necessary by a conventional method in the technical field of preparations.
  • film coating bases and coating additives can be used.
  • Examples of the film coating base include hydroxypropyl methyl cellulose (TC-5E, TC-5R; produced by Shin-etsu Chemical Co., Ltd.), hydroxypropyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, methyl cellulose, and hydroxyethyl methyl cellulose .
  • the coating additive examples include light-blocking agents such as titanium oxide; fluidizing agents such as talc, sterile talc; colorants such as ferric oxide and yellow ferric oxide; plasticizers such as polyethylene glycol (e.g., Macrogol 6000) , triethyl citrate, castor oil, and polysorbates; and organic acids such as citric acid, tartaric acid, malic acid, and ascorbic acid.
  • light-blocking agents such as titanium oxide
  • fluidizing agents such as talc, sterile talc
  • colorants such as ferric oxide and yellow ferric oxide
  • plasticizers such as polyethylene glycol (e.g., Macrogol 6000) , triethyl citrate, castor oil, and polysorbates
  • organic acids such as citric acid, tartaric acid, malic acid, and ascorbic acid.
  • the amount of the film coating is generally l%-8%, preferably 2%-6%, relative to the weight of the bare
  • the weight of the solid preparation of the present invention is generally 100 mg - 1,500 mg, preferably 200 mg - 1,000 mg.
  • the size of the single-layered tablet of the present invention is generally 6 mm - 20 mm, preferably 8 mm - 15 mm.
  • the size of the core (core tablet) of the dry coated tablet is generally 7.5 mm - 20 mm, preferably 8 mm - 15 mm.
  • invention is not particularly limited, and it may be any shape such as round, caplet-shaped, donut-shaped, oblong-shaped and the like.
  • the solid preparation of the present invention may be useful as an agent for ameliorating, preventing, or treating all serotonin 5-HT 2 c related diseases such as lower urinary tract symptoms (e.g., stress incontinence) in mammalian animals (such as human, monkey, cattle, horse, pig, mouse, rat, hamster, rabbit, cat, dog, sheep, and goat) .
  • the solid preparation of the present invention can be orally administered safely.
  • While the dose of N-methyl-N- (1-methylethyl) -6, 7, 8, 9- tetrahydropyrazi.no [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof in the solid preparation of the present invention varies depending on the administration subject, symptom, and the like, for oral administration to a patient with lower urinary tract symptom (adult; body weight about 60 kg) , it is generally an amount of about 0.01667 - about 16.67 mg/kg body weight, preferably about 0.08333 - about 13.33 mg/kg body weight, more preferably about 0.1667 - about 8.333 mg/kg body weight, which can be administered one to several times per day according to the symptoms.
  • the solid preparation of the present invention may release the active ingredient in a sustained manner, which may reduce the number of doses per day (one or two doses/day) . As a result, increased convenience for patients and improved medication compliance are expected.
  • the solid preparation of the present invention can be used in combination with an active ingredient other than N- methyl-N- ( 1-methylethyl ) -6, 7,8, 9-tetrahydropyrazino [2, 3- f] [1, 4] oxazepin-3-amine or a salt thereof (hereinafter
  • the time of administration of N-methyl-N- ( 1-methylethyl ) -6, 7 , 8 , 9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or salt thereof and that of the concomitant drug are not limited, and they may be administered simultaneously or in a staggered manner to the administration subject.
  • the solid preparation of the present invention and a concomitant drug may be
  • the dose of the concomitant drug can be appropriately determined based on the dose employed in clinical situations.
  • preparation additives e.g., polyethylene oxide, mannitol, magnesium stearate, hydroxypropyl cellulose,
  • dissolution tests were performed according to the Paddle Method described in the Japanese Pharmacopoeia 16th Edition.
  • the dissolution test, 2nd fluid used as the test liquid can be prepared according to a known method.
  • the amount of the dissolution test, 2nd fluid used as the test liquid is generally 900 mL.
  • Compound X used in the following Formulation Examples is N-methyl-N- ( 1-methylethyl) -6,7,8, 9-tetrahydropyrazino [2,3- f] [1, 4] oxazepin-3-amine.
  • the dissolution property of the preparations obtained in Examples 1-27 was evaluated by the Paddle Method (the Japanese Pharmacopoeia dissolution test, 2nd fluid, 50 rpm, 900 mL) by using a Varian dissolution tester.
  • Polyethylene oxide (PolyoxTM WSR 303, 15 g) , mannitol (1.83 g), and magnesium stearate (0.17 g) were blended to produce an outer shell blended powder.
  • the core tablet and 340 mg of the outer shell blended powder were tableted with a 11 mm ⁇ j) punch by using an autograph tablet press (AG-IS, Shimadzu) to produce dry coated tablets (510 mg per tablet) containing compound X hydrochloride (100 mg as compound X) shown in Table 1.
  • Polyethylene oxide (PolyoxTM WSR 303, 12.5 g) , mannitol (4.33 g) , and magnesium stearate (0.17 g) were blended to produce an outer shell blended powder.
  • the core tablet and 340 mg of the outer shell blended powder were tableted with a 11 mm(j> punch by using an autograph tablet press (AG-IS, Shimadzu) to produce dry coated tablets (510 mg per tablet) containing compound X hydrochloride (100 mg as compound X) shown in Table 2.
  • Polyethylene oxide (PolyoxTM WSR 303, 10 g) , mannitol (6.83 g) , and magnesium stearate (0.17 g) were blended to produce an outer shell blended powder.
  • the core tablet and 340 mg of the outer shell blended powder were tableted with a 11 mm ⁇ t) punch by using an autograph tablet press (AG-IS, Shimadzu) to produce dry coated tablets (510 mg per tablet) containing compound X hydrochloride (100 mg as compound X) shown in Table 4.
  • Compound X hydrochloride (4.074 g) , polyethylene oxide (PolyoxTM WSR 303, 2.5 g) , mannitol (0.356 g) , and magnesium stearate (0.07 g) were blended and tableted with a 6.5 ⁇ punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki) to produce core tablets (140 mg per tablet) .
  • HANDTAB manufactured by Ichihashi Seiki
  • Compound X hydrochloride (4.074 g) , polyethylene oxide (PolyoxTM WSR 303, 1.75 g) , mannitol (0.116 g) , and magnesium stearate (0.06 g) were blended and tableted with a 6.5 ⁇ punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki) to produce core tablets (120 mg per tablet) .
  • HANDTAB manufactured by Ichihashi Seiki
  • Compound X hydrochloride (2.91 g) , polyethylene oxide (PolyoxTM WSR 303, 1.25 g) , mannitol (0.0475 g) , and magnesium stearate (0.0425 g) were blended and tableted with a 5.5 mm ⁇
  • HANDTAB manufactured by Ichihashi Seiki
  • the granulated powder (362.8 g) was blended with polyethylene oxide (PolyoxTM WSR 303, 152 g) and magnesium stearate (5.2 g) and tableted with a 7 mm ⁇
  • Compound X hydrochloride (1.746 g) , polyethylene oxide (PolyoxTM WSR 303, 2.74 g) , mannitol (4.724 g ) , and magnesium stearate (0.09 g) were blended and tableted with a 6 mm ⁇ t> punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki) to produce core tablets (93 mg per tablet) .
  • HANDTAB manufactured by Ichihashi Seiki
  • Compound X hydrochloride (1.746 g) , polyethylene oxide (PolyoxTM WSR 303, 13 g) , mannitol (4.754 g) , and magnesium stearate (0.2 g) were blended to produce an outer shell blended powder.
  • the core tablet and 197 mg of the outer shell blended powder were tableted with a 9 ⁇ punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki) to produce dry coated tablets (290 mg per tablet) containing compound X hydrochloride (30 mg as compound X) shown in Table 14.
  • Compound X hydrochloride (1.398 g) , polyethylene oxide (PolyoxTM WSR 303, 17.55 g) , mannitol (4.622 g) , and magnesium stearate (0.23 g) were blended to produce an outer shell blended powder.
  • the core tablet and 238 mg of the outer shell blended powder were tableted with a 9 ⁇ punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki) to produce dry coated tablets (350 mg per tablet) containing compound X hydrochloride (30 mg as compound X) shown in Table 15.
  • Compound X hydrochloride (2.445 g) , polyethylene oxide (PolyoxTM WSR 303, 3.8 g) , mannitol (5.705 g) , hydroxypropyl cellulose (HPC-L, 0.42 g) , crystalline cellulose (0.5 g) , and magnesium stearate (0.13 g) were blended and tableted with a 7 ⁇ punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki) to produce core tablets (130 mg per tablet) .
  • HANDTAB manual tablet press manufactured by Ichihashi Seiki
  • Compound X hydrochloride (1.047 g) , polyethylene oxide (PolyoxTM WSR 303, 22 g) , mannitol (3.203 g) , hydroxypropyl cellulose (HPC-L, 0.22 g) , crystalline cellulose (0.26 g) , and magnesium stearate (0.27 g) were blended to produce an outer shell blended powder.
  • the core tablet and 270 mg of the outer shell blended powder were tableted with a 10 ⁇ punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi
  • Compound X hydrochloride (2.793 g) , polyethylene oxide (PolyoxTM WSR 303, 4.4 g) , mannitol (6.607 g) , hydroxypropyl cellulose (HPC-L, 0.45 g) , crystalline cellulose (0.6 g) , and magnesium stearate (0.15 g) were blended and tableted with a 7 ⁇ punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki) to produce core tablets (150 mg per tablet) .
  • HANDTAB manual tablet press manufactured by Ichihashi Seiki
  • Compound X hydrochloride (0.699 g) , polyethylene oxide (PolyoxTM WSR 303, 26 g) , mannitol (3.431 g) , hydroxypropyl cellulose (HPC-L, 0.25 g) , crystalline cellulose (0.31 g) , and magnesium stearate (0.31 g) were blended to produce an outer shell blended powder.
  • the core tablet and 310 mg of the outer shell blended powder were tableted with a 10 ⁇ punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki) to produce dry coated tablets (460 mg per tablet) containing compound X hydrochloride (30 mg as compound X) shown in Table 17.
  • Compound X hydrochloride (3.144 g) , polyethylene oxide (PolyoxTM WSR 303, 5 g) , mannitol (7.496 g) , hydroxypropyl cellulose (HPC-L, 0.51 g) , crystalline cellulose (0.68 g) , and magnesium stearate (0.17 g) were blended and tableted with a 8 ⁇ punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki) to produce core tablets (170 mg per tablet) .
  • HANDTAB manual tablet press
  • Compound X hydrochloride (0.348 g) , polyethylene oxide (PolyoxTM SR 303, 30 g) , mannitol (3.672 g) , hydroxypropyl cellulose (HPC-L, 0.28 g) , crystalline cellulose (0.35 g) , and magnesium stearate (0.35 g) were blended to produce an outer shell blended powder.
  • the core tablet and 350 mg of the outer shell blended powder were tableted with a 11 ⁇ punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi
  • Compound X hydrochloride (8.15 g) , polyethylene oxide (PEO-20NF, 3.8 g) , hydroxypropyl cellulose (HPC-L, 0.42 g) , crystalline cellulose (0.5 g) , and magnesium stearate (0.13 g) were blended and tableted with a 7 ⁇ punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki) to produce core tablets (130 mg per tablet) .
  • HANDTAB manual tablet press manufactured by Ichihashi Seiki
  • Compound X hydrochloride (8.15 g) , carboxyvinyl polymer (Carbopol 971PNF, 3.8 g) , hydroxypropyl cellulose (HPC-L, 0.42 g) , crystalline cellulose (0.5 g) , and magnesium stearate (0.13 g) were blended and tableted with a 7 miruj) punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki) to produce core tablets (130 mg per tablet) .
  • HANDTAB manual tablet press manufactured by Ichihashi Seiki
  • Compound X hydrochloride (3.49 g) , carboxyvinyl polymer (Carbopol 971PNF, 22 g) , mannitol (0.76 g) , hydroxypropyl cellulose (HPC-L, 0.22 g) , crystalline cellulose (0.26 g) , and magnesium stearate (0.27 g) were blended to produce an outer shell blended powder.
  • the core tablet and 270 mg of the outer shell blended powder were tableted with a 10 ⁇ punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki) to produce dry coated tablets (400 mg per tablet) containing compound X hydrochloride (100 mg as compound X) shown in Table 21.
  • HANDTAB manual tablet press
  • Compound X hydrochloride (97.9 g) , mannitol (329 g) , and polyethylene oxide (PEO-20NF, 44 g) were charged in a fluid bed granulator (MP-01, Powrex Corp.), granulated while spraying purified water, and dried to give a granulated powder.
  • the granulated powder (353.1 g) was blended with polyethylene oxide (PEO-20NF, 33 g) and magnesium stearate (3.9 g) and tableted with a 6.5 ⁇ punch by using a rotary tablet press (Kikusui Seisakusho) to give core tablets (130 mg per tablet) .
