US20120282191A1 - Orally dispersible tablet - Google Patents

Orally dispersible tablet Download PDF

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Publication number
US20120282191A1
US20120282191A1 US13/261,266 US201213261266A US2012282191A1 US 20120282191 A1 US20120282191 A1 US 20120282191A1 US 201213261266 A US201213261266 A US 201213261266A US 2012282191 A1 US2012282191 A1 US 2012282191A1
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US
United States
Prior art keywords
preparation
oral
medicament
administration
bipolar disorder
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.)
Abandoned
Application number
US13/261,266
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English (en)
Inventor
Yutaka Tanoue
Tetsuya Matsuura
Yutaka Yamagata
Naoki Nagahara
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=45567081&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20120282191(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Takeda Pharmaceutical Co Ltd filed Critical Takeda Pharmaceutical Co Ltd
Priority to US13/491,887 priority Critical patent/US8426461B2/en
Assigned to TAKEDA PHARMACEUTICAL COMPANY LIMITED reassignment TAKEDA PHARMACEUTICAL COMPANY LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MATSUURA, TETSUYA, NAGAHARA, NAOKI, YAMAGATA, YUTAKA, TANOUE, YUTAKA
Priority to US13/557,794 priority patent/US20130060052A1/en
Priority to US13/647,784 priority patent/US8642648B2/en
Priority to US13/647,788 priority patent/US8642649B2/en
Publication of US20120282191A1 publication Critical patent/US20120282191A1/en
Priority to US14/168,392 priority patent/US20140235709A1/en
Priority to US14/168,400 priority patent/US20140235879A1/en
Priority to US15/355,357 priority patent/US20170065553A1/en
Abandoned legal-status Critical Current

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    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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
    • 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
    • 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
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • 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
    • 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
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61K9/2063—Proteins, e.g. gelatin
    • 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
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical

Definitions

  • the present invention relates to a preparation with improved disintegration property, a preparation with improved bioavailability of medicament, production methods thereof and the like.
  • Patent document 1 discloses a tablet containing sugar alcohol or saccharide having an average particle size of 30 ⁇ m or below, an active ingredient and a disintegrant, and a production method of a tablet comprising compression molding a mixture containing sugar alcohol or sugar having an average particle size of 30 ⁇ m or below, an active ingredient and a disintegrant.
  • Patent document 2 discloses an orally dispersible solid pharmaceutical composition of agomelatine, which contains agomelatine and granules of simultaneously-dried lactose and starch.
  • Patent document 3 discloses an orally dispersible, coated solid pharmaceutical composition of agomelatine, which contains a central core or a central layer comprising agomelatine and excipients allowing an orally dispersible formulation to be obtained, and an orally dispersible coating.
  • patent documents 1-3 do not disclose improvement of preparation characteristics such as disintegration property and the like by enclosing components such as masking agent, binder and the like that prevent disintegration in granules.
  • An object of the present invention is to provide a novel formulation technique capable of improving disintegration property.
  • another object of the present invention is to provide a preparation useful as an orally rapidly disintegrating preparation.
  • an object of the present invention is to provide a preparation capable of promoting medicament absorption from the oral mucosa by rapid disintegration after sublingual administration, and improving the medicament bioavailability.
  • the present inventors have conducted intensive studies in an attempt to solve the aforementioned problems and found that the disintegration property of a medicament can be improved and the bioavailability thereof can also be improved by containing a component that prevents disintegration (masking agent, binder and the like) as a granulation component in granules, and formulating the preparation after coating a surface of the granule with sugar or sugar alcohol, which resulted in the completion of the present invention.
  • a component that prevents disintegration massaging agent, binder and the like
  • the present invention provides the following.
  • the “rapidly disintegrating preparation” of the present invention is also superior as a preparation for allowing absorption of a medicament from the oral mucosa. Specifically, it is as described below.
  • a rapidly disintegrating preparation superior in the disintegration property a preparation with improved medicament bioavailability and production methods thereof and the like can be provided.
  • the rapidly disintegrating preparations [1] to [7] of the present invention contain a medicament in granules, and a disintegrant as an extragranule component. Even when a medicament (e.g., compound A etc.) with poor compatibility with the disintegrant is to be used, therefore, an influence of the disintegrant on the medicament can be reduced, thus improving the stability of the medicament.