  • Compound X hydrochloride (36.7 g) , mannitol (128.9 g) , and polyethylene oxide (PEO-20NF, 385 g) were charged in a fluid bed granulator (MP-01, Powrex Corp.), granulated while spraying purified water, and dried to give a granulated powder.
  • the 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 blended powder.
  • the core tablet and 270 mg of the outer shell blended powder were tableted with a 10 ⁇ punch by using a rotary tablet press (Kikusui Seisakusho) to produce dry coated tablets (400 mg per tablet) containing compound X hydrochloride (30 mg as compound X) .
  • the dry coated tablets were charged in a coating pan (DRC-300, Powrex Corp.), and coated by spraying a coating suspension produced by dissolving hydroxypropyl methylcellulose (TC-5E) in purified water and dispersing yellow ferric oxide therein, and dried to produce film-coated dry coated tablets shown in Table 22.
  • Compound X hydrochloride (69.84 g) , mannitol (190.2 g) , and polyethylene oxide (PEO-20NF, 260 g) were charged in a fluid bed granulator (MP-1, Powrex Corp.), granulated while spraying purified water, and dried to give a granulated powder.
  • the granulated powder (455 g) was blended with polyethylene oxide (PEO-20NF, 227.5 g) and magnesium stearate (7 g) to produce an outer shell blended powder.
  • the core tablet and 197 mg of the outer shell blended powder were tableted with a 9 mm ⁇
  • the dry coated tablets were charged in a coating pan (DRC-300, Powrex Corp.), and coated by spraying a coating suspension produced by
  • the granulated powder (521 g) was blended with polyethylene oxide (PEO-20NF, 196.75 g) and magnesium stearate (7.25 g) , and tableted with a 9 mm ⁇
  • the uncoated tablets were charged in a coating pan (DRC-300, Powrex Corp.), and coated by spraying a coating suspension produced by dissolving hydroxypropyl methyl
  • Compound X hydrochloride (0.349 g) , polyethylene oxide (PolyoxTM WSR 303, 22 g) , mannitol (4.381 g) , and magnesium stearate (0.27 g) were blended to produce an outer shell blended powder.
  • the core tablet and 270 mg of the outer shell blended powder were tableted with a 10 ⁇ punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki) to produce dry coated tablets (400 mg per tablet) containing compound X hydrochloride (10 mg as compound X) shown in Table 25.
  • Compound X hydrochloride (0.582 g) , polyethylene oxide (PolyoxTM WSR 303, 1.45 g) , mannitol (7.178 g) , and magnesium stearate (0.09 g) were blended and tableted with a 6 mm ⁇
  • Compound X hydrochloride (125.82 g) and mannitol (125.82 g) were blended in a pouch and passed through a 16 mesh sieve.
  • the blended and sieved powder was additionally blended with spray-dried mannitol (297.45 g) , polyethylene oxide (PEO-20NF, 113.22 g) and magnesium stearate (6.69 g) in the pouch and tableted with a 5.5 ⁇ punch by using a rotary tablet press (Kikusui Seisakusho) to give core tablets (92.86 mg per tablet).
  • the blended and sieved powder was additionally blended with spray-dried mannitol (297.45 g) , polyethylene oxide (PEO-20NF, 113.22 g) and magnesium stearate (6.69 g) in the pouch to obtain an outer shell blended powder.
  • Compound X hydrochloride (125.82 g) and mannitol (125.82 g) were blended in a pouch and passed through a 16 mesh sieve.
  • the blended and sieved powder was additionally blended with spray-dried mannitol (297.45 g) , polyethylene oxide (PEO-20NF, 113.22 g) and magnesium stearate (6.69 g) in the pouch and tableted with a 6.5 mm ⁇
  • Compound X hydrochloride (41.88 g) and mannitol (41.88 g) were blended in a pouch and passed through a 16 mesh sieve.
  • the blended and sieved powder was additionally blended with spray-dried mannitol (105.44 g) , polyethylene oxide (PEO-20NF, 880 g) and magnesium stearate (10.8 g) in the pouch to obtain an outer shell blended powder.
  • the core tablet and 270 mg of the outer shell blended powder were tableted with a 10 ⁇ punch by using a rotary tablet press (Kikusui Seisakusho) to produce dry coated tablets (400 mg per tablet) containing compound X hydrochloride (30 mg as compound X) .
  • the dry coated tablets were charged in a coating pan (HICOATER LABO, Freund Corp.), and coated by spraying a coating suspension produced by dissolving hydroxypropyl methylcellulose (TC-5E) in purified water and dispersing talc and yellow ferric oxide therein, and dried to produce film-coated dry coated tablets shown in Table
  • Compound X hydrochloride (104.76 g) and mannitol (104.76 g) were blended in a pouch and passed through a 16 mesh sieve.
  • the blended and sieved powder was additionally blended with spray-dried mannitol (179.58 g) polyethylene oxide (PEO-20NF, 472.20 g) and magnesium stearate (8.7 g) in the pouch and tableted with a 9 mnuj) punch by using a rotary tablet press
  • the blended and sieved powder was additionally blended with spray-dried mannitol (497.2 g) , polyethylene oxide (PEO-20NF, 121 g) and magnesium stearate (7.15 g) in the pouch and
  • Compound X hydrochloride (23.28 g) and mannitol (23.28 g) were blended in a pouch and passed through a 16 mesh sieve.
  • the blended and sieved powder was additionally blended with spray-dried mannitol (214.12 g) , polyethylene oxide (PEO-20NF, 520 g) and magnesium stearate (7.88 g) in the pouch to obtain an outer shell blended powder.
  • the core tablet and 197.14 mg of the outer shell blended powder were tableted with a 9 mm ⁇ j> punch by using a rotary tablet press (Kikusui Seisakusho) to produce dry coated tablets (290 mg per tablet) containing compound X hydrochloride (10 mg as compound X) .
  • the dry coated tablets were charged in a coating pan (HICOATER LABO, Freund Corp.), and coated by spraying a coating suspension produced by dissolving hydroxypropyl methyl cellulose (TC-5E) in purified water and dispersing talc and yellow ferric oxide therein, and dried to produce film-coated dry coated tablets shown in Table 31.
  • Compound X hydrochloride (44.83 g) and mannitol (44.83 g) were blended in a pouch and passed through a 16 mesh sieve.
  • the blended and sieved powder was additionally blended with spray-dried mannitol (497.2 g) , polyethylene oxide (PEO-20NF, 121 g) and magnesium stearate (7.15 g) in the pouch and
  • Compound X hydrochloride (13.96 g) and mannitol (13.96 g) were blended in a pouch and passed through a 16 mesh sieve.
  • the blended and sieved powder was additionally blended with spray-dried mannitol (161.28 g) , polyethylene oxide (PEO-20NF, 880 g) and magnesium stearate (10.8 g) in the pouch to obtain an outer shell blended powder.
  • the core tablet and 270 mg of the outer shell blended powder were tableted with a 10 ⁇ punch by using a rotary tablet press (Kikusui Seisakusho) to produce dry coated tablets (400 mg per tablet) containing compound X hydrochloride (10 mg as compound X) .
  • the dry coated tablets were charged in a coating pan (HICOATER LABO, Freund Corp.), and coated by spraying a coating suspension produced by dissolving hydroxypropyl methylcellulose (TC-5E) in purified water and dispersing talc and yellow ferric oxide therein, and dried to produce film-coated dry coated tablets shown in Table 32.
  • a coating pan HICOATER LABO, Freund Corp.
  • TC-5E hydroxypropyl methylcellulose
  • Compound X hydrochloride (34.92 g) and mannitol (34.92 g) were blended in a pouch and passed through a 16 mesh sieve.
  • the blended and sieved powder was additionally blended with spray-dried mannitol (319.26 g) polyethylene oxide (PEO-20NF,
  • the core tablet and 270 mg of the " outer shell blended powder were tableted with a 10 ⁇ punch by using a rotary tablet press (HATA TEKKOSHO CO., LTD.) to produce dry coated tablets (400 mg per tablet) containing compound X (30 mg) .
  • the dry coated tablets were charged in a coating pan (DRC-900DS, Powrex Corp.), and coated by spraying a coating suspension produced by dissolving hydroxypropyl methylcellulose (TC-5E) in purified water and dispersing sterile talc and yellow ferric oxide therein, and dried to produce film-coated dry coated tablets shown in Table 34.
  • Compound X hydrochloride (3754 g) , mannitol (12630 g) , and polyethylene oxide (PEO-20NF, 1689 g) were charged in a fluid bed granulator (FD-WSG-30, Powrex Corp.), granulated while spraying purified water, and dried to give a granulated powder.
  • the obtained granulated powder (18070 g) was blended with polyethylene oxide (PEO-20NF, 1689 g) and magnesium stearate (200 g) and tableted with a 5.5 mm ⁇
  • Compound X hydrochloride (2270 g) , mannitol (6202 g) , and polyethylene oxide (PEO-20NF, 8450 g) were charged in a fluid bed granulator (FD-WSG-30, Powrex Corp.), granulated while spraying purified water, and dried to give a granulated powder.
  • the granulation operation was repeated twice and obtained granulated powder (33840 g) was blended with polyethylene oxide (PEO-20NF, 16900 g) and magnesium stearate (512.2 g) to produce an outer shell blended powder.
  • the core tablet and 197.14 mg of the outer shell blended powder were tableted with a 9 ⁇ punch by using a rotary tablet press (HATA TEKKOSHO CO., LTD.) to produce dry coated tablets (290 mg per tablet) containing compound X (30 mg) .
  • the dry coated tablets were charged in a coating pan (DRC-900DS, Powrex Corp.), and coated by spraying a coating suspension produced by dissolving hydroxypropyl methyl cellulose (TC-5E) in purified water and dispersing sterile talc and yellow ferric oxide therein, and dried to produce film- coated dry coated tablets shown in Table 35.
  • the granulation operation was repeated twice and obtained granulated powder (41680 g) was blended with polyethylene oxide (PEO-20NF, 15740 g) and magnesium stearate (580 g) and tableted with a 9 ⁇ punch by using a rotary tablet press (Kikusui Seisakusho) to produce uncoated tablets (290 mg per tablet) containing compound X (30 mg) .
  • the uncoated tablets were charged in a coating pan (DRC-900DS, Powrex Corp.), and coated by spraying a coating suspension produced by dissolving
  • hydroxypropyl methyl cellulose (TC-5E) in purified water and dispersing sterile talc and yellow ferric oxide therein, and dried to produce film-coated single-layered tablets shown in Table 36.
  • Example 37 Compound X hydrochloride (11410 g) , mannitol (564.5 g) , and polyethylene oxide (PEO-20NF, 5132 g) were charged in a fluid bed granulator (FD-WSG-30, Powrex Corp.), granulated while spraying purified water, and dried to give a granulated powder.
  • FD-WSG-30 fluid bed granulator
  • the obtained granulated powder (17110 g) was blended with mannitol (723.5 g) , polyethylene oxide (PEO-20NF, 188 g) , and magnesium stearate (182 g) and tableted with a 6.5 mmcj) punch by using a rotary tablet press (Kikusui Seisakusho) to give core tablets (130 mg per tablet) .
  • Compound X hydrochloride (10820 g) , mannitol (535.4 g) , and polyethylene oxide (PEO-20NF, 4866 g) were charged in a fluid bed granulator (FD-WSG-30, Powrex Corp.), granulated while spraying purified water, and dried to give 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 blended powder.
  • the core tablet and 270 mg of the outer shell blended powder were tableted with a 10 ⁇ punch by using a rotary tablet press (HA A TEKKOSHO CO., LTD.) to produce dry coated tablets (400 mg per tablet) containing compound X (100 mg) .
  • the dry coated tablets were charged in a coating pan (DRC-900DS, Powrex Corp.), and coated by spraying a coating suspension produced by dissolving hydroxypropyl methylcellulose (TC-5E) in purified water and dispersing sterile talc and yellow ferric oxide therein, and dried to produce film-coated dry coated tablets shown in Table 37.
  • Compound X hydrochloride (11060 g) , mannitol (547 g) , and polyethylene oxide (PEO-20NF, 4974 g) were charged in a fluid bed granulator (FD-WSG-30, Powrex Corp.), granulated while spraying purified water, and dried to give 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 blended powder.
  • the core tablet and 197 mg of the outer shell blended powder were tableted with a 9 ⁇ punch by using a rotary tablet press (HATA TEKKOSHO CO., LTD.) to produce dry coated tablets (290 mg per tablet) containing compound X (100 mg) .
  • the dry coated tablets were charged in a coating pan (DRC-900DS, Powrex Corp.), and coated by spraying a coating suspension produced by dissolving hydroxypropyl methylcellulose (TC-5E) in purified water and dispersing sterile talc and yellow ferric oxide therein, and dried to produce film-coated dry coated tablets shown in Table 38.
  • DRC-900DS hydroxypropyl methylcellulose
  • TC-5E hydroxypropyl methylcellulose
  • Compound X hydrochloride (13970 g) , mannitol (691.1 g) , and polyethylene oxide (PEO-20NF, 6282 g) were charged in a fluid bed granulator (FD-WSG-30, Powrex Corp.), granulated while spraying purified water, and dried to give a granulated powder.
  • FD-WSG-30 fluid bed granulator
  • the obtained granulated powder (20940 g) was blended with mannitol (904.9 g) , polyethylene oxide (PEO-20NF, 12610 g) , and magnesium stearate (348 g) and tableted with a 9 ⁇ punch by using a rotary tablet press (Kikusui Seisakusho) to produce uncoated tablets (290 mg per tablet) containing compound X (100 mg) .
  • the uncoated tablets were charged in a coating pan (DRC- 900DS, Powrex Corp.), and coated by spraying a coating
  • Examples 7, 8, and 9 was evaluated by the Paddle Method (the Japanese Pharmacopoeia dissolution test, 2nd fluid, 50 rpm, 900 mL) . The results are shown in Table 3.
  • Example 13 was evaluated by the Paddle Method (the Japanese
  • the dissolution property of the preparation obtained in Example 20 was evaluated by the Paddle Method (the Japanese Pharmacopoeia dissolution test, 2nd fluid, 50 rpm, 900 mL) .
  • Example 21 The dissolution property of the preparation obtained in Example 21 was evaluated by the Paddle Method (the Japanese Pharmacopoeia dissolution test, 2nd fluid, 50 rpm, 900 mL) . The results are shown in Table 8.

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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] oxazepin-3- amine or a salt thereof, and a hydrophilic gel-forming polymer.

Description

DESCRIPTION
Title of the Invention: SOLID PREPARATION [Technical field]
[0001]
The present invention relates to a solid preparation containing N-methyl-N- (1-methylethyl) -6, 7,8,9- tetrahydropyrazino [2, 3-f] [1, ] oxazepin-3-amine or a salt thereof, which may release the compound in a sustained manner.
[0002]
(Background of the invention)
N-methyl-N- (1-methylethyl) -6, 7, 8, 9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine and salts thereof exhibit serotonin 5-HT2c receptor-activating action, and are known to be useful as prophylactic or therapeutic agents for lower urinary tract symptoms, obesity, and/or organ prolapse (patent document 1) .
Patent document 2 discloses a nifedipine-containing dry coated tablet comprising a core containing nifedipine and a hydrophilic gel-forming polymer substance and exhibiting delayed release of nifedipine, and an outer shell formed by compression coating the core, which contains nifedipine, a hydrophilic gel-forming polymer substance, and a
disintegration-suppressive substance composed of a water- insoluble polymer that forms a pH-independent matrix with nifedipine and the hydrophilic gel-forming polymer substance.
Patent document 3 discloses a dry coated tablet
comprising a core containing 8-80% by weight of nifedipine, 15- 80% by weight of a hydrophilic gel-forming polymer substance composed of a cellulose derivative and the like, and 2-30% by weight of a disintegration-suppressive substance composed of a water-insoluble polymer, and an outer shell containing 5-50% by weight of nifedipine, 30-90% by weight of a hydrophilic gel- forming polymer substance composed of a cellulose derivative and the like, and 5-50% by weight of a disintegration- suppressive substance composed of a water-insoluble polymer. Patent document 4 discloses a dry coated tablet
comprising a core containing nifedipine and a hydrophilic gel- forming polymer substance, and an outer shell containing nifedipine, a hydrophilic gel-forming polymer substance, and a disintegration-suppressive substance composed of a water- insoluble polymer.
[Document List]
[Patent documents]
[0003]
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
[SUMMARY OF THE INVENTION]
[Problems to be Solved by the Invention]
[0004]
Since N-methyl-N- ( 1-methylethyl) -6, 7, 8, 9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine and salts thereof have high solubility and a short half-life, three doses per day are anticipated to avoid an adverse event in a typical rapid release tablet.
From the viewpoints of the convenience for patients and medication compliance, a preparation capable of reducing the number of doses is desired.
Thus, an object of the present invention is to provide a preparation which may release N-methyl-N- ( 1-methylethyl) - 6, 7, 8, 9-tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof in a sustained manner, which may permit
administration once or twice per day.
In addition, a preparation containing N-methyl-N- (1- methylethyl) -6, 7,8, 9-tetrahydropyrazino [2, 3-f] [1, ] oxazepin-3- amine or a salt thereof as an active ingredient has a problem of the stability of the active ingredient, since it is
influenced by an increase in the amount of additive. Therefore, the amount of the additive to be used is desirably small. Thus, another object of the present invention is to provide a preparation that may reduce the amount of additive to be used, which in turn may suppress a decrease in the stability of N-methyl-N- (1-methylethyl) -6, 7,8, 9-tetrahydropyrazino [2, 3- f] [1, 4 ] oxazepin-3-amine or a salt thereof.
[Means of Solving the Problems]
[0005]
The present inventor has conducted intensive studies in an attempt to solve the aforementioned problems and found that N-methyl-N- (1-methylethyl) -6, 7,8, 9-tetrahydropyrazino [2, 3- f] [ 1 , 4 ] oxazepin-3-amine and a salt thereof may be released in a sustained manner by using a hydrophilic gel-forming polymer.
The present inventor has also found that, in a solid preparation (such as a tablet) comprising a core, an outer shell, a hydrophilic gel-forming polymer in the core and the outer shell, and N-methyl-N- (1-methylethyl) -6, 7, 8, 9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof in the core and/or the outer shell, the release
behavior of N-methyl-N- (1-methylethyl) -6, 7, 8, 9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof may be controlled by adjusting the content thereof in the core and/or the outer shell, whereby the compound may be released in a sustained manner.
The present inventor has further found that use of a hydrophilic gel-forming polymer may enable maintenance of moldability even when the amount of additives other than the hydrophilic gel-forming polymer is reduced. It has been found that the chemical stability of N-methyl-N- (1-methylethyl) - 6, 7, 8, 9-tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine and salts thereof is affected when the amount of additive is increased. Therefore, the reduction of stability of the compound may be expected to be suppressed by decreasing the additives .
The present inventor has conducted further studies based on the above findings and completed the present invention. [0006]
Accordingly, the present invention provides the following.
[1] A solid preparation comprising N-methyl-N- (1-methylethyl) - 6, 7, 8, 9-tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof, and a hydrophilic gel-forming polymer.
[2] The solid preparation of the above-mentioned [1] ,
comprising (1) a core comprising N-methyl-N- ( 1-methylethyl) - 6, 7, 8, 9-tetrahydropyrazino [2, 3-f] [1, ] oxazepin-3-amine or a salt thereof, and a first hydrophilic gel-forming polymer; and (2) an outer shell comprising N-methyl-N- (1-methylethyl) - 6, 7, 8, 9-tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof, and a second hydrophilic gel-forming polymer.
[2-1] The solid preparation of the above-mentioned [1],
comprising (1) a core comprising N-methyl-N- (1-methylethyl) - 6, 7, 8, 9-tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof, and a first hydrophilic gel-forming polymer; and (2) an outer shell comprising a second hydrophilic gel-forming polymer and not comprising N-methyl-N- ( 1-methylethyl ) -6, 7 , 8 , 9- tetrahydropyrazino [2 , 3-f] [ 1 , 4 ] oxazepin-3-amine or a salt thereof.
[3] The solid preparation of the above-mentioned [2] or [2-1] , 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, hydroxypropyl methyl cellulose,
carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, carboxyvinyl polymer, methyl cellulose, and sodium carboxymethyl cellulose.
[4] The solid preparation of the above-mentioned [2], wherein, in the preparation, the content (by weight) of N-methyl-N- (1- methylethyl) -6, 7,8, 9-tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3- amine or a salt thereof in the core is the same as or higher than the content (by weight) of N-methyl-N- (1-methylethyl) - 6, 7, 8, 9-tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof in the outer shell. [Effects of the invention]
[0007]
The present invention can provide a preparation
containing N-methyl-N- (1-methylethyl) -6, 7,8,9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof as an active ingredient, which may release the compound in a sustained manner by using a hydrophilic gel-forming polymer .
In particular, according to the present invention, a solid preparation (such as a tablet) comprising a core, an outer shell, a hydrophilic gel-forming polymer in the core and the outer shell, and N-methyl-N- ( 1-methylethyl ) -6, 7 , 8 , 9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof in the core and/or the outer shell, which may release the compound in a sustained manner, can be provided by
adjusting the content of the compound in the core and/or the outer shell.
Furthermore, the present invention can provide a
preparation that may be administered once or twice per day.
In addition, the present invention can provide a
preparation that may exhibit good moldability due to the use of a hydrophilic gel-forming polymer, even when the amount of an additive other than the hydrophilic gel-forming polymer is reduced and, since the amount of the additive to be used may be reduced, the present invention can provide a preparation that may suppress lowering of the stability of N-methyl-N- (1- methylethyl) -6, 7,8, 9-tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3- amine and a salt thereof.
[Brief explanation of the drawings]
[0008]
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.
[Description of Embodiments]
[0009]
The present invention is described in detail below.
The solid preparation of the present invention contains N-methyl-N- ( 1-methylethyl ) -6, 7,8, 9-tetrahydropyrazino [2, 3- f] [1, 4] oxazepin-3-amine or a salt thereof as an active
ingredient .
[0010]
Examples of the salt of N-methyl-N- ( 1-methylethyl) - 6, 7, 8, 9-tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine include inorganic acid salts, organic acid salts, and basic or acidic amino acid salts.
Examples of the inorganic acid salt include
hydrochloride, hydrobromate, nitrate, sulfate, and phosphate.
Examples of the organic acid salt include formate, acetate, trifluoroacetate, fumarate, oxalate, tartrate, maleate, citrate, succinate, malate, methanesulfonate, benzenesulfonate, and p-toluenesulfonate .
Examples of the basic amino acid salt include salts with arginine, lysine, and ornithine.
Examples of the acidic amino acid salt include aspartate and glutamate.
Of these, a pharmacologically acceptable salt is
preferable .
As a salt of N-methyl-N- (1-methylethyl) -6, 7, 8, 9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine, N-methyl-N- (1- methylethyl) -6, 7,8, 9-tetrahydropyrazino [2, 3-f] [1,4] oxazepin-3- amine hydrochloride is especially preferable. [0011]
The amount of N-methyl-N- (1-methylethyl) -6, 7, 8, 9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or salt thereof in a free form in the solid preparation of the present
invention is generally 1-1000 mg, preferably 5-800 mg, more preferably 10-500 mg.
The amount of N-methyl-N- ( 1-methylethyl) -6, 7 , 8 , 9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or salt thereof in a free form in the solid preparation of the present
invention is generally 0.5-85% by weight, preferably 1-75% by weight, more preferably 1-65% by weight, relative to the weight of the bare preparation (uncoated tablet) .
[0012]
The solid preparation of the present invention
characteristically contains a hydrophilic gel-forming polymer.
[0013]
In the present invention, the viscosity (25°C, 1% aqueous solution) of the hydrophilic gel-forming polymer is generally not less than 100 cP, preferably not less than 5500 cP, more preferably not less than 7500 cP. In the present invention, the viscosity (25°C, 1% aqueous solution) of the hydrophilic gel-forming polymer is generally not more than 500,000 cP.
In the present invention, the hydrophilic gel-forming polymer is not particular limited as long as it has the above- mentioned viscosity. Examples include polyethylene oxide (for example, Polyox™ WSR 303 produced by The Dow Chemical Company, or PEO-20NF produced by Sumitomo Seika Chemicals Co., Ltd.), hydroxypropyl methyl cellulose (for example, METOLOSE 90SH- 100000SR produced by Shin-etsu Chemical Co., Ltd.),
carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, carboxyvinyl polymer (for example, Carbopol 971PNF produced by the Lubrizol Corporation) , methyl cellulose, and sodium carboxymethyl cellulose. Polyethylene oxide,
hydroxypropyl methyl cellulose, and carboxyvinyl polymer are preferable, and polyethylene oxide is especially preferable. [0014]
In the solid preparation of the present invention, it is preferable to use a highly viscous hydrophilic gel-forming polymer (such as polyethylene oxide) as the hydrophilic gel- forming polymer, because it may control dissolution of N- methyl-N- (1-methylethyl) -6, 7,8, 9-tetrahydropyrazino [2, 3- f] [1, 4 ] oxazepin-3-amine or salt thereof.
[0015]
In the solid preparation of the present invention, the content of the hydrophilic gel-forming polymer is generally 15- 95% by weight, preferably 25-85% by weight, more preferably 35- 75% by weight, relative to the weight of the bare preparation (uncoated tablet) .
[0016]
In the present description, the "bare preparation
(uncoated tablet)" refers to a preparation (tablet) prior to coating when the solid preparation is to be coated as described below, or a solid preparation (tablet) itself when the solid preparation is not coated.