  • a medicament e.g., compound A etc.
  • the rapidly disintegrating preparation of the present invention can improve disintegration property by enclosing a component that prevents disintegration (e.g., masking agent, binder etc.) in granules. In addition, it can achieve high disintegration property by ensuring the invasion route of water into the preparation by coating the component that prevents disintegration with sugar or sugar alcohol. Moreover, in the rapidly disintegrating preparation of the present invention, a medicament is coated with sugar or sugar alcohol. Therefore, the dissolution property of the medicament from the preparation can be improved even when the medicament has high surface hydrophobicity, by altering the surface to be hydrophilic.
  • a component that prevents disintegration e.g., masking agent, binder etc.
  • the rapidly disintegrating preparation of the present invention can achieve both the good disintegration property and the good preparation hardness.
  • the rapidly disintegrating preparations [1] to [7] of the present invention the rapidly disintegrating
  • preparations [5] to [7] for oral-mucosal absorption of the present invention are expected to provide an immediate effect by absorption of the medicament from the oral mucosa.
  • the rapidly disintegrating preparation for oral-mucosal absorption of the present invention can improve bioavailability by increasing the blood concentration of a medicament (e.g., compound A etc.) susceptible to a first pass effect by oral administration.
  • a medicament e.g., compound A etc.
  • the rapidly disintegrating preparation for oral-mucosal absorption of the present invention can suppress inconsistent absorption of such medicaments, and further, inconsistent effectiveness as medicaments.
  • the rapidly disintegrating preparation for oral-mucosal absorption of the present invention can afford a low dose medicament and a compact preparation based on the improved medicament bioavailability.
  • the rapidly disintegrating preparations [1] to [7] of the present invention having the above-mentioned effects can be produced.
  • the rapidly disintegrating preparation of the present invention contains granules comprising a medicament coated with a coating layer containing sugar or sugar alcohol, and a disintegrant.
  • the medicament to be used in the present invention is not particularly limited, for example, antipyretic analgesic antiphlogistic drugs, antipsychotic drugs, antianxiety drugs, antidepressant drugs, sedative-hypnotic drugs, gastrointestinal drugs, antacid drugs, antitussive expectorant drugs, antihypertensive agents, drugs for diabetes, drugs for osteoporosis, skeleton muscle relaxants, anti-cancer agents and the like can be recited.
  • the content of the medicament is generally 0.03-50 wt %, preferably 0.03-20 wt %, more preferably 0.03-3 wt %, relative to the total weight of the preparation.
  • the rapidly disintegrating preparation of the present invention contains a disintegrant as an extragranule component, and therefore, an influence of the disintegrant on the medicament can be reduced even when a medicament having poor compatibility with the disintegrant is used, and the medicament stability can be improved.
  • the present invention is particularly effective when a medicament having poor compatibility with the disintegrant (e.g. compound A, etc) is used as a medicament.
  • Compound A is a known therapeutic agent for sleep disorders, which is disclosed in U.S. Pat. No. 6,034,239 and the like, and can be produced by a known method such as the method described in this document and the like.
  • an excipient is contained in granules comprising a medicament coated with a coating layer containing sugar or sugar alcohol.
  • excipient examples include starches such as corn starch and the like; sugar or sugar alcohols such as lactose, fructose, glucose, mannitol (e.g., D-mannitol), sorbitol (e.g., D-sorbitol), erythritol (e.g., D-erythritol), sucrose and the like: anhydrous calcium phosphate, microcrystalline cellulose, micromicrocrystalline cellulose, powdered glycyrrhiza, sodium hydrogen carbonate, calcium phosphate, calcium sulfate, calcium carbonate, precipitated calcium carbonate, calcium silicate and the like, and corn starch, D-mannitol and microcrystalline cellulose are preferable.
  • sugar or sugar alcohols such as lactose, fructose, glucose, mannitol (e.g., D-mannitol), sorbitol (e.g., D-sorbitol), erythritol (e.g.
  • the content of the excipient is generally 13-94 wt %, preferably 54-94 wt %, more preferably 81-93 wt %, relative to the total weight of the preparation.
  • the rapidly disintegrating preparation of the present invention may further contain an additive, where necessary, in the granules comprising a medicament.