[0017]
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 embodiments (A) , (B) and (C) . (A) A single-layered solid preparation (e.g., tablet)
containing N-methyl-N- (1-methylethyl) -6, 7, 8, 9- tetrahydropyrazino [2, 3-f] [1, 4 ] oxazepin-3-amine or a salt thereof, and a hydrophilic gel-forming polymer (hereinafter also referred to as a single-layered tablet of the present invention) .
(B) A solid preparation (e.g., tablet) comprising:
(1) a core containing N-methyl-N- (1-methylethyl) -6, 7, 8, 9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof, and a first hydrophilic gel-forming polymer; and
(2) an outer shell containing N-methyl-N- (1-methylethyl) - 6, 7, 8, 9-tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof, and a second hydrophilic gel-forming polymer. (C) A solid preparation (e.g., tablet) comprising:
(1) a core containing N-methyl-N- (1-methylethyl) -6, 7, 8, 9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof, and a first hydrophilic gel-forming polymer; and
(2) an outer shell containing a second hydrophilic gel-forming polymer, and not containing N-methyl-N- (1-methylethyl) -6, 7, 8, 9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof.
(Hereinafter (B) and (C) are also referred to as a dry coated tablet of the present invention.)
[0018]
In the single-layered tablet of the present invention, the contents of N-methyl-N- (1-methylethyl) -6, 7, 8, 9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof and the hydrophilic gel-forming polymer are as
indicated above.
[0019]
The single-layered tablet of the present invention may be film-coated, as described below.
When the single-layered tablet of the present invention is film-coated, the content of the hydrophilic gel-forming polymer is the content thereof in the uncoated tablet before film coating.
[0020]
In the present invention, a shell of a hydrophilic gel- forming polymer and free of N-methyl-N- (1-methylethyl) -6, 7, 8, 9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine and a salt thereof may be formed on the outside of the single-layered tablet. This embodiment is to be described later as a dry coated tablet with a shell not containing N-methyl-N- (1- methylethyl) -6, 7,8, 9-tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3- amine or a salt thereof.
[0021] In the dry coated tablet of the present invention, the core may be a tablet (in the DESCRIPTION, a tablet as a core is referred to as a core tablet) .
In the dry coated tablet of the present invention, the content of N-methyl-N- (1-methylethyl) -6, 7, 8, 9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or salt thereof in a free form in the core is generally 0.5-1000 mg, preferably 2.5-800 mg, more preferably 5—500 mg.
In the dry coated tablet of the present invention, the content of N-methyl-N- (1-methylethyl) -6, 7, 8, 9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or salt thereof in a free form in the outer shell is generally 0-500 mg, preferably 0-400 mg, more preferably 0-250 mg.
[0022]
The dry coated tablet of the present invention may contain N-methyl-N- (1-methylethyl) -6, 7,8,9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof in both the core and the outer shell, or only in the core .
For example, a dry coated tablet containing N-methyl-N-
( 1-methylethyl) -6, 7,8, 9-tetrahydropyrazino [2, 3-f] [1, 4] oxazepin- 3-amine or a salt thereof in the core and not containing N- methyl-N- (1-methylethyl) -6, 7,8, 9-tetrahydropyrazino [2, 3- f] [1, 4 ] oxazepin-3-amine or a salt thereof in the outer shell is also encompassed in the solid preparation of the present invention.
[0023]
In the dry coated tablet of the present invention, the content (by weight) of N-methyl-N- (1-methylethyl) -6, 7, 8, 9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof in the core is preferably equal to or higher than the content (by weight) of N-methyl-N- (1-methylethyl) -6, 7, 8, 9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof in the outer shell, since further delayed and sustained release of the active ingredient can be expected. [0024]
The dry coated tablet of the present invention is a solid preparation (such as a tablet) comprising a core, an outer shell, a hydrophilic gel-forming polymer in the core and the outer shell, and the active ingredient in the core and/or the outer shell, which may control 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.
When measured according to the Paddle Method described in the Japanese Pharmacopoeia 16th Edition (the Japanese
Pharmacopoeia dissolution test, 2nd fluid, 100 rpm, 900 mL) , the dissolution ratio of the active ingredient is generally 0- 30% after 2 hr; 15-55% after 6 hr; 35-80% after 9 hr,
preferably 5-25% after 2 hr; 20-50% after 6 hr; 40-75% after 9 hr, more preferably 5-20%% after 2 hr; 25-45% after 6 hr; 45- 70% after 9 hr.
In another embodiment, it is generally 10-45% after 2 hr; 40-80% after 6 hr; 60-100% after 9 hr, preferably 15-40% after 2 hr; 45-75% after 6 hr; 65-95% after 9 hr, more preferably 20- 35% after 2 hr; 50-70% after 6 hr; 70-95% after 9 hr.
[0025]
Examples of the first and second hydrophilic gel-forming polymers in the dry coated tablet of the present invention include those recited above as the hydrophilic gel-forming polymer in the solid preparation of the present invention.
The first hydrophilic gel-forming polymer and the second hydrophilic gel-forming polymer may be identical or different.
In the dry coated tablet of the present invention, each of the first and second hydrophilic gel-forming polymers is preferably polyethylene oxide.
[0026]
In the dry coated tablet of the present invention, the content of the first hydrophilic gel-forming polymer in the core is generally 0.01-90% by weight, preferably 5-70% by weight, more preferably 10-50% by weight, relative to the weight of the core.
In the dry coated tablet of the present invention, the content of the second hydrophilic gel-forming polymer in the outer shell is generally 20-100% by weight, preferably 30-95% by weight, more preferably 40-90% by weight, relative to the weight of the outer shell.
[0027]
The dry coated tablet of the present invention may be film-coated as described below.
When the dry coated tablet of the present invention is film-coated, the content of the hydrophilic gel-forming polymer is the content of the preparation (uncoated tablet) prior to film coating.
[0028]
In the dry coated tablet of the present invention, the weight ratio of the core and the outer shell (core router shell) is generally 1:1.5-3.5, preferably 1:1.5-3.0, more preferably 1:2-2.5, still more preferably about 1:2.
[0029]
The solid preparation (single-layered tablet, dry coated tablet) of the present invention may further contain an
additive conventionally used in the field of preparations.
Examples of the additive include excipients (e.g., mannitol, spray-dried mannitol, starch, lactose, sucrose, calcium carbonate, calcium phosphate, and crystalline
cellulose), binders (e.g., starch, gum arabic, alginic acid, gelatin, polyvinyl pyrrolidone, and hydroxypropyl cellulose (having low viscosity preventing function as a hydrophilic gel- forming polymer, e.g., HPC-SL and HPC-L, produced by Nippon Soda Co., Ltd.), and lubricants (e.g., stearic acid, magnesium stearate, calcium stearate, and talc) .
[0030]
The use of a hydrophilic gel-forming polymer in the present invention may reduce the amount of additives other than the hydrophilic gel-forming polymer.
In the solid preparation of the present invention, the content of the total amount of the additive other than the hydrophilic gel-forming polymer is generally 5-95% by weight, preferably 15-75% by weight, more preferably 25-65% by weight, relative to the weight of the uncoated tablet.
[0031]
The solid preparation (single-layered tablet, dry coated tablet) of the present invention can be produced using the above-mentioned various components and according to a
conventional method in the technical field of preparations.
[0032]
The single-layered tablet of the present invention can be produced, for example, by blending N-methyl-N- ( 1-methylethyl ) - 6, 7, 8, 9-tetrahydropyrazino [2, 3-f] [1, ] oxazepin-3-amine or a salt thereof, a hydrophilic gel-forming polymer (e.g.,
polyethylene oxide, hydroxypropyl methyl cellulose,
carboxyvinyl polymer, etc.), and additive to be optionally added (for example, excipient (e.g., mannitol) , lubricant (e.g., magnesium stearate) , binder) , and compression-molding
(tableting) the mixture.
[0033]
The dry coated tablet of the present invention can be produced, for example, according to the following method.
N-methyl-N- (1-methylethyl) -6,7,8, 9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt
thereof, a hydrophilic gel-forming polymer (e.g., polyethylene oxide, hydroxypropyl methyl cellulose, carboxyvinyl polymer, etc.), and additive to be optionally added (for example,
excipient (e.g., mannitol), lubricant (e.g., magnesium
stearate) , binder) , and compression-molding the mixture to give a core (core tablet) .
Separately, N-methyl-N- (1-methylethyl) -6,7,8,9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt
thereof, a hydrophilic gel-forming polymer (e.g., polyethylene oxide, hydroxypropyl methyl cellulose, carboxyvinyl polymer, etc. ) , and additive to be optionally added (for example, excipient (e.g., mannitol) , lubricant (e.g., magnesium
stearate) , binder) are blended to give an outer shell blended powder (i.e., a powder mixture of components forming the outer shell) .
The core tablet and the outer shell blended powder are compression-molded to give a dry coated tablet.
[0034]
A dry coated tablet not contain N-methyl-N- ( 1- methylethyl) -6, 7,8, 9-tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3- amine or a salt thereof in the outer shell can be produced by not adding N-methyl-N- (1-methylethyl) -6, 7, 8, 9- tetrahydropyrazino [2, 3-f] [1, 4 ] oxazepin-3-amine or salt thereof during the process of producing the outer shell blended powder in the above-mentioned production method.
[0035]
Blending can be performed using a mixer such as V-mixer or tumbler mixer. Compression molding can be performed by tableting using, for example, a single-punch tablet press, rotary tablet press, or the like.
[0036]
The solid preparation (single-layered tablet, dry coated tablet) of the present invention may be coated as necessary by a conventional method in the technical field of preparations.
For example, the following film coating bases and coating additives can be used.
Examples of the film coating base include hydroxypropyl methyl cellulose (TC-5E, TC-5R; produced by Shin-etsu Chemical Co., Ltd.), hydroxypropyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, methyl cellulose, and hydroxyethyl methyl cellulose .
Examples of the coating additive include light-blocking agents such as titanium oxide; fluidizing agents such as talc, sterile talc; colorants such as ferric oxide and yellow ferric oxide; plasticizers such as polyethylene glycol (e.g., Macrogol 6000) , triethyl citrate, castor oil, and polysorbates; and organic acids such as citric acid, tartaric acid, malic acid, and ascorbic acid.
[0037]
When the solid preparation of the present invention is film-coated, the amount of the film coating is generally l%-8%, preferably 2%-6%, relative to the weight of the bare
preparation (uncoated tablet) .
[0038]
The weight of the solid preparation of the present invention is generally 100 mg - 1,500 mg, preferably 200 mg - 1,000 mg.
[0039]
The size of the single-layered tablet of the present invention is generally 6 mm - 20 mm, preferably 8 mm - 15 mm.
The size of the dry coated tablet of the present
invention is generally 4.5 mm - 17 mm, preferably 5 mm - 12 mm, and the size of the core (core tablet) of the dry coated tablet is generally 7.5 mm - 20 mm, preferably 8 mm - 15 mm.
[0040]
The shape of the solid preparation of the present
invention is not particularly limited, and it may be any shape such as round, caplet-shaped, donut-shaped, oblong-shaped and the like.
[0041]
The solid preparation of the present invention may be useful as an agent for ameliorating, preventing, or treating all serotonin 5-HT2c related diseases such as lower urinary tract symptoms (e.g., stress incontinence) in mammalian animals (such as human, monkey, cattle, horse, pig, mouse, rat, hamster, rabbit, cat, dog, sheep, and goat) . The solid preparation of the present invention can be orally administered safely.
[0042]
While the dose of N-methyl-N- (1-methylethyl) -6, 7, 8, 9- tetrahydropyrazi.no [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof in the solid preparation of the present invention varies depending on the administration subject, symptom, and the like, for oral administration to a patient with lower urinary tract symptom (adult; body weight about 60 kg) , it is generally an amount of about 0.01667 - about 16.67 mg/kg body weight, preferably about 0.08333 - about 13.33 mg/kg body weight, more preferably about 0.1667 - about 8.333 mg/kg body weight, which can be administered one to several times per day according to the symptoms.
[0043]
The solid preparation of the present invention may release the active ingredient in a sustained manner, which may reduce the number of doses per day (one or two doses/day) . As a result, increased convenience for patients and improved medication compliance are expected.
[0044]
The solid preparation of the present invention can be used in combination with an active ingredient other than N- methyl-N- ( 1-methylethyl ) -6, 7,8, 9-tetrahydropyrazino [2, 3- f] [1, 4] oxazepin-3-amine or a salt thereof (hereinafter
abbreviated as a "concomitant drug") . In this case, the time of administration of N-methyl-N- ( 1-methylethyl ) -6, 7 , 8 , 9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or salt thereof and that of the concomitant drug are not limited, and they may be administered simultaneously or in a staggered manner to the administration subject. Furthermore, the solid preparation of the present invention and a concomitant drug may be
administered as two kinds of preparations containing each active ingredient, or may be administered as a single
preparation containing both active ingredients.
The dose of the concomitant drug can be appropriately determined based on the dose employed in clinical situations.
Examples of the concomitant drug include other
therapeutic drugs for stress incontinence. [Examples]
[0045]
The present invention is explained in more detail in the following by referring to Examples, which are not to be construed as limitative.
As the preparation additives (e.g., polyethylene oxide, mannitol, magnesium stearate, hydroxypropyl cellulose,
crystalline cellulose, carboxyvinyl polymer, yellow ferric oxide, spray-dried mannitol, hydroxypropyl methyl cellulose, talc) used in the following Examples, the Japanese
Pharmacopoeia 16th Edition compatible products, Japanese
Pharmaceutical Excipients 2003 compatible products, the United States Pharmacopeia (USP) compatible products, and the National Formulary (NF) compatible products were used.
In the following Examples, dissolution tests were performed according to the Paddle Method described in the Japanese Pharmacopoeia 16th Edition. The dissolution test, 2nd fluid used as the test liquid can be prepared according to a known method. The amount of the dissolution test, 2nd fluid used as the test liquid is generally 900 mL.
Compound X used in the following Formulation Examples is N-methyl-N- ( 1-methylethyl) -6,7,8, 9-tetrahydropyrazino [2,3- f] [1, 4] oxazepin-3-amine. The dissolution property of the preparations obtained in Examples 1-27 was evaluated by the Paddle Method (the Japanese Pharmacopoeia dissolution test, 2nd fluid, 50 rpm, 900 mL) by using a Varian dissolution tester. The dissolution property of the preparations obtained in
Examples 34-39 was evaluated using a dissolution tester
manufactured by Toyama Sangyo Co., Ltd. and according to the Paddle Method (the Japanese Pharmacopoeia dissolution test, 2nd fluid, 100 rpm, 900 mL) .
[0046]
Example 1
Compound X hydrochloride (5.82 g) , polyethylene oxide (Polyox™ WSR 303, 2.5 g) , mannitol (0.095 g) , and magnesium stearate (0.085 g) were blended and tableted with a 7 πτπιφ punch by using a manual tablet press (HANDTAB, manufactured by
Ichihashi Seiki) to produce core tablets (170 mg per tablet) .
Polyethylene oxide (Polyox™ WSR 303, 15 g) , mannitol (1.83 g), and magnesium stearate (0.17 g) were blended to produce an outer shell blended powder. The core tablet and 340 mg of the outer shell blended powder were tableted with a 11 mm<j) punch by using an autograph tablet press (AG-IS, Shimadzu) to produce dry coated tablets (510 mg per tablet) containing compound X hydrochloride (100 mg as compound X) shown in Table 1.
[0047]
[Table 1]
Table 1 Composition of one dry coated tablet
Figure imgf000019_0001
[0048]
Example 2
Compound X hydrochloride (5.82 g) , polyethylene oxide (Polyox™ WSR 303, 2.5 g) , mannitol (0.095 g) , and magnesium stearate (0.085 g) were blended and tableted with a 7 mm<j) punch by using a manual tablet press (HANDTAB, manufactured by
Ichihashi Seiki) to produce core tablets (170 mg per tablet) .
Polyethylene oxide (Polyox™ WSR 303, 12.5 g) , mannitol (4.33 g) , and magnesium stearate (0.17 g) were blended to produce an outer shell blended powder. The core tablet and 340 mg of the outer shell blended powder were tableted with a 11 mm(j> punch by using an autograph tablet press (AG-IS, Shimadzu) to produce dry coated tablets (510 mg per tablet) containing compound X hydrochloride (100 mg as compound X) shown in Table 2.
[0049]
[Table 2]
Table 2 Composition of one dry coated tablet
Figure imgf000020_0001
[0050]
Example 3
Compound X hydrochloride (5.82 g) , polyethylene oxide
(Polyox™ WSR 303, 17.5 g) , mannitol (1.925 g) , and magnesium stearate (0.255 g) were blended to produce a powder mixture. 510 mg of the powder mixture was pressed into a tablet with a 11 ΐΐΐπιφ punch by using an autograph tablet press (AG-IS,
Shimadzu) to produce single-layered tablets (510 mg per tablet) containing compound X hydrochloride (100 mg as compound X) shown in Table 3.
[0051]
[Table 3]
Table 3 Composition of one single-layered tablet
Figure imgf000020_0002
[0052]
Example 4
Compound X hydrochloride (5.82 g) , polyethylene oxide (Polyox™ WSR 303, 2.5 g) , mannitol (0.095 g) , and magnesium stearate (0.085 g) were blended and tableted with a 7 πατιφ punch by using a manual tablet press (HANDTAB, manufactured by
Ichihashi Seiki) to produce core tablets (170 mg per tablet) .
Polyethylene oxide (Polyox™ WSR 303, 10 g) , mannitol (6.83 g) , and magnesium stearate (0.17 g) were blended to produce an outer shell blended powder. The core tablet and 340 mg of the outer shell blended powder were tableted with a 11 mm<t) punch by using an autograph tablet press (AG-IS, Shimadzu) to produce dry coated tablets (510 mg per tablet) containing compound X hydrochloride (100 mg as compound X) shown in Table 4.
[0053]
[Table 4]
Table 4 Composition of one dry coated tablet
Figure imgf000021_0001
[0054]
Example 5
Compound X hydrochloride (5.82 g) , polyethylene oxide (Polyox™ WSR 303, 2.5 g) , mannitol (0.095 g) , and magnesium stearate (0.085 g) were blended and tableted with a 7 ιππιφ punch by using a manual tablet press (HANDTAB, manufactured by
Ichihashi Seiki) to produce core tablets (170 mg per tablet) .
Polyethylene oxide (Polyox™ WSR 303, 7.5 g) , mannitol
(9.33 g) , and magnesium stearate (0.17 g) were blended to produce an outer shell blended powder. The core tablet and 340 mg of the outer shell blended powder were tableted with a 11 πιπιφ punch by using an autograph tablet press (AG-IS, Shimadzu) to produce dry coated tablets (510 mg per tablet) containing compound X hydrochloride (100 mg as compound X) shown in Table 5.
[0055]
[Table 5]
Table 5 Composition of one dry coated tablet
Figure imgf000022_0001
[0056]
Example 6
Compound X hydrochloride (5.238 g) , polyethylene oxide (Polyox™ WSR 303, 2.5 g) , mannitol (0.677 g) , and magnesium stearate (0.085 g) were blended and tableted with a 7 mm<j) punch by using a manual tablet press (HANDTAB, manufactured by
Ichihashi Seiki) to produce core tablets (170 mg per tablet) . Compound X hydrochloride (0.582 g) , polyethylene oxide (Polyox™ WSR 303, 12.5 g) , mannitol (3.748 g) , and magnesium stearate (0.17 g) were blended to produce an outer shell blended powder. The core tablet and 340 mg of the outer shell blended powder were tableted with a 11 mm<j) punch by using an autograph tablet press (AG-IS, Shimadzu) to produce dry coated tablets (510 mg per tablet) containing compound X hydrochloride (100 mg as compound X) shown in Table 6.
[0057]
[Table 6]
Table 6 Composition of one dry coated tablet
Figure imgf000023_0001
[0058]
Example 7
Compound X hydrochloride (4.074 g) , polyethylene oxide
(Polyox™ WSR 303, 2.5 g) , mannitol (1.841 g) , and magnesium stearate (0.085 g) were blended and tableted with a 7 ιηιηφ punch by using a manual tablet press (HANDTAB, manufactured by
Ichihashi Seiki) to produce core tablets (170 mg per tablet) .
Compound X hydrochloride (1.746 g) , polyethylene oxide
(Polyox™ WSR 303, 12.5 g) , mannitol (2.584 g) , and magnesium stearate (0.17 g) were blended to produce an outer shell blended powder. The core tablet and 340 mg of the outer shell blended powder were tableted with a 11 mm<j) punch by using an autograph tablet press (AG-IS, Shimadzu) to produce dry coated tablets (510 mg per tablet) containing compound X hydrochloride (100 mg as compound X) shown in Table 7.
[0059]
[Table 7]
Table 7 Composition of one dry coated tablet
Figure imgf000024_0001
[0060]
Example 8
Compound X hydrochloride (4.074 g) , polyethylene oxide (Polyox™ WSR 303, 2.5 g) , mannitol (0.356 g) , and magnesium stearate (0.07 g) were blended and tableted with a 6.5 ππηφ punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki) to produce core tablets (140 mg per tablet) .
Compound X hydrochloride (1.746 g) , polyethylene oxide (Polyox™ WSR 303, 12.5 g) , mannitol (0.109 g) , and magnesium stearate (0.145 g) were blended to produce an outer shell blended powder. The core tablet and 290 mg of the outer shell blended powder were tableted with a 10.5 mm<j) punch by using an autograph tablet press (AG-IS, Shimadzu) to produce dry coated tablets (430 mg per tablet) containing compound X hydrochloride (100 mg as compound X) shown in Table 8. [0061]
[Table 8]
Table 8 Composition of one dry coated tablet
Figure imgf000025_0001
[0062]
Example 9
Compound X hydrochloride (4.074 g) , polyethylene oxide (Polyox™ WSR 303, 1.75 g) , mannitol (0.116 g) , and magnesium stearate (0.06 g) were blended and tableted with a 6.5 πιπιφ punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki) to produce core tablets (120 mg per tablet) .
Compound X hydrochloride (1.746 g) , polyethylene oxide (Polyox™ WSR 303, 10 g) , mannitol (0.134 g) , and magnesium stearate (0.12 g) were blended to produce an outer shell blended powder. The core tablet and 240 mg of the outer shell blended powder were tableted with a 10 mm<|> punch by using an autograph tablet press (AG-IS, Shimadzu) to produce dry coated tablets (360 mg per tablet) containing compound X hydrochloride (100 mg as compound X) shown in Table 9. [0063]
[Table 9]
Table 9 Composition of one dry coated tablet
Figure imgf000026_0001
[0064]
Example 10
Compound X hydrochloride (3.492 g) , polyethylene oxide (Polyox™ WSR 303, 1.5 g) , mannitol (0.057 g) , and magnesium stearate (0.051 g) were blended and tableted with a 6 mm<j) punch by using a manual tablet press (HANDTAB, manufactured by
Ichihashi Seiki) to produce core tablets (102 mg per tablet) .
Compound X hydrochloride (2.328 g) , polyethylene oxide (Polyox™ WSR 303, 7.5 g) , mannitol (0.072 g) , and magnesium stearate (0.1 g) were blended to produce an outer shell blended powder. The core tablet and 200 mg of the outer shell blended powder were tableted with a 9.5 mmcj) punch by using an autograph tablet press (AG-IS, Shimadzu) to produce dry coated tablets (302 mg per tablet) containing compound X hydrochloride (100 mg as compound X) shown in Table 10. [0065]
[Table 10]
Table 10 Composition of one dry coated tablet
Figure imgf000027_0001
[0066]
Example 11
Compound X hydrochloride (2.91 g) , polyethylene oxide (Polyox™ WSR 303, 1.25 g) , mannitol (0.0475 g) , and magnesium stearate (0.0425 g) were blended and tableted with a 5.5 mm<|> punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki) to produce core tablets (85 mg per tablet) .
Compound X hydrochloride (2.91 g) , polyethylene oxide (Polyox™ WSR 303, 6 g) , and magnesium stearate (0.09 g) were blended to produce an outer shell blended powder. The core tablet and 180 mg of the outer shell blended powder were tableted with a 9 πυτιφ punch by using an autograph tablet press (AG-IS, Shimadzu) to produce dry coated tablets (265 mg per tablet) containing compound X hydrochloride (100 mg as compound X) shown in Table 11. [0067]
[Table 11]
Table 11 Composition of one dry coated tablet
Figure imgf000028_0001
[0068]
Example 12
Compound X hydrochloride (4.074 g) , hydroxypropyl methyl cellulose (METOLOSE 90SH-100000SR, 1.75 g) , mannitol (0.116 g) , and magnesium stearate (0.06 g) were blended and tableted with a 6.5 πΰπφ punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki) to produce core tablets (120 mg per tablet) .
Compound X hydrochloride (1.746 g) , hydroxypropyl methyl cellulose (METOLOSE 90SH-100000SR, 10 g) , mannitol (0.134 g) , and magnesium stearate (0.12 g) were blended to produce an outer shell blended powder. The core tablet and 240 mg of the outer shell blended powder were tableted with a 10 ητιηφ punch by using an autograph tablet press (AG-IS, Shimadzu) to produce dry coated tablets (360 mg per tablet) containing compound X hydrochloride (100 mg as compound X) shown in Table 12. [0069]
[Table 12]
Table 12 Composition of one dry coated tablet
Figure imgf000029_0001
[0070]
Example 13
Compound X hydrochloride (366.8 g) and crystalline cellulose (22.5 g) were charged in a fluid bed granulator (LAB- 1, Powrex Corp.), granulated while spraying an aqueous solution obtained by dissolving hydroxypropyl cellulose (HPC-L, 18.9 g) in purified water, and dried to produce a granulated powder. The granulated powder (362.8 g) was blended with polyethylene oxide (Polyox™ WSR 303, 152 g) and magnesium stearate (5.2 g) and tableted with a 7 mm<|) punch by using a rotary tablet press (Correct 19K, Kikusui Seisakusho) to produce core tablets (130 mg per tablet) .