  • Examples of the additive optionally contained in the granules comprising a medicament include binder, masking agent, solubilizer and the like, which may be used in combination where necessary.
  • binder examples include starches such as potato starch, wheat starch, rice starch, partly pregelatinized starch, pregelatinized starch, porous starch and the like, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gelatin, starch, gum arabic powder, tragacanth, carmellose, sodium alginate, pullulan, glycerol and the like, and partly pregelatinized starch, hydroxypropylcellulose and pregelatinized starch are preferable.
  • starches such as potato starch, wheat starch, rice starch, partly pregelatinized starch, pregelatinized starch, porous starch and the like, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gelatin, starch, gum arabic powder, tragacanth, carmellose, sodium alginate, pullulan, glycerol and the like, and partly pregelatinized starch, hydroxypropylcellulose and
  • the content of the binder is generally 0.5-20 wt %, preferably 0.5-15 wt %, more preferably 1-10 wt %, relative to the total weight of the preparation.
  • the masking agent examples include various flavoring agents (thaumatin, sucralose, saccharin, aspartame, xylitol, citric acid, L-sodium glutamate etc.), various receptor antagonists (BENECOAT, sodium chloride etc.), various cation channel antagonists (L-arginine etc.), various clathration agents ( ⁇ -cyclodextrin, ⁇ -cyclodextrin etc.), various flavors (strawberry flavor, mint flavor, orange flavor, vanillin etc.) and the like. Two or more thereof may be used in combination where necessary.
  • the content of the masking agent is generally 0.01-10 wt %, preferably 0.01-5 wt %, more preferably 0.01-1 wt %, relative to the total weight of the preparation.
  • solubilizer examples include various aqueous solvents (polyethylene glycol, propylene glycol, glycerol etc.), various clathration agents ( ⁇ -cyclodextrin, ⁇ -cyclodextrin etc.), various surfactants (sodium lauryl sulfate, polysorbate 80, polyoxyethylene(160)polyoxypropylene(30)glycol etc.) and the like. Two or more thereof may be used in combination where necessary.
  • aqueous solvents polyethylene glycol, propylene glycol, glycerol etc.
  • various clathration agents ⁇ -cyclodextrin, ⁇ -cyclodextrin etc.
  • surfactants sodium lauryl sulfate, polysorbate 80, polyoxyethylene(160)polyoxypropylene(30)glycol etc.
  • the content of the solubilizer is generally not more than 20 wt %, preferably not more than 15 wt %, more preferably not more than 10 wt %, relative to the total weight of the preparation.
  • disintegration property can be improved by including a component that prevents disintegration (e.g., masking agent, binder, solubilizer etc.) in granules.
  • a component that prevents disintegration e.g., masking agent, binder, solubilizer etc.
  • the preparation can achieve high disintegration property by ensuring the invasion route of water into the preparation by coating the component that prevents disintegration with sugar or sugar alcohol.
  • the rapidly disintegrating preparation of the present invention contains sugar or sugar alcohol in a coating layer formed on the granules comprising a medicament.
  • sugar or sugar alcohol examples include lactose, fructose, glucose, mannitol (e.g., D-mannitol), sorbitol (e.g., D-sorbitol), erythritol (e.g., D-erythritol); sucrose and the like, and D-mannitol is preferable.
  • the preparation can achieve high disintegration property by ensuring the invasion route of water into the preparation by coating the granules comprising a medicament with sugar or sugar alcohol.
  • the dissolution property of the medicament from the preparation can be improved.
  • the content of the sugar contained in the coating layer is generally 5-20 wt %, preferably 5-15 wt %, more preferably 5-10 wt %, relative to the total weight of the preparation.
  • the content of the sugar alcohol contained in the coating layer is generally 5-20 wt %, preferably 5-15 wt %, more preferably 5-10 wt %, relative to the total weight of the preparation.
  • the content of the sugar and sugar alcohol contained in the coating layer is generally 5-20 wt %, preferably 5-15 wt %, more preferably 5-10 wt %, relative to the total weight of the preparation.
  • the rapidly disintegrating preparation of the present invention may further contain an additive in the coating layer as necessary.
  • excipient examples include starches such as corn starch and the like; anhydrous calcium phosphate, microcrystalline cellulose, micromicrocrystalline cellulose, powdered glycyrrhiza, sodium hydrogen carbonate, calcium phosphate, calcium sulfate, calcium carbonate, precipitated calcium carbonate, calcium silicate and the like, and corn starch and microcrystalline cellulose are preferable.
  • disintegrant examples include amino acid, starch, corn starch, carmellose, carmellose sodium, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropyl starch, sodium carboxymethyl starch and the like, and crospovidone and carmellose are preferable.
  • the average particle size of the “granules comprising a medicament coated with a coating layer containing sugar or sugar alcohol” is generally 50 ⁇ m-500 ⁇ m, preferably 50 ⁇ m-355 ⁇ m, more preferably 50 ⁇ m-150 ⁇ m.
  • the average particle size is a value measured by a laser diffraction particle size analyzer, SYMPATEC: HELOS&RODOS and the like.
  • examples of the disintegrant contained as an extragranule component include amino acid, starch, corn starch, carmellose, carmellose sodium, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropyl starch, sodium carboxymethyl starch and the like, and crospovidone and carmellose are preferable.
  • the content of the disintegrant is generally 0.5-15 wt %, preferably 1-10 wt %, more preferably 2-5 wt %, relative to the total weight of the preparation.
  • examples of the lubricant optionally contained as an extragranule component include magnesium stearate, stearic acid, calcium stearate, talc (purified talc), sucrose esters of fatty acid, sodium stearyl fumarate and the like, and sodium stearyl fumarate is preferable.
  • the content of the lubricant is generally 0.5-2 wt %, preferably 0.5-1.5 wt %, more preferably 0.5-1 wt %, relative to the total weight of the preparation.
  • the rapidly disintegrating preparation of the present invention may further contain an additive as an extragranule component where necessary.
  • additive examples include masking agent, solubilizer and the like, explained above, which may be used in combination where necessary.
  • the rapidly disintegrating preparation of the present invention is not only useful as a so-called “orally disintegratable preparation” aiming at oral administration of a medicament, but also preferable as a preparation for oral-mucosal absorption (particularly, sublingual preparation, buccal preparation).
  • the rapidly disintegrating preparation for oral-mucosal absorption of the present invention can be expected to show immediate effect by absorption from the oral mucosa.
  • the rapidly disintegrating preparation for oral-mucosal absorption of the present invention is particularly effective when a medicament (e.g., compound A etc.) susceptible to a first pass effect by oral administration is used.
  • the rapidly disintegrating preparation for oral-mucosal absorption of the present invention can improve bioavailability by increasing the blood concentration of such medicament.
  • the rapidly disintegrating preparation for oral-mucosal absorption of the present invention can suppress inconsistent absorption of such medicaments, and further, inconsistent effectiveness as medicaments.
  • the rapidly disintegrating preparation for oral-mucosal absorption of the present invention can afford a low dose medicament and a compact preparation based on the improved medicament bioavailability.
  • the rapidly disintegrating preparation for oral-mucosal absorption of the present invention shows an effect in that the ratio of the medicament in an unchanged form and a metabolite of the medicament after transfer into blood is higher than that by oral administration.
  • the rapidly disintegrating preparation for oral-mucosal absorption of the present invention shows not less than about 10-fold improved bioavailability of compound A, as compared to that by oral administration.
  • the dosage form of the rapidly disintegrating preparation of the present invention is not particularly limited, it is preferably a tablet.
  • the weight of the preparation is preferably about 20-200 mg.
  • the absolute hardness is generally not less than 1.0 N/mm 2 , preferably not less than 1.5 N/mm 2 , more preferably not less than 2.0 N/mm 2 .
  • the absolute hardness is generally not more than 5.0 N/mm 2 .
  • the disintegration time is generally not more than 30 sec, preferably not more than 15 sec, more preferably not more than 10 sec.
  • the disintegration time is generally not less than 1 sec.
  • the disintegration property can be improved by including, in granules, a component that prevents disintegration, as described above.
  • it can achieve high disintegration property by ensuring the invasion route of water into the preparation by coating the component that prevents disintegration with sugar or sugar alcohol. Therefore, even when the rapidly disintegrating preparation of the present invention is molded to have the above-mentioned high absolute hardness, it shows good disintegration property.
  • the rapidly disintegrating preparation of the present invention can achieve both the good disintegration property and the good preparation hardness.