Compound X hydrochloride (279.2 g) , mannitol (60.8 g) and crystalline cellulose (20.8 g) were charged in a fluid bed granulator (LAB-1, Powrex Corp. ) , granulated while spraying an aqueous solution obtained by dissolving hydroxypropyl cellulose (HPC-L, 17.6 g) in purified water, and dried to produce a granulated powder. The granulated powder (189.2 g) was blended with polyethylene oxide (Polyox™ WSR 303, 880 g) , and
magnesium stearate (10.8 g) to produce an outer shell blended powder. The core tablet and 270 mg of the outer shell blended powder were tableted with a 10 ΐΐΐπιφ punch by using a rotary tablet press (manufactured by Kikusui Seisakusho) to produce dry coated tablets (400 mg per tablet) containing compound X hydrochloride (100 mg as compound X) shown in Table 13.
[0071]
[Table 13]
Table 13 Composition of one dry coated tablet
Figure imgf000030_0001
[0072]
Example 14
Compound X hydrochloride (1.746 g) , polyethylene oxide (Polyox™ WSR 303, 2.74 g) , mannitol (4.724 g ) , and magnesium stearate (0.09 g) were blended and tableted with a 6 mm<t> punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki) to produce core tablets (93 mg per tablet) .
Compound X hydrochloride (1.746 g) , polyethylene oxide (Polyox™ WSR 303, 13 g) , mannitol (4.754 g) , and magnesium stearate (0.2 g) were blended to produce an outer shell blended powder. The core tablet and 197 mg of the outer shell blended powder were tableted with a 9 πατιφ punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki) to produce dry coated tablets (290 mg per tablet) containing compound X hydrochloride (30 mg as compound X) shown in Table 14.
[0073]
[Table 14]
Table 14 Composition of one dry coated tablet
Figure imgf000031_0001
[0074]
Example 15
Compound X hydrochloride (2.094 g) , polyethylene oxide (Polyox™ WSR 303, 3.3 g) , mannitol (5.696 g) , and magnesium stearate (0.11 g) were blended and tableted with a 6 ΐΐΐπιφ punch by using a manual tablet press (HANDTAB, manufactured by
Ichihashi Seiki) to produce core tablets (112 mg per tablet) .
Compound X hydrochloride (1.398 g) , polyethylene oxide (Polyox™ WSR 303, 17.55 g) , mannitol (4.622 g) , and magnesium stearate (0.23 g) were blended to produce an outer shell blended powder. The core tablet and 238 mg of the outer shell blended powder were tableted with a 9 πυηφ punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki) to produce dry coated tablets (350 mg per tablet) containing compound X hydrochloride (30 mg as compound X) shown in Table 15.
[0075]
[Table 15]
Table 15 Composition of one dry coated tablet
Figure imgf000032_0001
[0076]
Example 16
Compound X hydrochloride (2.445 g) , polyethylene oxide (Polyox™ WSR 303, 3.8 g) , mannitol (5.705 g) , hydroxypropyl cellulose (HPC-L, 0.42 g) , crystalline cellulose (0.5 g) , and magnesium stearate (0.13 g) were blended and tableted with a 7 πιιτιφ punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki) to produce core tablets (130 mg per tablet) .
Compound X hydrochloride (1.047 g) , polyethylene oxide (Polyox™ WSR 303, 22 g) , mannitol (3.203 g) , hydroxypropyl cellulose (HPC-L, 0.22 g) , crystalline cellulose (0.26 g) , and magnesium stearate (0.27 g) were blended to produce an outer shell blended powder. The core tablet and 270 mg of the outer shell blended powder were tableted with a 10 Γηιτιφ punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi
Seiki) to produce dry coated tablets (400 mg per tablet) containing compound X hydrochloride (30 mg as compound X) shown in Table 16.
[0077]
[Table 16]
Table 16 Composition of one dry coated tablet
Figure imgf000033_0001
[0078]
Example 17
Compound X hydrochloride (2.793 g) , polyethylene oxide (Polyox™ WSR 303, 4.4 g) , mannitol (6.607 g) , hydroxypropyl cellulose (HPC-L, 0.45 g) , crystalline cellulose (0.6 g) , and magnesium stearate (0.15 g) were blended and tableted with a 7 πιπιφ punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki) to produce core tablets (150 mg per tablet) .
Compound X hydrochloride (0.699 g) , polyethylene oxide (Polyox™ WSR 303, 26 g) , mannitol (3.431 g) , hydroxypropyl cellulose (HPC-L, 0.25 g) , crystalline cellulose (0.31 g) , and magnesium stearate (0.31 g) were blended to produce an outer shell blended powder. The core tablet and 310 mg of the outer shell blended powder were tableted with a 10 ιιπηφ punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki) to produce dry coated tablets (460 mg per tablet) containing compound X hydrochloride (30 mg as compound X) shown in Table 17.
[0079]
[Table 17]
Table 17 Composition of one dry coated tablet
Figure imgf000034_0001
[0080]
Example 18
Compound X hydrochloride (3.144 g) , polyethylene oxide (Polyox™ WSR 303, 5 g) , mannitol (7.496 g) , hydroxypropyl cellulose (HPC-L, 0.51 g) , crystalline cellulose (0.68 g) , and magnesium stearate (0.17 g) were blended and tableted with a 8 πιιηφ punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki) to produce core tablets (170 mg per tablet) .
Compound X hydrochloride (0.348 g) , polyethylene oxide (Polyox™ SR 303, 30 g) , mannitol (3.672 g) , hydroxypropyl cellulose (HPC-L, 0.28 g) , crystalline cellulose (0.35 g) , and magnesium stearate (0.35 g) were blended to produce an outer shell blended powder. The core tablet and 350 mg of the outer shell blended powder were tableted with a 11 πιπιφ punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi
Seiki) to produce dry coated tablets (520 mg per tablet)
containing compound X hydrochloride (30 mg as compound X) shown in Table 18.
[0081]
[Table 18]
Table 18 Composition of one dry coated tablet
Figure imgf000035_0001
[0082]
Example 19
Compound X hydrochloride (1.746 g) , polyethylene oxide (Polyox™ WSR 303, 7.87 g) , mannitol (4.739 g) , and magnesium stearate (0.145 g) were blended to produce a powder mixture.
290 mg of the powder mixture was tableted with a 9 ητιηφ punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki) to produce single-layered tablets (290 mg per tablet) containing compound X hydrochloride (30 mg as compound X) shown in Table 19.
[0083]
[Table 19]
Table 19 Composition of one single-layered tablet
Figure imgf000036_0001
[0084]
Example 20
Compound X hydrochloride (8.15 g) , polyethylene oxide (PEO-20NF, 3.8 g) , hydroxypropyl cellulose (HPC-L, 0.42 g) , crystalline cellulose (0.5 g) , and magnesium stearate (0.13 g) were blended and tableted with a 7 πιπιφ punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki) to produce core tablets (130 mg per tablet) .
Compound X hydrochloride (3.49 g) , polyethylene oxide (PEO-20NF, 22g) , mannitol (0.76 g) , hydroxypropyl cellulose
(HPC-L, 0.22 g) , crystalline cellulose (0.26 g) , and magnesium stearate (0.27 g) were blended to produce an outer shell blended powder. The core tablet and 270 mg of the outer shell blended powder were tableted with a 10 πιιηφ punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki) to produce dry coated tablets (400 mg per tablet) containing compound X hydrochloride (100 mg as compound X) shown in Table 20.
[0085] [Table 20]
Table 20 Composition of one dry coated tablet
Figure imgf000037_0001
[0086]
Example 21
Compound X hydrochloride (8.15 g) , carboxyvinyl polymer (Carbopol 971PNF, 3.8 g) , hydroxypropyl cellulose (HPC-L, 0.42 g) , crystalline cellulose (0.5 g) , and magnesium stearate (0.13 g) were blended and tableted with a 7 miruj) punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki) to produce core tablets (130 mg per tablet) .
Compound X hydrochloride (3.49 g) , carboxyvinyl polymer (Carbopol 971PNF, 22 g) , mannitol (0.76 g) , hydroxypropyl cellulose (HPC-L, 0.22 g) , crystalline cellulose (0.26 g) , and magnesium stearate (0.27 g) were blended to produce an outer shell blended powder. The core tablet and 270 mg of the outer shell blended powder were tableted with a 10 πιΐΐΐφ punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki) to produce dry coated tablets (400 mg per tablet) containing compound X hydrochloride (100 mg as compound X) shown in Table 21. [0087]
[Table 21]
Table 21 Composition of one dry coated tablet
Figure imgf000038_0001
[0088]
Example 22
Compound X hydrochloride (97.9 g) , mannitol (329 g) , and polyethylene oxide (PEO-20NF, 44 g) were charged in a fluid bed granulator (MP-01, Powrex Corp.), granulated while spraying purified water, and dried to give a granulated powder. The granulated powder (353.1 g) was blended with polyethylene oxide (PEO-20NF, 33 g) and magnesium stearate (3.9 g) and tableted with a 6.5 ΐΐΐπιφ punch by using a rotary tablet press (Kikusui Seisakusho) to give core tablets (130 mg per tablet) .
Compound X hydrochloride (36.7 g) , mannitol (128.9 g) , and polyethylene oxide (PEO-20NF, 385 g) were charged in a fluid bed granulator (MP-01, Powrex Corp.), granulated while spraying purified water, and dried to give a granulated powder. The 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 blended powder. The core tablet and 270 mg of the outer shell blended powder were tableted with a 10 πιιηφ punch by using a rotary tablet press (Kikusui Seisakusho) to produce dry coated tablets (400 mg per tablet) containing compound X hydrochloride (30 mg as compound X) . The dry coated tablets were charged in a coating pan (DRC-300, Powrex Corp.), and coated by spraying a coating suspension produced by dissolving hydroxypropyl methylcellulose (TC-5E) in purified water and dispersing yellow ferric oxide therein, and dried to produce film-coated dry coated tablets shown in Table 22.
[0089]
[Table 22]
Table 22 Composition of one dry coated tablet
Figure imgf000039_0001
[0090]
Example 23
Compound X hydrochloride (87.3 g) , mannitol (300.7 g) , and polyethylene oxide (PEO-20NF, 36.25 g) were charged in a fluid bed granulator (MP-01, Powrex Corp.), granulated while spraying purified water, and dried to give 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 tableted with a 5.5 miruj) punch by using a rotary tablet press (Kikusui Seisakusho) to give core tablets (93 mg per tablet) .
Compound X hydrochloride (69.84 g) , mannitol (190.2 g) , and polyethylene oxide (PEO-20NF, 260 g) were charged in a fluid bed granulator (MP-1, Powrex Corp.), granulated while spraying purified water, and dried to give a granulated powder. The granulated powder (455 g) was blended with polyethylene oxide (PEO-20NF, 227.5 g) and magnesium stearate (7 g) to produce an outer shell blended powder. The core tablet and 197 mg of the outer shell blended powder were tableted with a 9 mm<|> punch by using a rotary tablet press (Kikusui Seisakusho) to produce dry coated tablets (290 mg per tablet) containing compound X hydrochloride (30 mg as compound X) . The dry coated tablets were charged in a coating pan (DRC-300, Powrex Corp.), and coated by spraying a coating suspension produced by
dissolving hydroxypropyl methyl cellulose (TC-5E) in purified water and dispersing yellow ferric oxide therein, and dried to produce film-coated dry coated tablets shown in Table 23.
[0091]
[Table 23]
■ Table 23 Composition of one dry coated tablet
Figure imgf000040_0001
[0092]
Example 24
Compound X hydrochloride (104.8 g) , mannitol (284.4 g) , and polyethylene oxide (PEO-20NF, 236.1 g) were charged in a fluid bed granulator (MP-01, Powrex Corp.), granulated while spraying purified water, and dried to obtain a granulated powder. The granulated powder (521 g) was blended with polyethylene oxide (PEO-20NF, 196.75 g) and magnesium stearate (7.25 g) , and tableted with a 9 mm<|> punch by using a rotary tablet press (Kikusui Seisakusho) to produce uncoated tablets (290 mg per tablet) containing compound X hydrochloride (30 mg as compound X) . The uncoated tablets were charged in a coating pan (DRC-300, Powrex Corp.), and coated by spraying a coating suspension produced by dissolving hydroxypropyl methyl
cellulose (TC-5E) in purified water and dispersing yellow ferric oxide therein, and dried to produce film-coated single- layered tablets shown in Table 24.
[0093]
[Table 24]
Table 24 Composition of one single-layered tablet
Figure imgf000041_0001
[0094]
Example 25
Compound X hydrochloride (0.815 g) , polyethylene oxide
(Polyox™ WSR 303, 2.3 g) , mannitol (9.855 g) , and magnesium stearate (0.13 g) were blended and tableted with a 7 πΜΐφ punch by using a manual tablet press (HANDTAB, manufactured by
Ichihashi Seiki) to produce core tablets (130 mg per tablet) .