  • the rapidly disintegrating preparation of the present invention preferably shows a disintegration time of not more than 30 sec, and absolute hardness of not less than 1.0 N/mm 2 .
  • the rapidly disintegrating preparation of the present invention can be produced by a method conventionally used in the pharmaceutical-technical field.
  • the preparation can be produced by the following production method of the rapidly disintegrating preparation of the present invention.
  • the production method of the rapidly disintegrating preparation of the present invention includes
  • an additive may be further added as necessary.
  • the kind and amount of the “medicament”, “sugar”, “sugar alcohol”, “disintegrant” and “additive” to be used in steps (1)-(3) those exemplified for the above-mentioned rapidly disintegrating preparation can be mentioned.
  • the particle size of the coated granules obtained in step (2) the range exemplified as the particle size of the “granules comprising a medicament coated with a coating layer containing sugar or sugar alcohol” of the above-mentioned rapidly disintegrating preparation can be mentioned.
  • step (1) The production of the granule in step (1) and formation of the coating layer in step (2) can also be carried out simultaneously.
  • the preparation can be specifically produced as follows.
  • Sugar or sugar alcohol e.g., D-mannitol etc.
  • a suitable solvent e.g., water etc.
  • a medicament e.g., compound A etc.
  • any additive e.g., excipient such as D-mannitol, microcrystalline cellulose and the like, binder such as partly pregelatinized starch and the like etc.
  • excipient such as D-mannitol, microcrystalline cellulose and the like
  • binder such as partly pregelatinized starch and the like etc.
  • the obtained mixture is granulated while spraying the coating solution thereon, and dried to give a granulated powder (coated granules).
  • the obtained granulated powder (coated granules) may be sieved as necessary.
  • the obtained coated granules, a disintegrant (e.g., crospovidone etc.) and any additive (e.g., lubricant such as sodium stearyl fumarate etc., and the like) are mixed to give a mixed powder.
  • the obtained mixed powder is compression-molded to give a tablet.
  • the mixing is carried out by using a preparation machine, for example, V-type mixer, tumbler mixer (TM-30, TM-15S; SHOWA KAGAKU KIKAI CO., LTD.: TM20-0-0; Suehiro Kakoki Co., Ltd.), high speed mixer granulator (FM-VG-10; POWREX CORPORATION), universal kneader (HATA IRON WORKS CO., LTD.), fluid bed dryer granulator (LAB-1, FD-3S, FD-3SN, FD-5S; POWREX CORPORATION), box type vacuum dryer (Kusuki Kikai Seisakusho), power mill grinding machine (P-3, SHOWA KAGAKU KIKAI CO., LTD.), centrifugation rolling granulator (CF-mini, CF-260, CF-360; Freund Corporation), dry type granulator, spray-drying granulator, rolling granulator (MP-10
  • Coating is carried out by using, for example, a preparation machine, for example, centrifugation rolling granulator (CF-mini, CF-260, CF-360; Freund Corporation), rolling granulator (MP-10; POWREX CORPORATION), general fluidized bed coater, wurster-type coater and the like.
  • a preparation machine for example, centrifugation rolling granulator (CF-mini, CF-260, CF-360; Freund Corporation), rolling granulator (MP-10; POWREX CORPORATION), general fluidized bed coater, wurster-type coater and the like.
  • Compression molding is carried out by using, for example, single punch tableting machine (Kikusui Seisakusho Ltd.), rotary tableting machine (AQUARIUS 36K, AQUARIUS 2L; Kikusui Seisakusho Ltd.), AUTOGRAPH (AG-5000B, SHIMADZU Corporation) and the like, and by punching generally at a pressure of 1-30 kN.
  • single punch tableting machine Kikusui Seisakusho Ltd.
  • rotary tableting machine AQUARIUS 36K, AQUARIUS 2L; Kikusui Seisakusho Ltd.
  • AUTOGRAPH AG-5000B, SHIMADZU Corporation
  • the present invention also relates to a preparation for oral-mucosal absorption containing compound A as a medicament; which shows a higher ratio of the medicament in an unchanged form and a metabolite of the medicament after transfer into blood than that by oral administration (preparations [9] to [11], [17] and [18]) (hereinafter sometimes to be abbreviated as preparation (A) of the present invention).
  • the disintegration time is preferably not more than 30 sec.
  • the disintegration time is not more than 30 sec, and the absolute hardness is not less than 1.0 N/mm 2 .
  • the present invention also relates to a preparation for oral-mucosal absorption, which contains compound A, and shows not less than about 10-fold improved bioavailability of compound A, as compared to that by oral administration (preparations [12] to [18]) (hereinafter sometimes to be abbreviated as preparation (B) of the present invention).
  • preparation (B) hereinafter sometimes to be abbreviated as preparation (B) of the present invention.
  • “about” means 5% error range.
  • the bioavailability is generally improved within the range of not more than about 30-fold, more specifically not more than about 20-fold.
  • the disintegration time is not more than 30 sec.
  • the disintegration time is not more than 30 sec, and the absolute hardness is not less than 1.0 N/mm 2 .
  • Each preparation is administered intravenously, orally or oral-mucosally, the plasma concentration after lapse of each time period is measured, and the area under the plasma concentration time curve (AUC) is calculated according to the trapezoidal rule.
  • AUC area under the plasma concentration time curve
  • BA bioavailability
  • BA (%) (oral or oral-mucosal administration AUC/ intravenous administration AUC ) ⁇ 100.
  • the ratio of the calculated BA by oral-mucosal administration relative to the calculated BA by oral administration is calculated.
  • the preparation is evaluated to show “not less than about 10-fold improved bioavailability of compound A as compared to that by oral administration”.
  • the present invention also relates to a preparation for oral-mucosal absorption, which contains compound A and shows a higher ratio of a medicament in an unchanged form and a metabolite of the medicament after transfer into blood than that by oral administration (preparations [9] to [11]) (hereinafter sometimes to be abbreviated as preparation (C) of the present invention).
  • the “greater than the ratio” specifically means not less than about 5-fold, preferably not less than about 10-fold. It is generally not more than about 30-fold, more specifically not more than about 20-fold.
  • “about” means 5% error range.
  • the disintegration time is not more than 30 sec.
  • disintegration time is not more than 30 sec, and the absolute hardness is not less than 1.0 N/mm 2 .
  • Each preparation is administered orally or oral-mucosally, the plasma concentration of both the unchanged form and metabolite after lapse of each time period is measured, and the area under the plasma concentration time curve (AUC) of the both is calculated according to the trapezoidal rule.
  • the ratio of the unchanged form and metabolite (i.e., AUC of unchanged form/AUC of metabolite) in each preparation is calculated.
  • the ratio by oral-mucosal administration is higher than that by oral administration, it is evaluated “the ratio of a medicament in an unchanged form and a metabolite of the medicament after transfer into blood is higher than that by oral administration”.
  • preparation (A), preparation (B) and preparation (C) are not particularly limited as long as they can be administered from the oral mucosa.
  • tablet e.g., sublingual tablet, buccal tablet
  • film e.g., film, troche, solution, suspension, freeze-dried preparation, chewing gum, spray and the like can be mentioned.
  • tablet is preferable.
  • the absolute hardness is hardness per unit area, and is defined according to the following formula.
  • the tablet hardness can be measured by a tablet hardness tester (TH-303MP, Toyama Sangyo CO., LTD.).
  • the disintegration time is a value measured by a disintegration tester (ODT-101, Toyama Sangyo CO., LTD.) for orally rapidly disintegrating tablet.
  • Preparations (A)-(C) can be produced, for example, according to the production method explained for “the rapidly disintegrating preparation of the present invention”. Particularly, when the dosage form of preparations (A)-(C) is tablet, such production method is preferable. It is also possible to apply other techniques for orally disintegrating preparations.
  • the preparations can be produced according to a conventional method as follows.
  • the preparation can be produced by applying or spraying a coating solution (solution or suspension, solvent is, for example, purified water) containing a medicament, a film carrier, other film carriers used as necessary and the like to the surface of a support medium, and drying same (JP-B-3460538).
  • a coating solution solution or suspension, solvent is, for example, purified water
  • the preparation can be produced according to a conventional method as follows.
  • the preparation can be produced by mixing a medicament, a polymer, sugars and the like, and dissolving and lyophilizing them (Manufacturing Chemist, February 36 (1990)).
  • the preparation can be produced according to a conventional method as follows.