Compound X hydrochloride (0.349 g) , polyethylene oxide (Polyox™ WSR 303, 22 g) , mannitol (4.381 g) , and magnesium stearate (0.27 g) were blended to produce an outer shell blended powder. The core tablet and 270 mg of the outer shell blended powder were tableted with a 10 ιτιιηφ punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki) to produce dry coated tablets (400 mg per tablet) containing compound X hydrochloride (10 mg as compound X) shown in Table 25.
[0095]
[Table 25]
Table 25 Composition of one dry coated tablet
Figure imgf000042_0001
[0096]
Example 26
Compound X hydrochloride (0.582 g) , polyethylene oxide (Polyox™ WSR 303, 1.45 g) , mannitol (7.178 g) , and magnesium stearate (0.09 g) were blended and tableted with a 6 mm<|> punch by using a manual tablet press (HANDTAB, manufactured by
Ichihashi Seiki) to produce core tablets (93 mg per tablet) . Compound X hydrochloride (0.582 g) , polyethylene oxide (Polyox™ WSR 303, 13 g) , mannitol (5.918 g) , and magnesium stearate (0.2 g) were blended to produce an outer shell blended powder. The core tablet and 197 mg of the outer shell blended powder were tableted with a 9 mm§ punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki) to produce dry coated tablets (290 mg per tablet) containing compound X hydrochloride (10 mg as compound X) shown in Table 26.
[0097]
[Table 26]
Table 26 Composition of one dry coated tablet
Figure imgf000043_0001
[0098]
Example 27
Compound X hydrochloride (1.164 g) , polyethylene oxide (Polyox™ WSR 303, 14.5 g) , mannitol (13.046 g) , and magnesium stearate (0.29 g) were blended to produce a powder mixture.
290 mg of the powder mixture was tableted with a 9 mm<j) punch by using a manual tablet press (HANDTAB, manufactured by Ichihashi Seiki) to produce single-layered tablets (290 mg per tablet) containing compound X hydrochloride (10 mg as compound X) shown in Table 27. [0099]
[Table 27]
Table 27 Composition of one single-layered tablet
Figure imgf000044_0001
[0100]
Example 28
Compound X hydrochloride (125.82 g) and mannitol (125.82 g) were blended in a pouch and passed through a 16 mesh sieve. The blended and sieved powder was additionally blended with spray-dried mannitol (297.45 g) , polyethylene oxide (PEO-20NF, 113.22 g) and magnesium stearate (6.69 g) in the pouch and tableted with a 5.5 πκηφ punch by using a rotary tablet press (Kikusui Seisakusho) to give core tablets (92.86 mg per tablet).
Compound X hydrochloride (69.84 g) and mannitol (69.84 g) were blended in a pouch and passed through a 16 mesh sieve.
The blended and sieved powder was additionally blended with spray-dried mannitol (297.45 g) , polyethylene oxide (PEO-20NF, 113.22 g) and magnesium stearate (6.69 g) in the pouch to obtain an outer shell blended powder. The core tablet and
197.14 mg of the outer shell blended powder were tableted with a 9 mrruj) punch by using a rotary tablet press (Kikusui
Seisakusho) to produce dry coated tablets (290 mg per tablet) containing compound X hydrochloride (30 mg as compound X) . The dry coated tablets were charged in a coating pan (HICOATER LABO, Freund Corp.), and coated by spraying a coating suspension produced by dissolving hydroxypropyl methylcellulose (TC-5E) in purified water and dispersing talc and yellow ferric oxide therein, and dried to produce film-coated dry coated tablets shown in Table 28. [0101]
[Table 28]
Table 28 Composition of one dry coated tablet
Figure imgf000045_0001
[0102]
Example 29
Compound X hydrochloride (125.82 g) and mannitol (125.82 g) were blended in a pouch and passed through a 16 mesh sieve. The blended and sieved powder was additionally blended with spray-dried mannitol (297.45 g) , polyethylene oxide (PEO-20NF, 113.22 g) and magnesium stearate (6.69 g) in the pouch and tableted with a 6.5 mm<|) punch by using a rotary tablet press (Kikusui Seisakusho) to give core tablets (130 mg per tablet) .
Compound X hydrochloride (41.88 g) and mannitol (41.88 g) were blended in a pouch and passed through a 16 mesh sieve. The blended and sieved powder was additionally blended with spray-dried mannitol (105.44 g) , polyethylene oxide (PEO-20NF, 880 g) and magnesium stearate (10.8 g) in the pouch to obtain an outer shell blended powder. The core tablet and 270 mg of the outer shell blended powder were tableted with a 10 πιπιφ punch by using a rotary tablet press (Kikusui Seisakusho) to produce dry coated tablets (400 mg per tablet) containing compound X hydrochloride (30 mg as compound X) . The dry coated tablets were charged in a coating pan (HICOATER LABO, Freund Corp.), and coated by spraying a coating suspension produced by dissolving hydroxypropyl methylcellulose (TC-5E) in purified water and dispersing talc and yellow ferric oxide therein, and dried to produce film-coated dry coated tablets shown in Table
[0103]
[Table 29]
Table 29 Composition of one dry coated tablet
Figure imgf000046_0001
[0104]
Example 30
Compound X hydrochloride (104.76 g) and mannitol (104.76 g) were blended in a pouch and passed through a 16 mesh sieve. The blended and sieved powder was additionally blended with spray-dried mannitol (179.58 g) polyethylene oxide (PEO-20NF, 472.20 g) and magnesium stearate (8.7 g) in the pouch and tableted with a 9 mnuj) punch by using a rotary tablet press
(Kikusui Seisakusho) to give uncoated tablets (290 mg per tablet) containing compound X hydrochloride (30 mg as compound X) . The uncoated tablets were charged in a coating pan
(HICOATER LABO, Freund Corp.), and coated by spraying a coating suspension produced by dissolving hydroxypropyl methylcellulose
(TC-5E) in purified water and dispersing talc and yellow ferric oxide therein, and dried to produce film-coated single-layered tablets shown in Table 30.
[0105]
[Table 30]
Table 30 Composition of one single-layered tablet
Figure imgf000047_0001
[0106]
Example 31
Compound X hydrochloride (44.83 g) and mannitol (44.83 g) were blended in a pouch and passed through a 16 mesh sieve.
The blended and sieved powder was additionally blended with spray-dried mannitol (497.2 g) , polyethylene oxide (PEO-20NF, 121 g) and magnesium stearate (7.15 g) in the pouch and
tableted with a 5.5 πιιηφ punch by using a rotary tablet press (Kikusui Seisakusho) to give core tablets (92.86 mg per tablet). Compound X hydrochloride (23.28 g) and mannitol (23.28 g) were blended in a pouch and passed through a 16 mesh sieve. The blended and sieved powder was additionally blended with spray-dried mannitol (214.12 g) , polyethylene oxide (PEO-20NF, 520 g) and magnesium stearate (7.88 g) in the pouch to obtain an outer shell blended powder. The core tablet and 197.14 mg of the outer shell blended powder were tableted with a 9 mm<j> punch by using a rotary tablet press (Kikusui Seisakusho) to produce dry coated tablets (290 mg per tablet) containing compound X hydrochloride (10 mg as compound X) . The dry coated tablets were charged in a coating pan (HICOATER LABO, Freund Corp.), and coated by spraying a coating suspension produced by dissolving hydroxypropyl methyl cellulose (TC-5E) in purified water and dispersing talc and yellow ferric oxide therein, and dried to produce film-coated dry coated tablets shown in Table 31.
[0107]
[Table 31]
Table 31 Composition of one dry coated tablet
Additive Dosage (mg/tablet)
Compound X hydrochloride 5.82
Polyethylene oxide (PEO-20NF) 15.71
Core Mannitol 5.82
tablet Spray-dried mannitol 64.57
Magnesium stearate 0.93
Subtotal (core tablet) 92.86
Compound X hydrochloride 5.82
Polyethylene oxide (PEO-20NF) 130
Outer Mannitol 5.82
shell Spray-dried mannitol 53.53
Magnesium stearate 1.97
Subtotal (outer shell) 197.14
Hydroxypropyl methylcellulose 9.57
Talc 1.74
Film
Yellow ferric oxide 0.29
Subtotal (film) 11.6
Total 301.6 [0108]
Example 32
Compound X hydrochloride (44.83 g) and mannitol (44.83 g) were blended in a pouch and passed through a 16 mesh sieve. The blended and sieved powder was additionally blended with spray-dried mannitol (497.2 g) , polyethylene oxide (PEO-20NF, 121 g) and magnesium stearate (7.15 g) in the pouch and
tableted with a 6.5 mm<j) punch by using a rotary tablet press (Kikusui Seisakusho) to give core tablets (130 mg per tablet) .
Compound X hydrochloride (13.96 g) and mannitol (13.96 g) were blended in a pouch and passed through a 16 mesh sieve. The blended and sieved powder was additionally blended with spray-dried mannitol (161.28 g) , polyethylene oxide (PEO-20NF, 880 g) and magnesium stearate (10.8 g) in the pouch to obtain an outer shell blended powder. The core tablet and 270 mg of the outer shell blended powder were tableted with a 10 πιπιφ punch by using a rotary tablet press (Kikusui Seisakusho) to produce dry coated tablets (400 mg per tablet) containing compound X hydrochloride (10 mg as compound X) . The dry coated tablets were charged in a coating pan (HICOATER LABO, Freund Corp.), and coated by spraying a coating suspension produced by dissolving hydroxypropyl methylcellulose (TC-5E) in purified water and dispersing talc and yellow ferric oxide therein, and dried to produce film-coated dry coated tablets shown in Table 32.
[0109]
[Table 32]
Table 32 Composition of one dry coated tablet
Figure imgf000050_0001
[0110]
5 Example 33
Compound X hydrochloride (34.92 g) and mannitol (34.92 g) were blended in a pouch and passed through a 16 mesh sieve. The blended and sieved powder was additionally blended with spray-dried mannitol (319.26 g) polyethylene oxide (PEO-20NF,
10 472.20 g) and magnesium stearate (8.7 g) in the pouch and
tableted with a 9 πιπιφ punch by using a rotary tablet press (Kikusui Seisakusho) to give uncoated tablets (290 mg per tablet) containing compound X hydrochloride (10 mg as compound X) . The uncoated tablets were charged in a coating pan
15 (HICOATER LABO, Freund Corp.), and coated by spraying a coating suspension produced by dissolving hydroxypropyl methylcellulose (TC-5E) in purified water and dispersing talc and yellow ferric oxide therein, and dried to produce film-coated single-layered tablets shown in Table 33. [0111]
[Table 33]
Table 33 Composition of one single-layered tablet
Figure imgf000051_0001
[0112]
Example 34
Compound X hydrochloride (3422 g) , mannitol (11520 g) , and polyethylene oxide (PEO-20NF, 1540 g) were charged in a fluid bed granulator (FD-WSG-30, Powrex Corp .), granulated while spraying, purified water, and dried to give a granulated powder. The granulation operation was repeated twice and obtained granulated powder (32960 g) was blended with
polyethylene oxide (PEO-20NF, 3080 g) and magnesium stearate (364 g) and tableted with a 6.5 mnj) punch by using' a rotary tablet press (Kikusui Seisakusho) to give core tablets (130 mg per tablet) .
Compound X hydrochloride (1153 g) , mannitol (4050 g) , and polyethylene oxide (PEO-20NF, 12100 g) were charged in a fluid bed granulator (FD-WSG-30, Powrex Corp.), granulated while spraying purified water, 'and dried to give a granulated powder. The granulation operation was repeated twice and obtained granulated powder (34600 g) was blended with polyethylene oxide (PEO-20NF, 24200 g) and magnesium stearate (594 g) to produce an outer shell blended powder. The core tablet and 270 mg of the" outer shell blended powder were tableted with a 10 πιπιφ punch by using a rotary tablet press (HATA TEKKOSHO CO., LTD.) to produce dry coated tablets (400 mg per tablet) containing compound X (30 mg) . The dry coated tablets were charged in a coating pan (DRC-900DS, Powrex Corp.), and coated by spraying a coating suspension produced by dissolving hydroxypropyl methylcellulose (TC-5E) in purified water and dispersing sterile talc and yellow ferric oxide therein, and dried to produce film-coated dry coated tablets shown in Table 34.
[0113]
[Table 34]
Table 34 Composition of one dry coated tablet
Figure imgf000052_0001
[0114]
Example
Compound X hydrochloride (3754 g) , mannitol (12630 g) , and polyethylene oxide (PEO-20NF, 1689 g) were charged in a fluid bed granulator (FD-WSG-30, Powrex Corp.), granulated while spraying purified water, and dried to give a granulated powder. The obtained granulated powder (18070 g) was blended with polyethylene oxide (PEO-20NF, 1689 g) and magnesium stearate (200 g) and tableted with a 5.5 mm<|> punch by using a rotary tablet press (Kikusui Seisakusho) to give core tablets (92.86 mg per tablet).