  • the preparation can be produced by adding a medicament, additive such as sweetener, flavor, colorant, softening agent, flavoring substance and the like to a gum base containing a resin for a gum base as a main component, wax, an emulsifier and a filler, uniformly kneading them in a kneader, and processing them into a plate form, a block form and the like (JP-A-2009-136240).
  • the preparation can be produced according to a general production method of tablets.
  • the preparation can be produced according to a. general production method of liquids.
  • the preparation can be produced according to a general production method of spray.
  • the preparation of the present invention can be safely administered to a mammal (e.g., human, mouse, rat, rabbit, dog, cat, bovine, horse, swine, monkey), particularly human.
  • a mammal e.g., human, mouse, rat, rabbit, dog, cat, bovine, horse, swine, monkey
  • the dose of the preparation of the present invention varies depending on the subject of administration, administration route, disease and the like.
  • the dose of compound A is about 0.0002—about 0.02 mg/kg body weight, preferably about 0.0002—about 0.01 mg/kg body weight, more preferably about 0.0002—about 0.005 mg/kg body weight, most preferably about 0.0002—about 0.004 mg/kg body weight, which can be administered in one to several portions a day.
  • Compound A is a superior melatonin receptor agonist; and considered to be effective for the prophylaxis or treatment of diseases possibly influenced by melatonin. In fact, compound A is suggested to be effective for the treatment of bipolar disorders (particularly maintenance of remission phase) in the clinical evaluation by oral administration.
  • the present invention provides a preparation showing superior absorption of compound A from the oral mucosa and improved bioavailability thereof. Hence, a more effective method for the prophylaxis and/or treatment of bipolar disorders, and a more effective drug for the prophylaxis and/or treatment of bipolar disorders are provided.
  • the bipolar disorders can be prevented and/or treated.
  • prophylaxis and/or treatment can be performed by appropriately administering the preparation of the present invention to humans.
  • the administration route of compound A is preferably sublingual administration or buccal administration, and sublingual administration is particularly preferable.
  • a tablet containing 0.05-1.5 mg (preferably, 0.05-1.0 mg, more preferably, 0.1-1.0 mg, and most preferably, 0.1 mg, 0.4 mg and 0.8 mg) of compound A per tablet is preferably administered to patients in one to three portions (preferably once) per day.
  • bipolar disorder I As the target disease, it is particularly effective for bipolar disorder I. Specifically, it is effective for the “treatment of depression symptoms (particularly, acute depression symptoms) associated with bipolar disorder” and “maintenance of remission phase of bipolar disorder”.
  • medicaments for the prophylaxis and/or treatment of bipolar disorders may be used in combination.
  • Such other medicaments for the prophylaxis and/or treatment of bipolar disorders to be used in combination with “compound A” may include mood stabilizer (e.g. lithium, valproic acid, carbamazepine, lamotrigine, etc) and antipsychotics (e.g. quetiapine, olanzapine, etc), and a combination of one or more medicaments selected from them.
  • mood stabilizer e.g. lithium, valproic acid, carbamazepine, lamotrigine, etc
  • antipsychotics e.g. quetiapine, olanzapine, etc
  • one or more SSRI selective serotonin reuptake inhibitors
  • SSRI selective serotonin reuptake inhibitors
  • fluvoxamine paroxetine
  • escitalopram e.g. fluoxetine
  • citalopram e.g. citalopram
  • administration mode of the “combination medicament” is not particularly restricted, and it is sufficient that “compound A” and “combination medicament” be combined in administration.
  • administration mode include the following:
  • the dosage of the “combination medicament” may be determined according to the dose clinically used, and can be appropriately selected depending on an administration subject, administration route, seriousness of the disease, combination, and the like.
  • the “combination medicament” can be administered in the same dosage form as clinically used or in a different dosage form suitable for this combination therapy.
  • compound A When compound A is administered oral-mucosally to a human subject, the blood kinetic of it is quite similar to that of the endogenous melatonin, and therefore compound A can regulate circadian rhythm, which is thought to be disturbed in bipolar patients, better than existing drugs and even melatonin/other melatonin agonists. Thus, compound A is expected to show superior effect on bipolar disease to existing drugs. In addition, this circadian rhythm regulating effect can also translate into better normalizing circadian rhythm and/or sleep/awake cycle in bipolar patients.