Compound X hydrochloride (2270 g) , mannitol (6202 g) , and polyethylene oxide (PEO-20NF, 8450 g) were charged in a fluid bed granulator (FD-WSG-30, Powrex Corp.), granulated while spraying purified water, and dried to give a granulated powder. The granulation operation was repeated twice and obtained granulated powder (33840 g) was blended with polyethylene oxide (PEO-20NF, 16900 g) and magnesium stearate (512.2 g) to produce an outer shell blended powder. The core tablet and 197.14 mg of the outer shell blended powder were tableted with a 9 ΐΐΐπιφ punch by using a rotary tablet press (HATA TEKKOSHO CO., LTD.) to produce dry coated tablets (290 mg per tablet) containing compound X (30 mg) . The dry coated tablets were charged in a coating pan (DRC-900DS, Powrex Corp.), and coated by spraying a coating suspension produced by dissolving hydroxypropyl methyl cellulose (TC-5E) in purified water and dispersing sterile talc and yellow ferric oxide therein, and dried to produce film- coated dry coated tablets shown in Table 35.
[0115]
[Table 35]
Table 35 Composition of one dry coated tablet
Figure imgf000053_0001
[0116]
Example 36
Compound X hydrochloride (3492 g) , mannitol (9478 g) , and polyethylene oxide (PEO-20NF, 7870 g) were charged in a fluid bed granulator (FD-WSG-30, Powrex Corp.), granulated while spraying purified water, and dried to give a granulated powder. The granulation operation was repeated twice and obtained granulated powder (41680 g) was blended with polyethylene oxide (PEO-20NF, 15740 g) and magnesium stearate (580 g) and tableted with a 9 ΐϊΐπιφ punch by using a rotary tablet press (Kikusui Seisakusho) to produce uncoated tablets (290 mg per tablet) containing compound X (30 mg) . The uncoated tablets were charged in a coating pan (DRC-900DS, Powrex Corp.), and coated by spraying a coating suspension produced by dissolving
hydroxypropyl methyl cellulose (TC-5E) in purified water and dispersing sterile talc and yellow ferric oxide therein, and dried to produce film-coated single-layered tablets shown in Table 36.
[0117]
[Table 36]
Table 36 Composition of one single-layered tablet
Figure imgf000054_0001
[0118]
Example 37 Compound X hydrochloride (11410 g) , mannitol (564.5 g) , and polyethylene oxide (PEO-20NF, 5132 g) were charged in a fluid bed granulator (FD-WSG-30, Powrex Corp.), granulated while spraying purified water, and dried to give a granulated powder. The obtained granulated powder (17110 g) was blended with mannitol (723.5 g) , polyethylene oxide (PEO-20NF, 188 g) , and magnesium stearate (182 g) and tableted with a 6.5 mmcj) punch by using a rotary tablet press (Kikusui Seisakusho) to give core tablets (130 mg per tablet) .
Compound X hydrochloride (10820 g) , mannitol (535.4 g) , and polyethylene oxide (PEO-20NF, 4866 g) were charged in a fluid bed granulator (FD-WSG-30, Powrex Corp.), granulated while spraying purified water, and dried to give 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 blended powder. The core tablet and 270 mg of the outer shell blended powder were tableted with a 10 ΐΐΐιτιφ punch by using a rotary tablet press (HA A TEKKOSHO CO., LTD.) to produce dry coated tablets (400 mg per tablet) containing compound X (100 mg) . The dry coated tablets were charged in a coating pan (DRC-900DS, Powrex Corp.), and coated by spraying a coating suspension produced by dissolving hydroxypropyl methylcellulose (TC-5E) in purified water and dispersing sterile talc and yellow ferric oxide therein, and dried to produce film-coated dry coated tablets shown in Table 37.
[0119]
[Table 37]
Table 37 Composition of one dry coated tablet
Figure imgf000056_0001
[0120]
Example 38
Compound X hydrochloride (11060 g) , mannitol (547 g) , and polyethylene oxide (PEO-20NF, 4974 g) were charged in a fluid bed granulator (FD-WSG-30, Powrex Corp.), granulated while spraying purified water, and dried to give a granulated powder. The obtained granulated powder (16580 g) was blended with mannitol (682.3 g) , polyethylene oxide (PEO-20NF, 232.4 g) , and magnesium stearate (176.7 g) and tableted with a 6 ιηιηφ punch by using a rotary tablet press (Kikusui Seisakusho) to give core tablets (93 mg per tablet) .
Compound X hydrochloride (11060 g) , mannitol (547 g) , and polyethylene oxide (PEO-20NF, 4974 g) were charged in a fluid bed granulator (FD-WSG-30, Powrex Corp.), granulated while spraying purified water, and dried to give 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 blended powder. The core tablet and 197 mg of the outer shell blended powder were tableted with a 9 ιταηφ punch by using a rotary tablet press (HATA TEKKOSHO CO., LTD.) to produce dry coated tablets (290 mg per tablet) containing compound X (100 mg) .
The dry coated tablets were charged in a coating pan (DRC-900DS, Powrex Corp.), and coated by spraying a coating suspension produced by dissolving hydroxypropyl methylcellulose (TC-5E) in purified water and dispersing sterile talc and yellow ferric oxide therein, and dried to produce film-coated dry coated tablets shown in Table 38.
[0121]
[Table 38]
Table 38 Composition of one dry coated tablet
Figure imgf000057_0001
[0122]
Example 39
Compound X hydrochloride (13970 g) , mannitol (691.1 g) , and polyethylene oxide (PEO-20NF, 6282 g) were charged in a fluid bed granulator (FD-WSG-30, Powrex Corp.), granulated while spraying purified water, and dried to give a granulated powder. The obtained granulated powder (20940 g) was blended with mannitol (904.9 g) , polyethylene oxide (PEO-20NF, 12610 g) , and magnesium stearate (348 g) and tableted with a 9 Γηιηφ punch by using a rotary tablet press (Kikusui Seisakusho) to produce uncoated tablets (290 mg per tablet) containing compound X (100 mg) . The uncoated tablets were charged in a coating pan (DRC- 900DS, Powrex Corp.), and coated by spraying a coating
suspension produced by dissolving hydroxypropyl methylcellulose (TC-5E) in purified water and dispersing sterile talc and yellow ferric oxide therein, and dried to produce film-coated single-layered tablets shown in Table 39.
[0123]
[Table 39]
Table 39 Composition of one single-layered tablet
Figure imgf000058_0001
[0124]
Experimental Example 1
The dissolution property of the preparations obtained in Examples 1, 2, 4, and 5 was evaluated by the Paddle Method (the Japanese Pharmacopoeia dissolution test, 2nd fluid, 50 rpm, 900 mL) . The results are shown in Table 1.
[0125]
Experimental Example 2
The dissolution property of the preparations obtained in Examples 2, 3, 6, 9, 10, and 11 was evaluated by the Paddle Method (the Japanese Pharmacopoeia dissolution test, 2nd fluid,
50 rpm, 900 mL) . The results are shown in Table 2.
[0126]
Experimental Example 3
The dissolution property of the preparations obtained in
Examples 7, 8, and 9 was evaluated by the Paddle Method (the Japanese Pharmacopoeia dissolution test, 2nd fluid, 50 rpm, 900 mL) . The results are shown in Table 3.
[0127]
Experimental Example 4
The dissolution property of the preparations obtained in
Examples 9 and 12 was evaluated by the Paddle Method (the
Japanese Pharmacopoeia dissolution test, 2nd fluid, 50 rpm, 900 mL) . The results are shown in Table 4.
[0128]
Experimental Example 5
The dissolution property of the preparation obtained in
Example 13 was evaluated by the Paddle Method (the Japanese
Pharmacopoeia dissolution test, 2nd fluid, 50 rpm, 900 mL) . The results are shown in Table 5.
[0129]
Experimental Example 6
The dissolution property of the preparations obtained in Examples 14, 15, 16, 17, 18, and 19 was evaluated by the Paddle Method (the Japanese Pharmacopoeia dissolution test, 2nd fluid, 50 rpm, 900 mL) . The results are shown in Table 6.
[0130]
Experimental Example 7
The dissolution property of the preparation obtained in Example 20 was evaluated by the Paddle Method (the Japanese Pharmacopoeia dissolution test, 2nd fluid, 50 rpm, 900 mL) .
The results are shown in Table 7.
[0131]
Experimental Example 8
The dissolution property of the preparation obtained in Example 21 was evaluated by the Paddle Method (the Japanese Pharmacopoeia dissolution test, 2nd fluid, 50 rpm, 900 mL) . The results are shown in Table 8.
[0132]
5 Experimental Example 9
The dissolution property of the preparations obtained in Examples 22, 23, and 24 was evaluated by the Paddle Method (the Japanese Pharmacopoeia dissolution test, 2nd fluid, 50 rpm, 900 mL) . The results are shown in Table 9.
10 [0133]
Experimental Example 10
The dissolution property of the preparations obtained in Examples 25, 26, and 27 was evaluated by the Paddle Method (the Japanese Pharmacopoeia dissolution test, 2nd fluid, 50 rpm, 900 15 mL) . The results are shown in Table 10.
[0134]
Experimental Example 11
The dissolution property of the preparations obtained in Examples 34, 35, and 36 was evaluated by the Paddle Method (the 20 Japanese Pharmacopoeia dissolution test, 2nd fluid, 100 rpm, 900 mL) . The results are shown in Table 11.
[0135]
Experimental Example 12
The dissolution property of the preparations obtained in 25 Examples 37, 38, and 39 was evaluated by the Paddle Method (the Japanese Pharmacopoeia dissolution test, 2nd fluid, 100 rpm, 900 mL) . The results are shown in Table 12.
[0136]
This application is based on a patent application No. 30 2015-252657 filed in Japan, the contents of which are
incorporated in full herein.

Claims

Claims
1. A solid preparation comprising N-methyl-N- ( 1-methylethyl) - 6, 7, 8, 9-tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof, and a hydrophilic gel-forming polymer.
2. The solid preparation of claim 1, comprising (1) a core comprising N-methyl-N- (1-methylethyl) -6, 7,8,9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof, and a first hydrophilic gel-forming polymer; and (2) an outer shell comprising N-methyl-N- ( 1-methylethyl ) - 6, 7, 8, 9-tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof, and a second hydrophilic gel-forming polymer.
3. The solid preparation of 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, hydroxypropyl methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, carboxyvinyl polymer, methyl cellulose, and sodium carboxymethyl cellulose.
4. The solid preparation of claim 2, wherein, in the
preparation, the content of N-methyl-N- (1-methylethyl) -6, 7, 8, 9- tetrahydropyrazino [2, 3-f] [1, 4] oxazepin-3-amine or a salt thereof in the core is the same as or higher than the content of N-methyl-N- (1-methylethyl) -6,7,8, 9-tetrahydropyrazino [2,3- f] [1, 4] oxazepin-3-amine or a salt thereof in the outer shell.
PCT/JP2016/089222 2015-12-24 2016-12-21 Solid preparation Ceased WO2017111178A1 (en)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09143073A (en) 1995-11-28 1997-06-03 Bayer Yakuhin Kk Prolonged action nifedipine preparation
EP1337518A1 (en) * 2000-11-20 2003-08-27 Biovitrum Ab Piperazinylpyrazines compounds as antagonists of serotonin 5-ht2 receptor
JP2004002348A (en) 2002-03-27 2004-01-08 Bayer Yakuhin Ltd Miniaturized nifidipine nucleated tablet
EP1591120A1 (en) * 2003-01-28 2005-11-02 Takeda Chemical Industries, Ltd. Receptor agonists
JP2009120600A (en) 2007-10-25 2009-06-04 Bayer Yakuhin Ltd Nifedipine-containing nucleated tablet and method for producing the same
US20100317651A1 (en) * 2009-06-15 2010-12-16 Takeda Pharmaceutical Company Limited Pyrazinooxazepine derivatives

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09143073A (en) 1995-11-28 1997-06-03 Bayer Yakuhin Kk Prolonged action nifedipine preparation
EP1337518A1 (en) * 2000-11-20 2003-08-27 Biovitrum Ab Piperazinylpyrazines compounds as antagonists of serotonin 5-ht2 receptor
JP2004002348A (en) 2002-03-27 2004-01-08 Bayer Yakuhin Ltd Miniaturized nifidipine nucleated tablet
EP1591120A1 (en) * 2003-01-28 2005-11-02 Takeda Chemical Industries, Ltd. Receptor agonists
JP2009120600A (en) 2007-10-25 2009-06-04 Bayer Yakuhin Ltd Nifedipine-containing nucleated tablet and method for producing the same
US20100317651A1 (en) * 2009-06-15 2010-12-16 Takeda Pharmaceutical Company Limited Pyrazinooxazepine derivatives
WO2010147226A1 (en) 2009-06-15 2010-12-23 Takeda Pharmaceutical Company Limited Pyrazinooxazepine derivatives

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