  • the present invention is explained in more detail in the following by referring to Examples, which are not to be construed as limitative.
  • the preparation additives e.g., D-mannitol, microcrystalline cellulose, and the like
  • the preparation additives e.g., D-mannitol, microcrystalline cellulose, and the like
  • the preparation additives used in the following Examples and Comparative Examples were the Japanese Pharmacopoeia 15th Edition or Japanese Pharmaceutical Excipients 2003 compatible products.
  • PEG400 Polyethylene glycol 400 (PEG400) (Wako Pure Chemical Industries, Ltd.) (15 g) was dissolved in purified water (35 g) to give PEG400 solution.
  • Compound A (12.5 mg) was added to PEG400 solution (50 ml), and the mixture was stirred and insonated, and filtered using a hydrophilic filter (0.45 ⁇ m). The obtained compound A solution was divided into small portions (1 ml each).
  • PEG400 (Wako Pure Chemical Industries, Ltd.) (60 g) was dissolved in purified water (110 g) to give PEG400 solution.
  • Compound A (100.0 mg) was added to the PEG400 solution (100 ml), and the mixture was stirred and insonated, and filtered using a hydrophilic filter (0.45 ⁇ m). The obtained compound A solution was divided into small portions (1 ml each).
  • HP- ⁇ -CyD Hydroxypropyl- ⁇ -cyclodextrin
  • KLEPTOSE HPB Roquette
  • D-Mannitol PEARLITOL 50C, Roquette
  • CEOLUS PH-101 microcrystalline cellulose
  • Asahi Kasei Corporation 7.5 g
  • the obtained granules were sieved through a 16 mesh (aperture 1.0 mm) sieve to give a sieved powder.
  • the obtained sieved powder was divided into small portions (114 mg each).
  • Example 1 The tablet obtained in Example 1 was measured for the tablet hardness and disintegration time.
  • the results are shown in Table 1.
  • the mixed powder obtained in Example 1 was measured for the dissolution property.
  • the mixed powder (15 g) (corresponding to 500 mg of compound A) was placed in the Japanese Pharmacopoeia 2nd fluid (500 ml), and the dissolution property was evaluated by the Paddle Method, rotation number 25 rpm, 37° C.
  • the eluate was sampled with time (0.25 min, 0.5 min, 0.75 min, 1 min, 5 min, 15 min, 30 min), filtered by using a hydrophilic filter (0.45 ⁇ m), dissolved by 10-fold diluting with the extract (water/acetonitrile mixed solution (1:1)), and quantified by high performance liquid column chromatography (HPLC) under the following conditions to calculate the solubility.
  • HPLC high performance liquid column chromatography
  • Oral preparation and preparation for oral-mucosal absorption were measured for blood kinetics of unchanged form and activity metabolite M-II after oral or sublingual administration to human.
  • the plasma concentration before administration, and 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 60 min, 90 min, 120 min, 180 min, 240 min, 360 min, 480 min, 600 min, 720 min and 1440 min after administration was measured, and the area under the plasma concentration time curve (AUC) was calculated according to the trapezoidal rule.
  • AUC area under the plasma concentration time curve
  • a methylcellulose powder (0.5 g) was dissolved in water (99.5 g) under ice-cooling, and compound A (100 mg) was added to the obtained solution (10 ml), stirred and uniformly dispersed therein.
  • the obtained suspension was filled in a spray device (spray amount: 100 ⁇ L/time) to give an oral spray preparation.
  • HP- ⁇ -CyD Hydroxypropyl- ⁇ -cyclodextrin
  • the present invention can provide a novel preparation showing improved bioavailability of a medicament and a production method thereof and the like.
  • compound A When compound A is administered nasally (through nasal mucosa) to a human subject, it is expected to be effective on prophylaxis and/or treatment of bipolar disease as administered oral-mucosally as disclosed above.
  • Compound A can be administered, for example, in the form of the formulation as disclosed in WO 01/15735.
  • compound A When compound A is administerd to a human subject, it can be also administered in the dosage forms suitable for inhalation (e.g. nebulizer, etc) in order to prevent and/or treat bipolar disease.
  • the dosage forms can be produced according to a general production method in this art.
  • the dose of compound A can be decided referring to, for example, the preparations (A) to (C) in the present application.

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